ES2366973T3 - COMPOUNDS AND PROCEDURE TO MODULATE GENE EXPRESSION. - Google Patents

Abstract

A short antisense compound of 10 to 14 monomers in length, comprising a hollow region of 2'deoxyribonucleotide flanked on each side by a wing, in which each wing independently consists of 1 to 3 modified high affinity monomers that are nucleotides modified with sugar comprising a bridge between the 4 'and 2' position of sugar, for use in the treatment of a metabolic disorder in an animal.

Description

Background

Using disease-causing gene sequences as a target was first suggested almost 40 years ago (Belikova et al., Tet.Lett., 1967, 37, 3557-3562) and, a decade later, antisense activity was demonstrated in cell cultures (Zamecnik et al., Proc. Natl. Acad. Sci. USA, 1978, 75, 280-284). An advantage of antisense technology in the treatment of a disease or condition caused by a disease-causing gene is that it is a direct genetic approach that has the ability to modulate the expression of genes causing specific diseases.

In general, the principle behind antisense technology is that an antisense compound hybridizes with a target nucleic acid and modulates the activity of gene expression or its function, such as transcription, translation or splicing. Modulation of gene expression can be achieved by, for example, degradation of the target or inhibition based on occupancy. An example of modulation of RNA target function by degradation is RNase, H-based degradation of the target RNA by hybridization with an antisense compound similar to DNA. Another example of gene expression modulation by target degradation is by interference RNA (RNAi). RNAi is a form of antisense-mediated gene silencing, which involves the introduction of mRNAs, which leads to the specific sequence reduction of target endogenous mRNA levels. Sequence specificity makes antisense compounds extremely attractive tools for target validation and gene functionalization, as well as research tools to identify and characterize nucleases and as therapeutic agents to selectively modulate the expression of genes involved in the pathogenesis of any one of several diseases.

Antisense technology is an effective means of reducing the expression of one or more specific gene products and, therefore, can be shown to be useful only in a number of therapeutic, diagnostic and research applications. Routinely, chemically modified nucleosides are used for incorporation into antisense compounds in order to enhance one or more properties, such as resistance to nucleases, pharmacokinetics or affinity for a target RNA.

Despite the expansion of information since the discovery of antisense technology, there remains an unmet need for antisense compounds with greater efficiency, lower toxicity and lower costs. Up to the present disclosure, no high affinity modifications have been employed in the design of short antisense compounds to reduce the target RNA in vivo. This is due to problems with the degree of target specificity that would have employed a sequence of 15 nucleotides or shorter to reduce the target in a living system. In previous studies it has been described that greater specificity and, therefore, greater potency potential is achieved, with the antisense compounds of length between 16 and 20 nucleotide bases.

WO 2004/044181 (ISIS PHARMACEUTICALS, INC.) ISIS PHARMACEUTICALS, INC.) Describes antisense compounds, compositions and methods for modulating the expression of apolipoprotein B.

Frieden et al. (Nucleic Acids Res., 2003, 31 (21), 6365-72) evaluated oligonucleotides containing blocked nucleic acids (LNA) for antisense activity, RNase H recruitment, nuclease stability and thermal affinity.

Fluiter et al. (Chembiochem., 2005, 6 (6), 1104-9) investigated the in vitro and in vivo properties of four different LNAs in an antisense oligonucleotide.

WO 2006/020676 (ISIS PHARMACEUTICALS, INC.) Describes a method for reducing serum cholesterol levels in a human subject, comprising administering to said subject a plurality of doses of an oligonucleotide directed to apolipoprotein B.

WO 2007/031081 (SANTARIS PHARMA) describes oligonucleotides directed against the Apo-B100 gene to modulate the expression of Apo-B 100.

The present disclosure describes that the incorporation of chemically modified high affinity nucleotides into antisense compounds allows antisense compounds of a length of 8-16 nucleotide bases useful for target RNAs in animals with higher potency and better therapeutic index. Therefore, herein it discloses antisense compounds comprising high affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than the antisense compounds described above, which allows a reduction in toxicity and treatment costs.

Summary of the invention

The invention provides a short antisense compound of 10 to 14 monomers in length, comprising a hollow region in 2'-deoxyribonucleotide flanked on each side by a wing, in which each wing consists of an independent form of 1 to 3 modified monomers of high affinity that are sugar-modified nucleotides that comprise a bridge between the 4 'and 2' position of sugar, for use in the treatment of a metabolic disorder in an animal.

The invention also provides the use of a short antisense compound of 10 to 14 monomers in length, which comprises a hollow region in 2'-deoxyribonucleotide flanked on each side by a wing, in which each wing consists of an independent form of 1 to 3 high affinity modified monomers that are sugar modified nucleotides comprising a bridge between the 4 'and 2' position of sugar, for the preparation of a medicament for treating a metabolic disorder in an animal.

The invention also provides a short antisense compound of 10 to 14 monomers in length, comprising a hollow region in 2'-deoxyribonucleotide flanked on each side by a wing, in which each wing consists of an independent form of 1 to 3 modified monomers of high affinity that are nucleotides modified with sugar that comprise a bridge between the position 4 'and 2' of the sugar, for use in the treatment of a cardiovascular disorder in an animal. The invention also provides the use of a short antisense compound of 10 to 14 monomers in length, which comprises a hollow region in 2'-deoxyribonucleotide flanked on each side by a wing, in which each wing consists of an independent form of 1 to 3 high affinity modified monomers that are sugar modified nucleotides comprising a bridge between the 4 'and 2' position of sugar, for the preparation of a medicament for treating a cardiovascular disorder in an animal.

Other aspects of the invention are set forth in the appended claims.

Summary of the disclosure

Short antisense compounds and methods of using said compounds to reduce the expression of the target RNA in cells or tissues are disclosed herein. In certain embodiments, a method of reducing the expression of a target in an animal, comprising administering to the animal and short antisense compound directed to the nucleic acid of said target, is disclosed herein. In certain embodiments, short antisense compounds are oligonucleotide compounds. In certain embodiments, the short antisense oligonucleotides have a length of about 8 to 16, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14, and comprise a hollow region flanked on each side by a wing, in which each wing consists of an independent form of 1 to 3 nucleotides. Preferred motifs include deoxy-wing wing-hollow patterns selected from 3-10-3, 2-10-3, 2-10-2, 1-10-1, 24-2, 14-1, 3-6 -3 or 1-6-1. In a preferred embodiment, the short antisense oligonucleotide comprises at least one high affinity modification. In a further embodiment, the high affinity modification includes chemically modified high affinity nucleotides. In a preferred embodiment, each wing consists of an independent form of 1 to 3 modified high affinity nucleotides. In reality, high affinity modified nucleotides are sugar modified nucleotides.

In certain embodiments, short antisense compounds exhibit greater uptake in the intestine compared to longer antisense compounds. Therefore, methods of reducing a target in an animal are also disclosed herein, comprising orally administering the short antisense compounds of the present disclosure.

In certain embodiments, the short antisense compounds are directed to a nucleic acid encoding a protein selected from ApoB, SGLT2, PCSK9, SOD1, CRP, GCCR, GCGR, DGAT22, PTP1B and PTEN.

Methods of treating a metabolic disorder in an animal are also disclosed, which comprises administering to an animal in need of such therapy a short antisense compound directed to a nucleic acid involved in the regulation of glucose metabolism or clearance, lipid metabolism. , cholesterol metabolism or insulin signaling.

Methods of increasing insulin sensitivity, lowering blood glucose or lowering HbAic in an animal are also disclosed, comprising administering to said animal a short antisense compound directed to a nucleic acid encoding a target involved in regulation. of glucose metabolism or clearance, lipid metabolism, cholesterol metabolism or insulin signaling.

Additional methods of lowering total serum cholesterol, serum LDL, serum VLDL, serum HDL, serum triglycerides, serum apolipoprotein (s) or free fatty acids are disclosed in an animal, comprising administering to said animal a short antisense compound. directed to a nucleic acid encoding a target involved in the regulation of glucose metabolism or clearance, lipid metabolism, cholesterol metabolism or insulin signaling, in which said short antisense compound is 8 in length at 16 nucleotides and comprises a hollow region flanked on each side by an anal, in which each wing consists of an independent form of 1 to 3 modified high affinity nucleotides.

Certain targets involved in the regulation of glucose metabolism or clearance, lipid metabolism, cholesterol metabolism or insulin signaling include, among others, GCGR and ApoB-100. Thus, short antisense compounds targeting nucleic acids encoding GCGR and ApoB-100 and reducing the expression of said targets and / or target nucleic acids in animals are disclosed. In addition, the use of short antisense compounds targeting nucleic acids encoding CGCR and ApoB-100 for the treatment of a metabolic or cardiovascular disease or condition is disclosed.

In certain embodiments, short antisense compounds further comprise a conjugate group. Conjugated groups include, C16 and cholesterol.

In certain embodiments, short antisense compounds comprise at least one modified nucleotide base, internucleoside linkage or sugar moiety. In certain embodiments, said modified internucleoside bond is an internucleoside phosphorothioate bond. In certain embodiments, each internucleoside bond is an internucleoside phosphorothioate bond.

In certain embodiments, short antisense compounds comprise at least one high affinity modification. In certain of said embodiments, the high affinity modification is a chemically modified high affinity nucleotide. In certain embodiments, chemically modified high affinity nucleotides are sugar modified nucleotides. In certain embodiments, at least one of the sugar modified nucleotides comprises a bridge between the 4 ’position and the 2’ position of the sugar. Each of the sugar modified nucleotides is, independently, in the conformation of the ß-D or α-L sugar. In certain embodiments, each of said modified nucleotides confers a Tm of at least 1 to 4 degrees per nucleotide. In certain embodiments, each of said sugar-modified nucleotides comprises a 2 'substituent group that is different from H or OH. Such sugar-modified nucleotides include those that have a bicyclic sugar moiety with bridges at positions 4 'to 2 ’. In certain embodiments, each of the 2 ’substituent groups is independently alkoxy, substituted alkoxy or halogen. In certain embodiments, each of the 2 ’substituent groups is OCH2CH2OCH3 (2’-MOE).

In certain embodiments, short antisense compounds have one or more sugar-modified nucleotides, which comprise a bridge between the 4 'and 2' position of the sugar, in which each of said bridges independently comprises 2 to 4 groups of sugar. junction independently selected from - [C (R1) (R2)] n-, -C (R1) = C (R2) -, C (R1) = N-, -C (= NR1) -, -C ( = O) -, -C (= S) -, -O-, n-Si (R1) 2, -S (= O) x- and -N (R1) -;

in which

x is 0, 1, or 2;

n is 0, 1, 2, 3 or 4;

each R1 and R2 is independently H, a protecting group, hydroxy, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl , C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C (= O) -H), substituted acyl, CN, sulfonyl (S (= O) 2-J1 or sulfoxyl (S (= O) -J1); and

and each J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl , substituted C5-C20 aryl, acyl (C (= O) -H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group.

In one aspect, each of said bridges is, independently, - [C (R1) (R2)] n-, - [C (R1) (R2)] nO-, -C (R1R2) -N (R1 ) O- or nn-C (R1R2) -ON (R1) -. In another aspect, each of said bridges is, independently, 4 '- (CH2) 3-2', 4 '(CH2) 2-2', 4'-CH2O-2 ', 4' - (CH2) 2-O-2 ', 4'-CH2-ON (R1) -2' and 4'-CH2-N (R1) -O-2'-, in which each R1 is, independently, H, a protective group or C1-C12 alkyl.

In certain embodiments, short antisense compounds useful in reducing targets and / or RNA targets associated with disease states in animals are disclosed herein. In certain embodiments, methods of using short antisense compounds to reduce the expression of a target RNA in an animal are disclosed. In certain embodiments, the use of a short antisense compound in the preparation of a medicament for the treatment of a metabolic disorder in an animal is disclosed. In certain embodiments, the use of a short antisense compound in the preparation of a medicament for increasing insulin sensitivity, lowering blood glucose or lowering HbA1c in an animal is disclosed. The use of a short antisense compound in the preparation of a medicament for lowering total serum cholesterol, serum LDL levels, serum VLDL levels, serum HDL levels, serum triglycerides, a polyprotein is also disclosed. (a) in serum or free fatty acids in an animal.

In certain embodiments, the short antisense compounds herein exhibit an equal or greater potency with respect to the target RNA defect compared to the longer parental antisense oligonucleotide, at least 20 nucleotides in length. In certain embodiments, short antisense compounds exhibit a faster onset of action (reduction of target RNA) compared to the parental antisense oligonucleotide. In certain embodiments, the increase in potency occurs in the kidney. In certain embodiments, the target RNA is predominantly expressed in the kidneys. In certain embodiments, the increase in potency occurs in the liver. In certain embodiments, the target RNA is predominantly expressed in the liver.

Detailed description

It should be understood that both the above general description and the following detailed description are examples and explanations only and are not restrictive of the claimed invention. In this document, the use of the singular includes the plural unless specifically indicated otherwise. As used herein, "o" means "and / or", unless otherwise indicated. In addition, the use of the term "including", as well as other forms, such as "includes" and "included" is not limiting. Likewise, terms such as "element" or "component" encompass both elements and components that comprise a unit and elements and components that comprise more than one subunit, unless specifically indicated otherwise.

The section headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter described.

A. Definitions

Unless specific definitions are provided, the nomenclature used in relation to analytical chemistry, synthetic organic chemistry and medicinal and pharmaceutical chemistry described herein and the procedures and techniques thereof described herein are well known. and commonly used in the art. Standard techniques for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and release, and treatment of subjects can be used. Some of these techniques and procedures can be found in, for example, "Carbohydrate Modifications in Antisense Research" Edited by Sangvi and Cook, American Chemical Society, Washington D.C., 1994; and "Remington’s Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 18th edition, 1990

Unless otherwise specified, the following terms have the following meanings:

As used herein, the term "nucleoside" means a glycosylamine comprising a nucleotide base and a sugar. Nucleosides include, among others, natural nucleosides, abbasic nucleosides, modified nucleosides and nucleosides having mimetic bases and / or sugar groups.

As used herein, the term "nucleotide" refers to a glycosylamine comprising a nucleotide base and a sugar having a phosphate group covalently bonded to sugar. Nucleotides can be modified with any of several substituents.

As used herein, the term "nucleotide base" refers to a base part of a nucleoside or nucleotide. A nucleotide base may comprise any atom or group of atoms capable of binding hydrogen with a base of another nucleic acid.

As used herein, the term "heterocyclic base moiety" refers to a nucleotide base comprising a heterocycle.

As used herein, the term "deoxyribonucleotide" means a nucleotide that has a hydrogen at the 2 'position of the sugar portion of the nucleotide. Deoxyribonucleotides can be modified with any of several substituents.

As used herein, the term "ribonucleotide" means a nucleotide that has a hydroxy at the 2 'position of the sugar portion of the nucleotide. Ribonucleotides may be modified with any of several substituents.

As used herein, the term "oligomeric compound" refers to a polymeric structure that comprises two or more substructures and that is capable of hybridizing with a region of a nucleic acid molecule. In certain embodiments, the oligomeric compounds are oligonucleosides. In certain embodiments, the oligomeric compounds are oligonucleotides. In certain embodiments, the oligomeric compounds are antisense compounds. In certain embodiments, the oligomeric compounds are antisense oligonucleotides. In certain embodiments, the oligomeric compounds are short antisense compounds. In certain embodiments, the oligomeric compounds are short antisense oligonucleotides. In certain embodiments, the oligomeric compounds are chimeric oligonucleotides.

As used herein, the term "monomer" refers to a single unit of an oligomer. Monomers include, among others, nucleosides and nucleotides, natural or modified.

As used herein, "oligonucleoside" refers to an oligonucleotide in which the internucleoside bonds do not contain a phosphorus atom.

As used herein, the term "oligonucleotide" refers to an oligomeric compound comprising a plurality of linked nucleotides. In a certain embodiment one or more nucleotides of an oligonucleotide is modified. In certain embodiments, an oligonucleotide comprises ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). In certain embodiments, the oligonucleotides are composed of natural and / or unnatural nucleotide bases, sugars and covalent internucleotide bonds and may also include non-nucleic acid conjugates.

As used herein, "internucleotide linkage" refers to a covalent bond between adjacent nucleotides.

As used herein, "monomeric bond" refers to a covalent bond between two monomers. Monomeric links include, among others, internucleotide bonds and internucleoside bonds.

As used herein, "natural internucleotide bond" refers to a 3 ′ to 5 ′ phosphodiester bond.

As used herein, the term "antisense compound" refers to an oligomeric compound that is, at least partially, complementary to a target nucleic acid molecule with which it hybridizes. In certain embodiments, an antisense compound modulates (increases or decreases) the expression of a target nucleic acid. Antisense compounds include, among others, compounds that are oligonucleotides, oligonucleosides, oligonucleotide analogs, oligonucleotide mimetics and chimeric combinations thereof. Consequently, although all antisense compounds are oligomeric compounds, not all oligomeric compounds are antisense compounds.

As used herein, the term "antisense oligonucleotide" refers to an antisense compound that is an oligonucleotide.

As used herein, the term "parental antisense oligonucleotide" refers to an oligonucleotide 20 nucleotides in length that has a hollow deoxy region that is ten 2'-deoxyribonucleotides, flanked by a first and a second wing region, each having one of them five 2'-O- (2-methoxyethyl) ribonucleotides (a 510-5 MOE captamer) and comprising the sequence of the corresponding short antisense compound of which it is a parent,

As used herein, "short antisense compound" refers to an antisense compound of approximately 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers in length. In certain embodiments, an antisense compound has at least one high affinity modification.

As used herein, the term "short antisense oligonucleotide" refers to an antisense oligonucleotide approximately 8, 9, 10, 11, 12, 13, 14, 15 or 16 nucleotides in length. In certain embodiments, a short antisense oligonucleotide has at least one high affinity modification.

As used herein, the term "short catheter" refers to a short antisense oligonucleotide having a first and a second wing region, each independently having 1 to 3 nucleotides in length and a hollow region. from 2 to 14 nucleotide bases in length.

As used herein, the term "motif" refers to a pattern of unmodified and modified nucleotides in a short antisense compound.

As used herein, the term "chimeric antisense oligomer" refers to an antisense oligomeric compound having at least one sugar, a nucleotide base or an internucleoside bond that is differentially modified compared to at least one other sugar, nucleotide base. or internucleoside bond within the same antisense oligomeric compound. The rest of the sugars, nucleotide bases and internucleoside bonds can be modified independently or unmodified, be the same or different.

As used herein, the term "chimeric antisense oligonucleotide" refers to an antisense oligonucleotide having at least one sugar, a nucleotide base or an internucleoside bond that is differentially modified compared to at least one other sugar, nucleotide base or internucleoside bond within the same antisense oligonucleotide. The rest of the sugars, nucleotide bases and internucleoside bonds can be modified independently or unmodified, be the same or different.

As used herein, the term "mixed structure antisense oligonucleotide" refers to an antisense oligonucleotide in which at least one internucleoside linkage of the antisense oligonucleotide is different from at least one other internucleotide linkage of the antisense oligonucleotide.

As used herein, the term "target" refers to a protein whose modulation is desired.

As used herein, "target gene" refers to a gene that encodes a target.

As used herein, the terms "target nucleic acid" and "nucleic acid molecule encoding a target" refer to any nucleic acid molecule whose expression or activity can be modulated by an antisense compound. Target nucleic acids include, among others, RNA (including, among others, pre-mRNA and mRNA or portions thereof) transcribed from DNA encoding a target, and, also, cDNA derived from said RNA, and mRNA. For example, the target nucleic acid may be a cellular gene (or mRNA transcribed from the gene), whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule of an infectious agent.

As used herein, the term "directed" or "directed to" refers to the association of an antisense compound with a particular target nucleic acid molecule or a specific region of nucleotides within a target nucleic acid molecule.

As used herein, the term "5" target site "refers to the nucleotide of a target nucleic acid that is complementary to the 5 'plus nucleotide of a particular antisense compound.

As used herein, the term "3" target site "refers to the nucleotide of a target nucleic acid that is complementary to the 3 'plus nucleotide of a particular antisense compound.

As used herein, the term "target region" refers to a portion of a target nucleic acid with which one or more antisense compounds are complementary.

As used herein, the term "target segment" refers to a smaller part or sub-portions of a region within a target nucleic acid.

As used herein, the term "complementarity with the nucleotide base" refers to a nucleotide base that can mate with another nucleotide base. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleotide base refers to a nucleotide base of an antisense compound that can be paired with bases with a nucleotide base of its target nucleic acid. For example, if a nucleotide base at a given position of an antisense compound can be linked by hydrogen bonds to a nucleotide base at a certain position of a target nucleic acid, the position of the hydrogen bond between the nucleotide and the target nucleic acid is considered complementary in said pair of nucleotide bases.

As used herein, the term "non-complementary nucleotide base" refers to a pair of nucleotide bases that do not form hydrogen bonds with each other or, otherwise, support hybridization.

As used herein, the term "complementarity" refers to the ability of an oligomeric compound to hybridize with another oligomeric compound or nucleic acid through complementarity of nucleotide base. In certain embodiments, an antisense compound and its target are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotide bases that can be linked together to allow a stable association between the antisense compound and the target. One skilled in the art recognizes that the inclusion of mismatches is possible without eliminating the ability of oligomeric compounds to remain in association. Therefore, antisense compounds are described herein that may comprise up to about 20% of nucleotides that are missing (ie, they are not complementary nucleotide bases to the corresponding target nucleotides). Preferably, the antisense compounds do not contain more than about 15%, more preferably no more than about 10%, more preferably no more than about or no mismatch. The remaining nucleotides are complementary nucleotide bases or, on the other hand, do not alter hybridization (e.g., universal bases). One skilled in the art would recognize that the compounds provided herein are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% complementary to a target nucleic acid.

As used herein, the term "mismatch" refers to a non-complementary nucleotide base in a complementary oligomeric compound.

As used herein, "hybridization" means the pairing of complementary oligomeric compounds (eg, antisense compound and its target nucleic acid). Although not limited to a specific mechanism, the most common mating mechanism involves hydrogen bonds that can be hydrogen bonds of Watson-Crick, Hoogsteen or reverse Hoogsteen, between nucleosides or complementary nucleotide bases. For example, the natural adenine base is a nucleotide base complementary to the natural nucleotide bases thymidine and uracil, which mate through the formation of hydrogen bonds. The natural guanine base is a nucleotide base complementary to the natural cytosine and 5-methyl-cytosine bases. Hybridization can occur in several circumstances.

As used herein, the term "specifically hybridizes" refers to the ability of an oligomeric compound to hybridize with a site in the nucleic acid with greater affinity than with that which hybridizes with another site in the nucleic acid. In certain embodiments, an antisense oligonucleotide specifically hybridizes with more than one target site.

As used herein, "design" or "designed" refers to the process of designing an oligomeric compound that specifically hybridizes with a selected nucleic acid molecule.

As used herein, the term "modulation" refers to a disturbance of the function or activity when compared to the level of the function or activity before modulation. For example, modulation includes change, an increase (stimulation or induction) or a decrease (inhibition or reduction) of gene expression. As a further example, expression modulation may include disturbing the selection of a splice site of pre-mRNA processing.

As used herein, the term "expression" refers to all functions and steps by which information encoded in a gene is converted into structures present and functioning in a cell. Such structures include, among others, the products of transcription and translation.

As used herein, "variant" refers to an alternative RNA transcript that can be produced from the same genomic region of the DNA. Variants include, among others, "pre-mRNA variants" that are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA at their initiation or termination position and contain intronic and exonic sequences. they also include, among others, those with those with alternative splice joints or alternative start and end codons.

As used herein, "modified high affinity monomer" refers to a monomer having at least one modified nucleotide base, an internucleoside bond or a sugar moiety, when compared to natural monomers, so that the modification It increases the affinity of an antisense compound comprising a high affinity monomer for its target nucleic acid. High affinity modifications include, among others, monomers (eg, nucleosides and nucleotides), which comprise 2 ′ modified sugars.

As used herein, the term "modified in 2" or "substituted in 2" means a sugar comprising a substituent in the 2 "position other than H or OH. 2 'modified monomers include, but are not limited to, BNA and monomers (eg, nucleosides and nucleotides) with 2' substituents, such as allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl , -OCF3, O- (CH2) 2-O-CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), or O-CH2-C (= O) - N (Rm) (Rn), in which each Rm and Rn is independently H or C1-C10 alkyl substituted or unsubstituted. In certain embodiments, short antisense compounds comprise a 2 ′ modified monomer that does not have the formula 2’-O (CH2) nH, in which n is one to six. In certain embodiments, short antisense compounds comprise a 2 ′ modified monomer that does not have the formula 2’-OCH3. In certain embodiments, short antisense compounds comprise a 2 ′ modified monomer that does not have the formula or, in the alternative, 2’-O (CH2) 2OCH3.

As used herein, the term "bicyclic nucleic acid" or "BNA" or "bicyclic nucleoside" or "bicyclic nucleotide" refers to a nucleoside or nucleotide in which the furanic portion of the nucleoside includes a bridge that connects two carbon atoms on the furanose ring, thereby forming a bicyclic ring system.

As used herein, unless otherwise indicated, the term "methylene BNA" only refers to β-D-methyloxy BNA.

As used herein, the term "MOE" refers to the 2′-methoxyethyl substituent.

As used herein, the term "gimer" refers to a chimeric oligomeric compound comprising a central region (a "hole") and a region on either side of the central region (the "wings"), in which the gap comprises at least one modification that is different from that of each wing. Such modifications include modifications in the nucleotide base, the monomeric bond and sugar, as well as the absence of modification (unmodified). Therefore, in certain embodiments, the nucleotide bonds in each of the wings are different from the nucleotide bonds in the recess. In certain embodiments, each wing comprises nucleotides with high affinity modifications and the gap comprises nucleotides that do not comprise said modification. In certain embodiments, the nucleotides in the hollow and the nucleotides in the wings all comprise high affinity modifications, but the high affinity modifications in the hollow are different from the high affinity modifications in the wings. In certain embodiments, the modifications in the wings are the same with each other. In certain embodiments, the modifications in the wings are different from each other. In certain embodiments, the nucleotides in the recess are not modified and the nucleotides in the wings are modified. In certain embodiments, the modification (s) in each wing are the same. In certain embodiments, the modification (s) in one wing are different from the modification (s) in the other wings. In certain embodiments, the short antisense compounds are cathamers that have 2'-deoxynucleotides in the hollow and nucleotides with high affinity modifications in the wing.

As used herein, the term "prodrug" refers to a therapeutic agent that is prepared inactively that becomes an active form (ie, the drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and / or conditions.

As used herein, the term "pharmaceutically acceptable salts" refers to salts of active compounds that retain the desired biological activity of the active compound and that do not produce unwanted toxicological effects.

As used herein, the term "cap structures" or "terminal cap residue" refers to chemical modifications that have been incorporated into any end of an antisense compound.

As used herein, the term "prevention" refers to delaying or preventing the onset or development of a condition or disease for a period of time ranging from hours to days, preferably weeks to months.

As used herein, the term "improvement" refers to a decrease of at least one indicator of the severity of a condition or disease. The severity of the indicators can be determined by subjective or objective measures that are known to those skilled in the art.

As used herein, the term "treatment" refers to administering a composition of the disclosure to effect an alteration or improvement of the condition or disease. Prevention, improvement and / or treatment may require the administration of multiple doses at regular intervals or before the onset of the condition or disease to alter the course of the disease or condition. In addition, a single agent can be used in a single individual for each prevention, improvement and treatment of a condition or disease sequentially or concurrently.

As used herein, the term "pharmaceutical agent" refers to a substance that provides a therapeutic benefit when administered to a subject.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that provides a therapeutic benefit to an animal.

As used herein, "administering" means providing a pharmaceutical agent to an animal and includes, among others, administration by a medical professional and self-administration.

As used herein, the term "co-administration" refers to the administration of two or more pharmaceutical agents to an animal. The two or more pharmaceutical agents may be in a single pharmaceutical composition or they may be in different pharmaceutical compositions. Each of the two or more pharmaceutical agents can be administered by the same route of administration or by different routes. Co-administration encompasses parallel or sequential administration.

As used herein, the term "pharmaceutical composition" refers to a mixture of substances suitable for administration to an individual. For example, a pharmaceutical composition may comprise an antisense oligonucleotide and a sterile aqueous solution.

As used herein, the term "individual" refers to a human being or a non-human animal selected for treatment or therapy.

As used herein, the term "animal" refers to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs and nonhuman primates, including, among others, monkeys. and chimpanzees.

As used herein, the term "subject" refers to an animal, including, but not limited to, the human being, to whom a pharmaceutical composition is administered.

As used herein, the term "duration" refers to the period of time during which an activity or event continues. In certain embodiments, the duration of treatment is the period of time during which the doses of a pharmaceutical composition are administered.

As used herein, the term "parenteral administration" refers to administration by injection or infusion. Parenteral administration includes, among others, subcutaneous administration, intravenous administration or intramuscular administration.

As used herein, the term "subcutaneous administration" refers to administration just below the skin. "Intravenous administration" means administration in a vein.

As used herein, the term "dose" refers to a specified amount of a pharmaceutical agent provided in a single administration. In certain embodiments, one dose may be administered in two.

or more bowling, tablets or injections. For example, in certain embodiments, in which subcutaneous administration is desired, the desired dose requires a volume that is not easily accommodated by a single injection. In such embodiments, two or more injections can be used to reach the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize the reaction at the injection site in an individual.

As used herein, the term "dosage unit" refers to a form in which a pharmaceutical agent is provided. In certain embodiments, a dosage unit is a vial comprising lyophilized antisense oligonucleotide. In certain embodiments, a dosage unit is a vial comprising reconstituted antisense oligonucleotide.

As used herein, the term "pharmaceutical agent" refers to a substance that provides a therapeutic benefit when administered to an individual. For example, in certain embodiments an antisense oligonucleotide is a pharmaceutical agent.

As used herein, the term "active pharmaceutical ingredient" refers to the substance in a pharmaceutical composition that provides a desired effect.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual. In certain embodiments, a therapeutically effective amount of an antisense compound is the amount that needs to be administered to result in an observable benefit.

As used herein, the term "hypercholesterolemia" refers to a condition characterized by elevated serum cholesterol levels.

As used herein, the term "hyperlipidemia" refers to a condition characterized by elevated serum lipid levels.

As used herein, the term "hypertriglyceridemia" refers to a condition characterized by elevated serum triglyceride levels.

As used herein, the term "unfamiliar hypercholesterolemia" refers to a condition characterized by elevated cholesterol levels that is not the result of a single inherited gene mutation.

As used herein, the term "polygenic hypercholesterolemia" refers to a condition characterized by elevated cholesterol levels that is the result of the influence of various genetic factors. In certain embodiments, polygenic hypercholesterolemia can be exacerbated by dietary lipid intake.

As used herein, the term "familial hypercholesterolemia (HF)" refers to an autosomal dominant metabolic disorder characterized by a mutation in the LDL receptor gene (LDL-R), markedly elevated levels of LDL-C and onset premature atherosclerosis A diagnosis of familial hypercholesterolemia is made when an individual meets one or more of the following criteria: genetic tests confirming 2 mutated genes of the LDL receptor; genetic tests confirming a mutated genes of the LDL receptor; documented history of Untreated serum LDL-cholesterol higher than 500 mg / dl; tendon and / or cutaneous xanthoma before 10 years of age: or both parents have elevated serum LDL-cholesterol levels documented before hypolipidemic therapy consistent with familial hypercholesterolemia heterozygous

As used herein, the term "homozygous familial hypercholesterolemia" or "HFHo" refers to a condition characterized by a mutation in both maternal and paternal LDL-R genes.

As used herein, the term "heterozygous familial hypercholesterolemia" or "HFHe" refers to a condition characterized by a mutation in the LDL-R or maternal or paternal genes.

As used herein, the term "mixed dyslipidemia" refers to a condition characterized by elevated serum cholesterol levels and elevated serum triglyceride levels.

As used herein, the term "diabetic dyslipidemia" or "type II diabetes with dyslipidemia" refers to a condition characterized by type II diabetes, reduced levels of HDL-C, elevated serum triglyceride levels and levels high dense small LDL particles.

As used herein, the term "CPC risk equivalents" refers to clinical atherosclerotic disease indicators that confer a high risk of coronary heart disease. For example, in certain embodiments, CPC risk equivalents include, without limitation, clinical coronary heart disease, symptomatic carotid artery disease, peripheral arterial disease and / or abdominal aortic aneurysm.

As used herein, the term "non-alcoholic fatty acid disease (EAGNA") refers to a condition characterized by fatty inflammation of the liver that is not due to an abuse of alcohol consumption (eg, consumption of alcohol of more than 20 g / days). In certain embodiments, EAGNA is related to insulin resistance and metabolic syndrome.

As used herein, the term "non-alcoholic steatohepatitis (NASH)" refers to a condition characterized by inflammation and the accumulation of fat and fibrous tissue in the liver that is not due to alcohol abuse. EHNA is an extreme form of EAGNA.

As used herein, the term "main risk factors" refers to factors that contribute to a high risk of a particular disease or condition. In certain embodiments, the main risk factors for coronary heart disease include, among others, smoking, hypertension, low levels of HDL-C, family history of coronary heart disease and age.

As used herein, the term "CPC risk factors" refers to CPC risk equivalents and major risk factors.

As used herein, the term "coronary heart disease (CPC)" refers to a narrowing of the small blood vessels that supply blood and oxygen to the heart, which often results in atherosclerosis.

As used herein, the term "reduced risk of coronary heart disease" refers to a reduction in the likelihood of an individual developing coronary heart disease. In certain embodiments, a reduction in the risk of coronary heart disease is measured by an improvement in one or more risk factors for CPC, for example a decrease in LDL-C levels.

As used herein, the term "atherosclerosis" refers to a hardening of the arteries that affects the arteries of large and medium size and that is characterized by the presence of fat deposits. Fat deposits are called "atheromas" or "plaques", which consist mainly of cholesterol and other fats, calcium and scar tissue, and damage to the lining of the arteries.

As used herein, the term "history of coronary heart disease" refers to the occurrence of clinically evident coronary heart disease in the medical history of an individual or a family member of the individual.

As used herein, the term "early onset coronary heart disease" refers to a diagnosis of coronary heart disease before the age of 50.

As used herein, the term "statin intolerant individual" refers to an individual who, as a result of statin therapy, experiences one or more increases in creatinine kinase, abnormal liver function tests, pains muscle or side effects in the central nervous system.

As used herein, the term "efficacy" refers to the ability to produce a desired effect. For example, the efficacy of a lipid lowering therapy may be the reduction in the concentration of one or more of LDL-C, VLDL-C, IDL-C, non-HDL-C, ApoB, lipoprotein (a), or triglycerides.

As used herein, the term "acceptable safety profile" refers to a pattern of side effects that is within the clinically acceptable limits.

As used herein, the term "side effects" refers to physiological responses attributable to a treatment other than the desired effects. In certain embodiments, side effects include, without limitation, injection site reactions, abnormal liver function tests, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, and myopathies. For example, increases in serum aminotransferase levels may indicate liver toxicity or liver function abnormalities. For example, increases in bilirubin levels may indicate liver toxicity or abnormal liver function.

As used herein, the term "injection site reaction" refers to inflammation or abnormal redness of the skin at the injection site in an individual.

As used herein, the term "compliance of the individual" refers to adherence to a therapy recommended or prescribed by an individual.

As used herein, the term "lipid-lowering therapy" refers to a therapeutic regimen provided to an individual to reduce one or more lipids in an individual. In certain embodiments, a lipid-lowering therapy is provided to reduce one or more of ApoB, total cholesterol, LDL-C, VLDL-C, IDL-C, non-HDL-C, triglycerides, small dense LDL particles and Lp (a) in an individual

As used herein, the term "lipid lowering agent" refers to a pharmaceutical agent provided to an individual to achieve a decrease in lipid levels in the individual. For example, in certain embodiments, an individual is provided with a lipid lowering agent to reduce one or more of ApoB, LDL-C, total cholesterol and triglycerides.

As used herein, the term "target LDL-C" refers to a level of LDL-C that is desired after lipid-lowering therapy.

As used herein, the term "compliance" refers to adherence to a therapy recommended by an individual.

As used herein, the term "recommended therapy" refers to a therapeutic regimen recommended by a medical professional for the treatment, improvement or prevention of a disease.

As used herein, the term "low LDL receptor activity" refers to the activity of the LDL receptor that is not high enough to maintain clinically acceptable levels of LDL-C in the bloodstream.

As used herein, the term "cardiovascular outcome" refers to the occurrence of major adverse cardiovascular events.

As used herein, the term "improved cardiovascular outcome" refers to a reduction in the occurrence of major adverse cardiovascular events or the risk thereof. Examples of major adverse cardiovascular events include, without limitation, death, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest and atrial dysrhythmia.

As used herein, the term "substitute markers of cardiovascular outcome" refers to indirect indicators of adverse cardiovascular events or their risk. For example, substitute markers for cardiovascular outcome include the thickness of the intimate carotid mean (IACML). Another example of a substitute marker for cardiovascular outcome includes atheroma size. Atheroma size can be determined by intravascular ultrasound (USIV).

As used herein, the term "increased HDL-C levels" refers to an increase in serum HDL-C levels in an individual over time.

As used herein, the term "lipid lowering" refers to a reduction of one or more serum lipids in an individual over time.

As used herein, the term "metabolic disorder" refers to a condition characterized by an alteration or disruption of metabolic function. "Metabolic" and "metabolism" are terms well known in the art and generally include the full range of biochemical processes that occur within a living organism. Metabolic disorders include, among others, hyperglycemia, prediabetes, diabetes (type I and type II), obesity, insulin resistance and metabolic syndrome.

As used herein, the term "metabolic syndrome" refers to a combination of lipid and non-lipid cardiovascular risk factors of metabolic origin. It has been closely linked to the generalized metabolic disorder known as insulin resistance. The Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program (NCEP) established criteria for the diagnosis of metabolic syndrome when three or more of five risk determinants are present. The five risk determinants are abdominal obesity, defined as a waist circumference greater than 102 cm for men or greater than 88 cm for women, triglyceride levels greater than or equal to 150 mg / dl, HDL-cholesterol levels below 40 mg / dl for men and less than 50 mg / dl for women, blood pressure greater than or equal to 130/85 mmHg and fasting glucose levels greater than or equal to 110 mg / dl. These determinants can be easily measured in clinical practice (JAMA, 2001, 285: 2486-2497).

The term "alkyl" as used herein refers to a saturated linear or branched hydrocarbon radical containing up to twenty-four carbon atoms. Examples of alkyl groups include, among others, methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, decyl, dodecyl and the like. Typically, the alkyl groups include from 1 to about 24 carbon atoms, more usually from 1 to about 12 carbon atoms (C1C12 alkyl) with 1 to about 6 carbon atoms being more preferred. The term "minor alkyl" as used herein includes from 1 to about 6 carbon atoms. The alkyl groups, as used herein. they may optionally include one or more additional substituents.

The term "alkenyl," as used herein, refers to a straight or branched chain hydrocarbon radical containing up to twenty-four carbon atoms and having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, dienes such as 1,3-butadiene and the like. Typically, alkenyl groups include from 2 to about 24 carbon atoms, more usually from 2 to about 12 carbon atoms, with 2 to about 6 carbon atoms being more preferred. Alkenyl groups, as used herein, may optionally include one or more additional substituents.

The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon radical containing up to twenty-four carbon atoms and having at least one carbon-carbon triple bond. Examples of alkynyl groups include, among others, ethynyl, 1-propynyl, 1-butynyl and the like. Typically, alkynyl groups include from 2 to about 24 carbon atoms, more usually from 2 to about 12 carbon atoms, with 2 to about 6 carbon atoms being more preferred. Alkynyl groups, as used herein, may optionally include one or more additional substituents.

The term "aminoalkyl," as used herein, refers to a substituted amino alkyl radical. This term is intended to include C1-C12 alkyl groups that have an amino substituent at any position and in which the alkyl group binds the aminoalkyl group to the parent molecule. The alkyl and / or amino portions of the aminoalkyl group may be further substituted with substituent groups.

The term "aliphatic," as used herein, refers to a straight or branched chain hydrocarbon radical containing up to twenty-four carbon atoms, in which saturation between any two carbon atoms is a single, double bond. or triple. Preferably, an aliphatic group contains from 1 to about 24 carbon atoms, more usually from 1 to about 12 carbon atoms, with 1 to about 6 carbon atoms being more preferred. The linear or branched chain of an aliphatic group can be interrupted with one or more heteroatoms that include nitrogen, oxygen, sulfur or phosphorus. Such aliphatic groups interrupted by heteroatoms include, without limitation, polyalkoxies, such as polyalkylene glycols, polyamines and polyimines. Aliphatic groups as used herein may optionally include additional substituent groups.

The term "alicyclic" or "alicyclyl" refers to a cyclic ring system in which the ring is aliphatic. The ring system may comprise one or more rings of which at least one ring is aliphatic. Preferred alicyclics include rings having from about 5 to about 9 ring atoms. Alicyclic groups, as used herein, may optionally include additional substituent groups.

The term "alkoxy", as used herein, refers to a radical formed between an alkyl group and an oxygen atom, in which the oxygen atom is used to bind the alkoxy group to a parent molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like. Alkoxy groups as used herein may optionally include additional substituent groups.

The terms "halo" and "halogen", as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.

The terms "aryl" and "aromatic", as used herein, refer to a mono or polycyclic carbocyclic ring system having one or more aromatic rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Preferred aryl ring systems have from about 5 to about 20 atoms in one or more rings. Aryl groups, as used herein, may optionally include additional substituent groups.

The terms "aralkyl" and "arylalkyl," as used herein, refer to a radical formed between an alkyl group and an aryl group, in which the alkyl group is used to bind the aralkyl group to a parent molecule. Examples include, among others, benzyl, phenethyl and the like Aralkyl groups, as used herein, may optionally include additional substituent groups attached to the alkyl, aryl or both groups, which form the radical group.

The term "heterocyclic radical" is used herein. It refers to a mono or polycyclic ring system radical that includes at least one heteroatom and is unsaturated, partially saturated or completely saturated, so that it includes heteroaryl groups. With heterocyclic it is also intended to include condensed ring systems, in which one or more of the condensed rings contain at least one heteroatom and the other rings may contain one or more heteroatoms or optionally contain no heteroatom. Normally, a heterocyclic group includes at least one atom selected from sulfur, nitrogen or oxygen. Examples of heterocyclic groups include [1,3] dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, tetrahydrinyl, pyrinoxininyl Heterocyclic groups, as used herein, may optionally include additional substituent groups.

The term "heteroaryl" and "heteroaromatic," as used herein, refers to a radical comprising a ring, ring system or mono or polycyclic fused ring system, in which at least one of the rings is aromatic and includes one or more heteroatoms. With heteroaryl, it is also desired to include condensed ring systems that include systems in which one or more of the condensed rings do not contain heteroatoms. Typically, heteroaryl groups include a ring atom selected from sulfur, nitrogen or oxygen. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, similar. Heteroaryl radicals can be attached to a parent molecule directly or through a linker moiety, such as an aliphatic or heteroatom group. Heteroaryl groups, as used herein, may optionally include additional substituent groups.

The term "heteroarylalkyl," as used herein, refers to a heteroaryl group as defined above that has an alkyl radical that can bind the heteroarylalkyl group to a parent molecule. Examples include, among others, pyridinylmethyl, pyrimidinylethyl, naphthyridinylpropyl and the like. Heteroarylalkyl groups, as used herein, may optionally include additional substituent groups in one or both portions of heteroaryl or alkyl.

The term "mono or polycyclic structure", as used herein, includes all ring systems that are simple or polycyclic having rings that are condensed or bonded, and are intended to include single and mixed ring systems selected from individual form of aliphatic, alicyclic, aryl, heteroaryl, aralkyl, arylalkyl, heterocyclic, heteroaryl, heteroaromatic, heteroarylalkyl. Such mono and polycyclic structures may contain rings that are uniform or have varying degrees of saturation, including fully saturated, partially saturated or completely unsaturated. Each ring may comprise ring atoms selected from C, N, O and S, to give heterocyclic rings, as well as rings that only comprise C ring atoms that may be present in a mixed motif, such as, for example, benzimidazole, in the one that a ring has only C ring atoms and the condensed ring has two nitrogen atoms. Mono and polycyclic structures can also be substituted with substituent groups, such as, for example, phthalimide, which has two = 0 groups attached to one of the rings. In another aspect, the mono and polycyclic structures can be linked to a parent molecule directly through a ring atom, through a substituent group or a bifunctional linker moiety.

The term "acyl," as used herein, refers to a radical formed by removing a hydroxyl group from an organic acid and d has the general formula -C (O) -X, in which X is normally aliphatic , alicyclic or aromatic. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates, aliphatic phosphates and the like. Acyl groups, as used herein, may optionally include additional substituent groups.

The term "hydrocarbyl" includes groups comprising C, O and H. Linear, branched and cyclic groups having any degree of saturation are included. Said hydrocarbyl groups may include one or more heteroatoms selected from N, O and S, and may also be mono or polysubstituted with one or more substituent groups.

The terms "substituent" and "substituent group", as used herein, include groups that are normally added to other groups or parental compounds to enhance the desired properties or give desired effects. Substituent groups may be protected or unprotected and may be added to an available site or to many available sites in a parent compound. The substituent groups may also be substituted with other substituent groups and may be linked directly or through a linker group, such as an alkyl or hydrocarbyl group, to a parent compound. Such subgroups include, without limitation, halogen, hydroxyl, alkyl, alkenyl, alkynyl, acyl (-C (O) Raa), carboxy (-C (O) O-Raa), aliphatic groups, alicyclic groups, alkoxy, oxo (- O-Raa) substituted, aryl, aralkyl, heterocyclic, heteroaryl, heteroarylalkyl, amino (-NRbbRcc), imino (= NRbb), amido (-C (O) NRbbRcc or N (Rbb) C (O) Raa), azido ( -N3), nitro (-NO2), cyano (-CN), carbamido (-OC (O) NRbbRcc or -N (Rbb) C (O) OR), ureido (N (Rbb) C (O) NRbbRcc), thioureido (-N (Rbb) C (S) NRbbRcc), guanidinyl (-N (Rbb) C (= NRbb) Rbb-Rcc), amidinyl (C (= NRbb) NRbbRcc or (-C (= NRbb) NRbbR), thiol (-SRbb), sulfinyl (-S (O) Rbb), sulfonyl (-S (O) 2Rbb), sulfonamidyl (S (O) 2NRbbRccor -N (Rbb) S (O) 2Rbb) and conjugated groups. that each Raa, Rbb and Rcc is, independently, H, an optionally linked chemical functional group or an additional substituent group with a preferred list, including, without limitation, alkyl, alkenyl, alkyne, aliphatic, alkoxy, acyl, aryl, aralkyl, heteroaryl, alicyclic, heter ocyclic and heteroaryl-alkyl.

B. Certain oligomeric compounds

In certain embodiments it is desirable to chemically modify oligomeric compounds, compared to natural oligomers, such as DNA or RNA. Certain of these modifications alter the activity of the oligomeric compound. Certain of these modifications may alter activity by, for example: increasing the affinity of an antisense compound for its target nucleic acid, increasing its resistance to one or more nucleases and / or altering the pharmacokinetics or tissue distribution of the oligomeric compound. In certain cases, the use of chemical substances that increase the affinity of an oligomeric compound for its target may allow the use of shorter oligomeric compounds.

1. Certain monomers

In a certain embodiment, the oligomeric compounds comprise one or more modified monomers. In certain of these embodiments, the oligomeric compounds comprise one or more high affinity monomers. In certain embodiments, said high affinity monomer is selected from monomers (e.g., nucleosides and nucleotides), which comprise sugars modified in 2, including, but not limited to: BNA and monomers (e.g., nucleosides and nucleotides) with substituents in 2 ', such as allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3. O- (CH2) -O-CH3, 2’-O (CH2) 2SCH3. O- (CH2) 2-ON (Rm) (Rn), or O-CH2-C (= O) -N (Rm) (Rn), in which Rm and Rn are independently H or C1 alkyl -C10 substituted or unsubstituted.

In certain embodiments, oligomeric compounds that include, among others, short antisense compounds of the present disclosure, comprise one or more affinity monomers, provided that the oligomeric compound does not comprise a nucleotide comprising 2'-O (CH2) nH, in which n is one to six.

In certain embodiments, oligomeric compounds that include, among others, short antisense compounds of the present disclosure, comprise one or more affinity monomers, provided that the oligomeric compound does not comprise a nucleotide comprising 2'-OCH3 or a 2'-O (CH2) 2OH3.

In certain embodiments, the oligomeric compounds that include, among others, short antisense compounds of the present disclosure, comprise one or more affinity monomers, provided that the oligomeric compound does not comprise a nucleotide comprising an α-L-Methyleneoxy (4'- CH2-O-2 ') BNA.

In certain embodiments, the oligomeric compounds that include, among others, short antisense compounds of the present disclosure, comprise one or more affinity monomers, provided that the oligomeric compound does not comprise a nucleotide comprising a β-D-Methyleneoxy (4'- CH2-O-2 ') BNA.

In certain embodiments, oligomeric compounds that include, among others, short antisense compounds of the present disclosure, comprise one or more affinity monomers, provided that the oligomeric compound does not comprise an α-L-Methyleneoxy (4'-CH2-O- 2 ') BNA or a β-D-Methyloxy (4'-CH2-O-2') BNA.

to. Certain nucleotide bases

The natural base portion of a nucleoside is usually a heterocyclic base. The two most common classes of such heterocyclic bases are purines and pyrimidines. For nucleosides that include a pentofuranosyl sugar, a phosphate group can be attached to the hydroxyl moiety in 2 ', 3' or 5 'of the sugar. When forming oligonucleotides, phosphate groups covalently bind adjacent nucleosides together to form a linear polymeric compound within oligonucleotides, phosphate groups are usually referred to as forming the oligonucleotide internucleotide structure. The natural bond or structure of RNA and DNA is a 3 'to 5' phosphodiester bond.

In addition to the "unmodified" or "natural" nucleotide bases, such as the purine adenine (A) and guanine (G) nucleotide bases, and the thyroid pyrimidine nucleotide (T), cytosine (C) and uracil (U) nucleotide bases ), many modified nucleotide bases or mimetics of nucleotide bases known to those skilled in the art are susceptible to the compounds described herein. In certain embodiments, a modified nucleotide base is a nucleotide base that is quite similar in structure to the parental nucleotide base, such as, for example, 7-deaza purine, a 5-methylcytosine or a clamp G. In certain embodiments, the mimetics of the nucleotide bases include more complicated structures, such as, for example, a mimetic of a nucleotide base of tricyclic phenozacin. The procedures for the preparation of the modified nucleotide bases indicated above are well known to those skilled in the art.

b. Certain sugars

The oligomeric compounds described herein may comprise one or more monomers, including a nucleoside or nucleotide, which has an unmodified sugar moiety. For example, the furanosyl sugar ring of a nucleoside can be modified in various ways, including, but not limited to, the addition of a substituent group, bridged with two non-germinal ring atoms, to form a bicyclic-nucleic acid (BNA ) not germinal.

In certain embodiments, the oligomeric compounds comprise one or more monomers that is a BNA. In certain embodiments, the BNAs include, among others, (A) -L-methyloxy (4'-CH2-O-2 ') BNA, (B) ß-D-menyloxy (4'-CH2-O-2' ) BNA,

(C) Ethyleneoxy (4 '- (CH2) 2-O-2') BNA, (D) aminooxy (4'-CH2-ON (R) -2 ') BNA and (E) oxyamino (4'-CH2- N (R) -O-2 ') BNA, as depicted in Figure 1.

image 1

Figure 1 Certain BNA structures

In certain embodiments, the BNAs include, among others, compounds that have at least one bridge between the 4 'position and the 2' position of the sugar, in which each of the bridges independently comprises 1 or 2 to 4 binding groups independently selected from - [C (R1) (R2)] n-, -C (R1) = C (R2) -, -C (R1) = N-, -C (= NR1) -, -C (= O) -, -C (= S) -, -O, n-Si (R1) 2, -S (= O) x- and -N (R1) -;

in which:

x is 0, 1, or 2;

n is 1, 2, 3 or 4,

each R1 and R2 is independently H, a protecting group, hydroxyl, C1-C11 alkyl, substituted C1-C12 alkyl, C2-C11 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl , C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C (= O) -H), substituted acyl, CN, sulfonyl (S (= O) 2-J1 or sulfoxyl (S (= O) -J1); and

each J1 and J2 is independently H, C1-C12 alkyl, substituted C1-C12 alkyl, C1-C12 alkenyl, C1C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, C3 aryl -C20 substituted, acyl (C (= O) -H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group.

In one embodiment, each of the bridges or BNA compounds is, independently, - [C (R1) (R2)] n-, [C (R1) (R2)] nQ-, -C (R1R2) -N (R1) -O- or -C (R1R2) -ON (R1) -. In another embodiment, each of said bridges is, independently, 4 '- (CH2) -2', 4 '- (CH2) 2-2', 4'-CH2O-2 ', 4' - (CH2) 2-O-2 ', 4'-CH2-ON (R1) -2' and 4'-CH2-N (R1) -O-2'-, in which each R1 is, independently, H, a protective group or C1-C12 alkyl.

Certain BNAs have been prepared and disseminated in the patent literature, as well as in the scientific literature (Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607 -3630; Wahlestedt et al., Proc.Natl. Acad. Sci. USA, 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; WO document 94/14226; WO 2005/021570; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Examples of US patents filed and published applications disclosing BNA include, for example, U.S. Patent Nos. 7,053,207; 6,268,490; 6,770,748; 6,794,499; 7,034,133; and 6,525,191; and U.S. Pre-Grant Publications No. 2004-0171570; 2004 -0219565; 2004-0014959; 2003-0207841; 2004-0143114; and 20030082807.

BNA is also disclosed herein in which the 2'-hydroxyl group of the ribosyl sugar ring is attached to the 4'-carbon atom of the sugar ring, thereby forming a methyloxy bond (4'-CH2-O -2 ') to form the remaining bicylic sugar (Revised in Elayadi et al., Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 81-7; and Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; see also US Pat.

6,268,490 and 6,670,461). The bond may be a methylene group (CH2-) that forms a bridge between the 2 'oxygen atom and the 4' carbon atom, for which the term methylene (4'-CH2-O-2 ') BNA it is used for the bicyclic moiety; in the case that there is an ethylene group in this position the term ethyleneoxy (4'-CH2CH2-O-2 ') BNA (Singh et al., Chem. Commun., 1998, 4, 55-456: Morita and col., Bioorganic Medicinal Chemistry, 2003, 11, 2211-2226). Methyloxy (4'-CH2-O2 ') BNA and other bicyclic sugar analogues show very high thermal duplex stability with complementarity of DNA and RNA (Tm = +3 at + 10 ° C), stability against 3' degradation -exonucleolytic and good solubility properties. Powerful non-toxic antisense oligonucleotides comprising BNA have been described (Wahlestedt et al., Proc. Natl. Acad. Sci. U. S.A., 2000, 97, 5633-5638).

A methyloxy (4'-CH2-O-2 ') BNA isomer that has also been treated is alpha-L-methyloxy (4'-CH2-O-2') BNA, which has been shown to have superior stability against a 3'-exonuclease. The alpha-L-methyloxy (4'-CH2-O-2 ') BNAs were incorporated into antisense gammers and chimeras, which showed potent antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372) .

5

10

fifteen

twenty

25

30

35

40

Four. Five

The synthesis and preparation of the methyloxy (4'-CH2-O-2 ') BNA adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil monomers have been described, together with their oligomerization and nucleic acid recognition properties (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). BNA and its preparation have also been described in WO 98/39352 and WO 99/14226.

Methoxy (4'-CH2-O-2 ') BNA, phosphorothioate-methylene (4'-CH2-O-2') BNA and 2'-thio-BNA analogues (Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222). The preparation of blocked nucleoside analogs comprising duplex oligodeoxyribonucleotides as substrates for nucleic acid polymerases has also been described (Wengel et al., WO 99/14226). In addition, the synthesis of 2'-amino-BNA, a novel high affinity oligonucleotide analog restricted by conformation has been described (Singh et al., J. Org. Chem., 1998, 63, 1003510039). In addition, 2’-amino and 2’-methylamino-BNA have been prepared and previously the thermal stability of other duplexes with complementary strands of RNA and DNA has been shared.

Modified sugar moieties are well known and can be used to alter, usually increase, the affinity of the antisense compound for its target and / or increase nuclease resistance. A representative list of preferred modified sugars includes, but is not limited to, bicyclic modified sugars (BNA), including methyloxy (4’-CH2-O-2 ’) BNA and ethyleneoxy (CH2) 2-O-2’-bridge) BNA; substituted sugars, especially 2 ’substituted sugars having a 2’-F, 2’-OCH3 or 2’-O (CH2) 2-OCH3 substituent group; and modified sugars in 4’-uncle. Sugars can also be replaced with sugar mimetic groups, among others. Those skilled in the art are well aware of procedures for the preparation of modified sugars. Some patents and representative publications that instruct on the preparation of such modified sugars include, among others, US Pat. No. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; 5,700,920; 6,531,584; and 6,600,032; and WO 2005/121371.

In certain embodiments, BNAs include bicyclic nucleosides that have the formula:

image 1

in which:

Bx is a heterocyclic base moiety;

T1 is H or a hydroxyl protecting group;

T2 is H, a hydroxyl protecting group or a reactive phosphorus group;

Z is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2C6 alkynyl, acyl, substituted acyl or substituted amide.

In one embodiment, each of the substituted groups is, independently, mono or polysubstituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3C (= X) NJ1J2 and CN, where each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1.

In certain of these embodiments, each of the substituted groups is, independently, mono or polysubstituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ1, NJ1J2, SJ1, N3, OC (= X) NJ1 and NJ3C (= X) NJ1J2, in which each J1, J2 and J3 is, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl and X is O or NJ1.

In certain embodiments, the group Z is C1-C6 alkyl substituted with one or more Xx, where each Xx is, independently, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1. In another embodiment, group Z is C1-C6 alkyl substituted with one or more Xx, in which each Xx is independently halo (e.g., fluorine), hydroxyl, alkoxy (e.g., CH3O-) , alkoxy or substituted azido.

In certain embodiments, the group Z is -CH2Xx, in which Xx is OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1. In other

embodiment, the group Z is CH2Xx, in which Xx is halo (e.g., fluorine), hydroxyl, alkoxy (e.g., CH3O-) or azido. In certain of these embodiments, the group Z is in the configuration (R).

image 1

In certain of these embodiments, group Z is in configuration (S).

image 1

In certain embodiments, each T1 and T2 is a hydroxyl protecting group. A preferred list of hydroxyl protecting groups includes benzyl, benzoyl, 2,6-dichlorobenzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, mesylate, tosylate, dimethoxytrityl (DMT), 9-phenylxanthine-9-yl (Pixyl) and 9- ( p-methoxyphenyl) xanthine-9-yl (MOX). In certain embodiments, T1 is a hydroxyl protecting group selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl, in which a more preferred hydroxyl protecting group is T1 is 4,4'-dimethoxytrityl.

In certain embodiments, T2 is a reactive phosphorus group in which preferred reactive phosphorus groups include diisipropylcyanoethoxy phosphoramidite and H-phosphonate. In certain embodiments, T1 is 4,4′-dimethoxytrityl and T2 is diisipropylcyanoethoxy phosphoramidite.

In certain embodiments, the oligomeric compounds have at least one monomer of the formula:

image 1

or of the formula:

or of the formula:

image 1

in which

Bx is a heterocyclic base moiety;

T3 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside binding group linked to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound; T4 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside binding group linked to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound; wherein at least one of T3 and T4 is an internucleoside binding group linked to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound; Y

Z is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2C6 alkynyl, acyl, substituted acyl or substituted amide.

In one embodiment, each of the substituted groups is, independently, mono or polysubstituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3C (= X) NJ1J2 and CN, where each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1.

In one embodiment, each of the substituted groups is, independently, mono or polysubstituted with substituent groups independently selected from halogen, oxo, hydroxyl, OJ1, NJ1J2, SJ1, N3, OC (= X) NJ1 and NJ3C ( = X) NJ1J2, in which each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O or NJ1.

In certain of these embodiments, at least one Z is C1-C6 alkyl or substituted C1-C6 alkyl. In certain embodiments, each Z is independently C1-C6 alkyl or substituted C1-C6 alkyl. In certain embodiments, at least one Z is C1-C6 alkyl. In certain embodiments, each Z is independently C1-C6 alkyl. In certain embodiments, at least one Z is methyl. In certain embodiments, each Z is methyl. In certain embodiments, at least one Z is ethyl. In certain embodiments, each Z is ethyl. In certain embodiments, at least one Z is substituted C1-C6 alkyl. In certain embodiments, each Z is independently substituted C1-C6 alkyl. In certain embodiments, at least one Z is substituted methyl. In certain embodiments, each Z is substituted methyl. In certain embodiments, at least one Z is substituted ethyl. In certain embodiments, each Z is substituted ethyl.

In certain embodiments, at least one substituent group is C1-C6 alkoxy (eg, at least one Z is C1-C6 alkyl substituted with one or more C1-C6 alkoxy). In another embodiment, each substituent group is, independently, C1-C6 alkoxy (eg, each Z is, independently, C1-C6 alkyl substituted with one or more C1-C6 alkoxy).

In certain embodiments, at least one C1-C6 alkoxy substituent group is CH3O- (eg, at least one Z is CH3OCH2-). In another embodiment, each C1-C6 alkoxy substituent group is CH3O- (eg, each Z is CH3OCH2-).

In certain embodiments, at least one substituent group is halogen (eg, at least one Z is C1-C6 alkyl substituted with one or more halogens). In certain embodiments, each substituent group is independently halogen (eg, each Z is independently C1-C6 alkyl substituted with one or more halogens). In certain embodiments, at least one halogen substituent group is fluorine (eg, at least one Z is CH2FCH2-, CHF2 CH2- or CF3CH2-). In certain embodiments, each halogen substituent group is fluorine (e.g., each Z is, independently, CH2FCH2-, CHF2 CH2-

or CF3CH2-).

In certain embodiments, at least one substituent group is hydroxyl (eg, at least one Z is C1-C6 alkyl substituted with one or more hydroxyls). In certain embodiments, each substituent group is, independently, hydroxyl (eg, each Z is, independently, C1-C6 alkyl substituted with one or more hydroxyls). In certain embodiments, at least one Z is HOCH2-. In another embodiment, each Z is HOCH2.

In certain embodiments, at least one Z is CH3-, CH3CH2-, CH2OCH3-, CH2F- or HOCH2-. In certain embodiments, each Z is, independently, CH3-, CH3CH2-, CH2OCH3-, CH2F- or HOCH2-.

In certain embodiments, at least one group Z is C1-C6 alkyl substituted with one or more Xx, wherein each Xx is, independently, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1. In another embodiment, at least one group Z is C1-C6 alkyl substituted with one or more Xx, in which each Xx is, independently, halo (e.g., fluorine, alkoxy (e.g., CH3O- ) or azido.

In certain embodiments, each group Z is, independently, C1-C6 alkyl substituted with one or more Xx, wherein each Xx is, independently, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1. In another embodiment, each group Z is, independently, C1-C6 alkyl substituted with one or more Xx, in which each Xx is independently halo (e.g., fluorine), hydroxyl, alkoxy (e.g. eg, CH3O-) or azido.

In certain embodiments, at least one group Z is -CH2Xx, in which Xx is OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1.

In certain embodiments, at least one group Z is CH2Xx, in which Xx is halo (e.g., fluorine), hydroxyl, alkoxy (e.g., CH3O-) or azido.

In certain embodiments, each group Z is, independently, -CH2Xx, in which Xx is, independently, OJ1, NJ1J2, SJ1, N3, OC (= X) J1, OC (= X) NJ1J2, NJ3 C (= X) NJ1J2 or CN; wherein each J1, J2 and J3 is, independently, H or C1-C6 alkyl and X is O, S or NJ1. In another embodiment, each group Z is, independently, CH2Xx, in which Xx is, independently, halo (eg, fluorine), hydroxyl, alkoxy (eg, CH3O-) or azido.

In certain embodiments, at least one Z is CH3-. In another embodiment, each Z is CH3- ..

In certain embodiments, the Z group of at least one monomer is in the configuration (R) represented by the formula:

or the formula:

or the formula:

image 1

In certain embodiments, the Z group of each monomer of the formula is in the configuration (R). In certain embodiments, the Z group of at least one monomer is in the configuration (S) represented by the formula:

or the formula:

or the formula:

image 1

In certain embodiments, the Z group of each monomer of the formula is in the configuration (S).

In certain embodiments, each T3 is H or a hydroxyl protecting group. In certain embodiments, each T4 is H or a hydroxyl protecting group. In a further embodiment, T3 is an internucleoside binding group linked to a nucleoside, nucleotide or a monomeric subunit. In certain embodiments, T4 is an internucleoside binding group linked to a nucleoside, nucleotide or a monomeric subunit. In certain embodiments, T3 is an internucleoside binding group linked to an oligonucleoside or an oligonucleotide. In certain embodiments, T4 is an internucleoside binding group linked to an oligonucleoside or an oligonucleotide. In certain embodiments, T3 is an internucleoside binding group bound to an oligomeric compound. In certain embodiments, T4 is an internucleoside binding group bound to an oligomeric compound. In certain embodiments, at least one of T3 and T4 comprises an internucleoside binding group selected from phosphodiester or phosphorothioate.

In certain embodiments, the oligomeric compounds have at least one region of at least two contiguous monomers of the formula:

or of the formula:

or of the formula:

image 1

image 1

In certain embodiments, the oligomeric compound comprises at least two regions of at least two contiguous monomers of the above formula. In certain embodiments, the oligomeric compound comprises an oligomeric compound with a gap. In certain embodiments, the oligomeric compound comprises at least one region of about 8 to about 14 contiguous β-D-2'-deoxyribofuranosyl nucleosides. In certain embodiments, the oligomeric compound comprises at least one region of about 9 to about 12 contiguous β-D-2'-deoxyribofuranosyl nucleosides.

In certain embodiments, the monomers include sugar mimetics. In certain of these embodiments, a mimetic is used instead of the sugar or the sugar-internucleoside junction combination, and the nucleotide base is maintained by hybridization to a selected target. Representative examples of sugar mimetics include, among others, cyclohexenyl or morpholino. Representative examples of a mimetic for a combination of sugar-internucleoside binding include, but are not limited to, peptide nucleic acids (PNAs) or morpholino groups linked by uncharged achiral linkages. In some cases a mimetic is used instead of the nucleotide base. Representative nucleotide base mimetics are well known in the art and include, among others, tricyclic phenoxacin analogs and universal bases (Berger et al., Nuc Acid Res. 2000, 28: 2911-14). Methods for the synthesis of sugar, nucleosides and mimetics of nucleotide bases are well known to those skilled in the art.

3. Monomeric links

This document describes linking groups that bind monomers (including, among others, modified and unmodified nucleosides and nucleotides), thereby forming an oligomeric compound. The two main classes of binding groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing bonds include, but are not limited to, phosphorodiesters (P = O), phosphorothiesters, methylphosphonates, phosphoramidate and phosphorothioates (P = S). Representative phosphorus-free binding groups include, but are not limited to, methylenemethylimino (-CH2-N (CH3) O-CH2-), thio diester (-OC (O) -S-), thionocarbamate (-OC (O) (NH) -S -); siloxane (-O-Si (H) 2-O-); and N, N’-dimethylhydrazine (-CH2-N (CH3) N (CH3) -). Oligomeric compounds that have phosphorus-free binding groups are called oligonucleosides. Modified bonds, compared to natural phosphodiester bonds, can be used to alter, normally increase, the nuclease resistance of the oligomeric compound. In certain embodiments, bonds having a chiral atom can be prepared, such as racemic mixtures in the form of separate enantiomers. Representative chiral bonds include, among others, alkyl phosphonates and phosphorothioates. The procedures for preparing links

5 which contain phosphorus and which do not contain phosphorus are well known to those skilled in the art.

The oligomeric compounds described herein contain one or more asymmetric centers and may, therefore, give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined in terms of stereochemistry as (R) or (S),  or , such as for sugar anomers, or as (D) or (L), such as for amino acids. Included in the antisense compounds disclosed herein are all these possible isomers, as well as their racemic and optimally pure forms.

4. Oligomeric compounds

In certain embodiments, oligomeric compounds having reactive phosphorus groups useful for forming bonds are disclosed herein, including, for example, phosphodiester and phosphorothioate internucleoside bonds. Methods of preparation and / or purification of precursors or oligomeric compounds are not a limitation of the

15 compositions or procedures described herein. Methods for the synthesis and purification of oligomeric compounds, including DNA, RNA, oligonucleotides, oligonucleosides and antisense compounds are well known to those skilled in the art.

In general, oligomeric compounds comprise a plurality of monomeric subunits linked by binding groups. Non-limiting examples of oligomeric compounds include primers, probes, antisense compounds, antisense oligonucleotides, external guide sequence oligonucleotides (SGE), alternative splices and siRNA. As such, these compounds can be introduced in the form of single-stranded, double-stranded, circular, branched or hairpin and can contain structural elements such as bumps or loops. Double stranded oligomeric compounds may be two strands hybridized to form double stranded compounds or a single strand with sufficient self-complementarity to allow hybridization and the formation of a compound completely or

25 partially double-stranded.

In certain embodiments, chimeric oligomeric compounds are disclosed herein. In certain of these embodiments, the chimeric oligomeric compounds are chimeric oligonucleotides. In certain of these embodiments, the chimeric oligonucleotides comprise differently modified nucleotides. In certain embodiments, the chimeric oligonucleotides are mixed structure antisense oligonucleotides.

In general, a chimeric oligomeric compound will have modified nucleosides that may be in isolated positions.

or grouped into regions that will define a specific reason. Any combination of modifications and / or mimetic groups may comprise a chimeric oligomeric compound, as described herein.

In certain embodiments, the chimeric oligomeric compounds typically comprise at least one modified region such that they confer an increase in resistance to degradation by nucleases, an increase in the

Cellular uptake and / or increased binding affinity for the target nucleic acid. In certain embodiments, an additional region of the oligomeric compound may serve as a substrate for enzymes capable of cleaving RNA: DNA or RNA: RNA hybrids. As an example, RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA: DNA duplex. Therefore, the activation of RNase H results in the cleavage of the target RNA, so that the efficiency of gene expression inhibition is greatly enhanced. Accordingly, comparable results can often be obtained with shorter oligomeric compounds when chimeras are used, compared to, for example, deoxyoligonucleotide phosphorothioate that hybridize with the same target region. Excision of the target RNA can be detected routinely by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.

In certain embodiments, the chimeric oligomeric compounds are gápmeros. In certain embodiments, the compounds

45 chimerics are short antisense compounds. In certain embodiments, the short antisense compounds are gápmeros. In certain of these embodiments, a mixed structure antisense oligomer has a type of internucleotide bond in one or both wings and a different type of internucleotide bonds in the recess. In certain of these embodiments, the mixed structure antisense oligomer has phosphodiester bonds on the wings and phosphorothioate bonds in the recess. In certain embodiments where the internucleotide bond in a wing is different from the internucleotide bond in the hollow, the internucleotide bond that joins said wing and the hollow is the same as the internucleotide bond of the wing. In certain embodiments in which the internucleotide bond in a wing is different from the internucleotide bond in the recess, the internucleotide bond that joins said wing and the recess is the same as the internucleotide bond in the recess.

C. Certain short antisense compounds

Antisense compounds of 8 to 16, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length are disclosed herein. In certain embodiments, short antisense compounds have a length of 9 to 14 nucleotides. In certain embodiments, short antisense compounds have a length of 10 to 14 nucleotides. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds comprise one or more chemical modifications. In certain of these embodiments, short antisense compounds comprise at least one modified nucleotide. In certain embodiments, short antisense compounds comprise at least two or more modified nucleotides. In certain embodiments, short antisense compounds comprise at least one modified internucleotide bond. In certain embodiments, the chimeric oligonucleotides are mixed structure oligonucleotides. In certain embodiments, the short antisense compounds are chimeric oligonucleotides. In certain embodiments, the short antisense compounds are uniformly modified. In certain embodiments, short antisense compounds comprise independently selected modifications at each nucleotide base and at each linkage.

In certain embodiments, the short antisense compounds are short captamers. In certain of these embodiments, the short cathamers comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds comprise 1 to 3 high affinity modifications in each wing. In certain embodiments, high affinity modifications of the short antisense compounds allow an affinity for the target similar, or even greater, to the affinity for the target of longer antisense compounds. In certain embodiments, high affinity modified nucleotides are sugar modified nucleotides. Said sugar modified nucleotides include those that comprise a bridge between the 4 'and 2' positions of the sugar. Example high affinity modifications include, but are not limited to, BNA and other 2 ’modifications, such as 2’-MOE. In an alternative embodiment of the disclosure, the high affinity modification is not a modified nucleotide with 2'-O- (CH2) nH sugar (n = 16). In a further alternative embodiment, the modified high affinity nucleotide is not a 2’-OCH3 nucleotide or a 2’OCH2CH2OCH3. In certain embodiments, modified high affinity nucleotides confer a T of at least 1, at least 1.5, at least 2, at least 2.5, at least 3.0, at least 3.5 or at least 4 , 0 degrees per nucleotide. It is known in the art that some high affinity nucleotide modifications increase toxicity. As shown herein, cs that have a limited number (generally 2 to 6) of high affinity modifications exhibit little or no toxicity, but retain or increase affinity for the target RNA, while also reducing significantly the expression of the target RNA. The short antisense compounds of the disclosure may optionally comprise a conjugate group, such as, for example, cholesterol or C16.

1. Certain wings

In certain embodiments, short antisense compounds comprise a 5 'wing and / or a 3' wing. In such embodiments, the characteristics of the wing at 3 ’and the characteristics of the wing at 5’ are independently selected. Therefore, in said embodiments, the number of monomers in the 5 ′ wing and the number of monomers (length) in the 5 ′ wing may be the same or they may be different; the modifications, if any, in wing 5 ’may be the same as the modifications, if any, in wing 3 ', or such modifications, if any, may be different; and the monomeric links in the 5 'wing and the monomeric links in the 3' wing may be the same or may be different.

In certain embodiments, a wing comprises one, two or three monomers (ie, it has a length of 1, 2 or 3). In certain embodiments, the monomers of a wing are modified. In certain of said embodiments, the wing monomers are modified to increase the affinity of the antisense compound for its target nucleic acid. In certain embodiments, the monomers of a wing are nucleosides or nucleotides. In certain of said embodiments, the nucleosides

or wing nucleotides comprise a 2 'modification. In certain of said embodiments, the monomers (nucleosides

or nucleotides) of the wing are BNA. In certain of said embodiments, the wing monomers are selected from -L-methyloxy (4'-CH2O-2 ') BNA, ß-D-methyloxy (4'-CH2O-2') BNA -2 ', ethyloxy 4'- (CH2) 2-O-2 ') BNA, aminooxy (4'-CH2-ON (R) 2') BNA and oxyamino (4'-CH2-N (R) -O-2 ') BNA. In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn) and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, the monomeric bonds in a wing are natural internucleotide bonds. In certain embodiments, the monomeric bonds in a wing are unnatural internucleotide bonds or internucleotide bonds. In certain of said embodiments, the monomeric bonds in the wing are more resistant to one or more nucleases than the natural internucleotide bonds. In certain of said embodiments, the monomeric bonds in the wing are phosphorothioate (P = S) bonds. In certain embodiments in which a wing has more than one monomeric bond, the monomeric bonds are equal to each other. In certain embodiments in which a wing has more than one monomeric bond, the monomeric bonds are different from each other.

One skilled in the art will recognize that the features and modifications discussed above can be used in any combination to prepare a wing. The following table provides non-limiting examples that show how a wing could be prepared by selecting a certain monomer number, monomeric modifications (if any) and monomeric bonds within the wing.

Length

Type of monomer / modifications Monomeric links within the wing

one

2’MOE None

one

BNA None

one

Methylene BNA None

one

ENA None

2

2’MOE P = S

2

BNA P = S

2

Methylene BNA P = S

2

ENA P = S

2

2’ MOE P = O

2

BNA P = O

2

Methylene BNA P = O

2

ENA F = O

3

2’ MOE P = S

3

BNA P = S

3

Methylene BNA P = S

3

ENA P = S

3

2’ MOE P = O

3

BNA P = O

3

Methylene BNA P = O

3

ENA P = O

In certain embodiments in which a wing comprises two, three or four monomers, said two, three or four monomers all comprise the same modifications, if any. In certain embodiments in which a wing comprises two, three or four monomers, one or more of said two, three or four nucleotide bases comprises one or more

5 modifications that are different from one or more of the modifications of one or more of the rest of the monomers.

2. Certain gaps

In certain embodiments, short antisense compounds comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments,

10 the monomers of the gap are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, the monomeric bonds in the gap are natural internucleotide bonds. In certain embodiments, the monomeric bonds in the gap are unnatural internucleotide bonds. In certain of these

In embodiments, the monomeric bonds in the recess are more resistant to one or more nucleases than the natural internucleotide bonds. In certain of said embodiments, the monomeric bonds in the gap are phosphorothioate bonds (P = S). In certain embodiments, the monomeric bonds in the gap are equal to each other. In certain embodiments, the monomeric bonds in the gap are not all the same.

One skilled in the art will recognize that the features and modifications discussed above can be used in any combination to prepare a gap. The following table provides non-limiting examples that show how a hole could be prepared by selecting a certain number of monomers, monomer modifications (if any) and monomer bonds within the hole.

Length

Type of monomer / modifications Monomeric links inside the hole

5

DNA P = S

6

DNA P = S

7

DNA P = S

8

DNA P = S

9

DNA P = S

10

DNA P = S

eleven

DNA P = S

12

DNA P = S

13

DNA P = S

14

DNA P = S

6

DNA P = O

7

DNA P = O

8

DNA P = O

9

DNA P = O

10

DNA P = O

eleven

DNA P = O

12

DNA P = O

8

RNA P = S

9

RNA P = S

10

RNA P = S

eleven

RNA P = S

12

RNA P = S

5 3. Certain oligomeric antisense compounds with gaps

One skilled in the art will recognize that previously treated wings and voids can be selected and then combined in various combinations to generate oligomeric compounds with voids, including, among others, antisense oligomeric compounds with voids and antisense oligonucleotides with voids. The characteristics (length, modifications, links) of the wing at 5 ’and the wing at 3’ can be independently selected from each other. The

10 features of the gap include at least one difference in the modification compared to the characteristics of the wing at 5 'and at least one difference compared to the characteristics of the wing at 3' (i.e. there must be at least one difference in the modification between adjacent regions to distinguish said adjacent regions from each other). The characteristics of the hole can, on the other hand, be selected independently.

In certain embodiments, the monomeric bonds in a wing are monomeric bonds within the gap are the same. In

In certain embodiments, the monomeric bonds in a wing are monomeric bonds within the gap are different. In certain of said embodiments, the monomeric bond linking the wing and the gap is the same as the monomeric bonds within the wing. In certain embodiments, the monomeric bond that joins the wing and the gap is the same as the monomeric bonds within the gap. In certain embodiments, short antisense compounds have uniform bonds throughout the compound. In certain of said embodiments, all bonds are phosphorothioate (P = S) bonds.

One skilled in the art will recognize that 3 'wings, 5' wings, gaps and links discussed above can be used in any combination to prepare a catheter. The following table provides non-limiting examples that show how a catheter could be prepared by selecting a certain wing number at 5 ’, a hole, a wing at 3’ and certain links that link the hole and each wing.

5 ’wing

5 ’bridge Hole 3 ’bridge 3 ’wing

Length

Monomer Link Link  Length Monomer Link Link  Length Monomer Link

2

MOE P = S P = S 6 DNA P = S P = S  2 MOE P = S

2

BNA P = S P = O 8 DNA P = O P = S 3 BNA P = S

one

MOE None P = S 10 DNA P = S P = S  one MOE P = S

2

MOE P = S P = S 8 RNA P = S P = S  2 MOE P = S

3

Methylene BNA P = S P = S 8 RNA P = S P = S  3 MOE P = S

3

DNA P = O P = O 10 RNA P = S P = O  3 2’OH P = O

2

2-F P = S P = S 5 RNA P = S P = S  2 2’-F P = S

one

MOE P = O P = S 5 DNA P = O P = S 4 MOE P = S

In certain embodiments, the oligomeric compounds described herein may comprise

10 to about 8 to about 16, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises antisense compounds of 8, 9, 10, 11, 12, 13, 14, 15 or 16 nucleotide bases. In certain embodiments, the oligomeric compounds are antisense compounds.

In certain embodiments, the short antisense compounds have a length of 8 nucleotide bases.

In certain embodiments, short antisense compounds have a length of 9 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 10 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 11 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 12 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 13 nucleotide bases.

In certain embodiments, short antisense compounds have a length of 14 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 15 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 16 nucleotide bases.

In certain embodiments, the short antisense compounds have a length of 8 monomers. In certain embodiments, the short antisense compounds have a length of 9 monomers. In certain embodiments, short antisense compounds have a length of 10 monomers. In certain embodiments, the short antisense compounds have a length of 11 monomers. In certain embodiments, short antisense compounds have a monomer length. In certain embodiments, the short antisense compounds have a length of 13 monomers. In certain embodiments, the short antisense compounds have a length of 14 monomers. In certain embodiments, the short antisense compounds are 15 monomers in length. In certain embodiments, the compounds

30 short antisense have a length of 16 monomers. In certain embodiments, short antisense compounds comprise 9 to 15 monomers. In certain embodiments, short antisense compounds comprise 10 to 15 monomers. In certain embodiments, short antisense compounds comprise 12 to 14 monomers. In certain embodiments, short antisense compounds comprise 12 to 14 nucleotides or nucleosides.

A person skilled in the art and informed by the short antisense compounds illustrated herein may, without undue experimentation, identify other short antisense compounds.

In certain embodiments, short antisense compounds comprise a gap flanked by more than one wing on both sides. Therefore, in certain embodiments, a short antisense compound comprises two or more wings in 5 'and two or more wings in 3'. In certain embodiments, a short antisense compound comprises a 5 'wings and two or more 3' wings. In certain embodiments, a short antisense compound comprises a 3 'wing and two or more 5' wings. Certain of these embodiments comprise, for example, the following regions: a first wing in 5'- a bridge- a second wing in 5'- a bridge - a gap - a bridge - a second wing in 3 '- a bridge - a first wing in 3 '. In such embodiments, each region has at least one difference in the modification when compared to its adjacent region. Therefore, in said embodiments, the second wing at 5 'and the second wing at 3', each independently, comprise one or more differences in the modification when compared to the gap and when compared to the first wing in 5 'and with the first wing in 3'- In said embodiments, the modifications of the first wing in 3' and with the first wing in 5 'can be each or both the same or different from the modifications of the gap, if any .

4. Certain conjugate groups

In one aspect, the oligomeric compounds are modified by covalent binding of one or more conjugated groups. In general, conjugated groups modify one or more properties of the bound oligomeric compound including, but are not limited to, pharmacodynamics, pharmacokinetics, binding, absorption, cell distribution, cell uptake, loading and clearance. Conjugated groups are routinely used in chemical techniques and are directly or by means of a binding moiety or optional binding group to a parent compound, such as an oligomeric compound. A preferred list of conjugated groups includes, without limitation, intercalants, indicator molecules, polyamines, polyamides, polyethylene glycols, thioethers, polyesters, cholesterols, thiocholesteroles, traces of colic acid, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamanta, adamanta, adamanta acridine, fluoresceins, rhodamines, coumarins and pigments.

Preferred conjugated groups in the present disclosure include lipid moieties, such as cholesterol moiety ((Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553); colic acid (Manoharan et al., Bioorg. Med Chem. Lett., 1994, 4, 1053); a thioether, for example hexyl-S-tritylthiol (Manoharan et al., Ann. NY Acad. Sci., 1992, 660, 306; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765); a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533); an aliphatic chain, for example residues of dodecandiol or undecyloyl (Saison-Hehmoaras et al., EMBO J., 1991, 10, 111; Kabanov et al., FEBS Lett., 1990, 259, 327; Svinarchuk et al., Biochimie, 1993, 75, 49); a phospholipid, for example, dihexadecil -racglycerol or triethylammonium-1,2-di-O-hexadecyl-rac-glycerol-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651; Shea et al., Nucl. Acids Res. , 1990, 18, 3777); a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleoti des, 1995, 14, 969); adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651); a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229); or u octadecylamine or hexylaminocarbonyloxycholesterol moiety (Crooke et al., J. Pharmacol: Exp. Ther., 1996, 277, 923).

Binding groups or bifunctional binding moieties, such as those known in the art, are suitable for the compounds disclosed herein. Binding groups are useful for the binding of functional chemical groups, conjugated groups, reporter groups and other groups for selective sites in a parent compound, such as, for example, an oligomeric compound. In general, a bifunctional binding moiety comprises a hydrocarbyl moiety having two functional groups. One of the functional groups is selected so that it binds to a parental molecule or compound of interest and the other is selected so that it essentially joins any selected group, such as a functional chemical group or a conjugate groups. In some embodiments, the linker comprises a chain structure or an oligomer of repeated units, such as ethylene glycol or amino acid units. Examples of functional groups that are routinely used in a bifunctional binding moiety include, among others, electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In some embodiments, bifunctional binding moieties include amino, hydroxyl, carboxylic acid, thiol, unsaturations (eg, double or triple bonds) and the like. Some non-limiting examples of bifunctional binding moieties include 8-amino-3,6-dioxaoctanoic acid (ADO), 4- (N-maleimidomethyl) cyclohexane-1-carboxylate succinimidyl (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other binding groups include, among others, substituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or substituted or unsubstituted C2-C10 alkynyl, in which a non-limiting list of preferred substituent groups include hydroxyl, amino, alkoxy, carboxy , benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

5. Synthesis, purification and analysis

The oligomerization of modified and unmodified nucleosides and nucleotides can be performed routinely according to the procedures of the literature (Protocols for Oligonucleotides and Analogs, Ed. Agrawal (1993), Humana Press) and / or RNA (Scaringe, Methods ( 2001), 23, 206-217. Gait et al., Applications of Chemically synthesized RNA in RNA: Protein Interactions, Ed. Smith (1998), 1-36. Gallo et al., Tetrahedron (2001), 57, 5707- 5713).

The oligomeric compounds disclosed herein can be conveniently and routinely manufactured through the well-known technique of solid phase synthesis. The equipment for such synthesis is marketed in different suppliers including, for example, Applied Biosystems (Foster City, CA). Any other means for such synthesis can also be used additionally or as an alternative. The use of similar techniques to prepare oligonucleotides such as phosphorothioates and alkylated derivatives is well known. The disclosure is not limited by the method of synthesis of antisense compounds.

5 Those skilled in the art are aware of methods of purification and analysis of oligomeric compounds. The analysis procedures include capillary electrophoresis (EC) and electrospray mass spectroscopy. Such synthesis and analysis procedures can be performed in multiwell plates. The disclosure process is not limited by the oligomer purification process.

D. Antisense

10 Antisense mechanisms are all those that involve hybridization of a compound with a target nucleic acid, in which the result or effect of hybridization is the degradation of the target or the occupation of the target with the arrest of the cellular machinery that it implies, for example, transcription or cutting and splicing.

A type of antisense mechanism that involves target degradation includes an RNase H. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA: DNA duplex. It is known in the art that the compounds

Single stranded antisense that are "DNA-like" cause RNase H activity in mammalian cells. Therefore, the activation of RNase H results in the cleavage of the target RNA, so that the efficiency of inhibition of gene expression mediated by DNA-like oligonucleotides is greatly enhanced.

In certain embodiments, chemically modified antisense compounds have a higher affinity for target RNAs than unmodified DNA. In certain of said embodiments, said higher affinity in turn provides greater

20 potency, which allows the administration of lower doses of said compounds, lower potential for toxicity and improvement of the therapeutic index and lower overall costs of therapy.

The present disclosure demonstrates that the incorporation of chemically modified high affinity nucleotides and nucleosides into antisense compounds allows the design of short antisense compounds of a length of 8-16 nucleotide bases useful for the reduction of target RNAs and / or target proteins in cells, tissues and animals, including,

25 among others, human beings with greater potency and better therapeutic index. Therefore, in certain embodiments, antisense compounds comprising high affinity nucleotide modifications useful in reducing a target RNA in vivo are disclosed herein. Certain of these short antisense compounds are effective at lower doses than the antisense compounds described above, which allows a reduction in toxicity and treatment costs. In addition, certain short antisense compounds have greater potential for oral dosing.

30 To address the need for more potent antisense compounds, short antisense compounds (8 to 16, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length) are disclosed herein with greater activity in vivo with respect to longer compounds. Certain short antisense compounds are capmere compounds comprising chemically modified nucleosides of high affinity at the 3 'and 5' ends (wings) of the compound. In certain embodiments, the addition of high affinity modified nucleotides

35 allows antisense compounds to be active, or specific, against, of, their target target RNA in vivo despite having a shorter length. Antisense compounds are contemplated herein in which each of the wings independently comprises 1 to 3 modified high affinity nucleotides. In certain embodiments, high affinity modifications are sugar modifications. High affinity modified nucleotides include, but are not limited to, BNA or other 2 ′ modified nucleotides, such as 2’-MOE nucleotides. Compounds are also contemplated.

Short antisense that have at least one modified internucleotide bond, such as an internucleotide phosphorothioate bond. In certain embodiments, the short antisense compounds of the present disclosure may have all phosphorothioate internucleotide linkages. Short antisense compounds optionally comprise a conjugate group. As shown herein, the compounds have higher affinity for target DNA than for DNA and are significantly more potent in vivo, as demonstrated by reduction of target mRNA as well as

45 the improvement of a variety of disease indications.

As used herein, an RNA that is involved in the regulation of glucose metabolism or clearance, lipid metabolism, cholesterol metabolism or insulin metabolism is any RNA involved in the biochemical pathways that regulate these processes Such RNAs are well known in the art. Examples of target genes include, among others, ApoB-100 (also known as APOB; Ag (x) antigen; apoB-48; apolipoprotein B;

50 apolipoprotein B-100; apolipoprotein B-48) and GCGR (also known as the glucagon receptor, GR), CRP, DGAT2, GCCR, PCSK9, PTEN, PTP1B, SGLT2, and SOD1

1. Modulation of the target expression

In certain embodiments, a target is identified and antisense oligonucleotides are designed to modulate said target or its expression. In certain embodiments, the design of an oligomeric compound for a target nucleic acid molecule can be a multi-stage process. Normally the procedure begins with the identification of a target protein whose activity has to be modulated and then the identification of the nucleic acid whose expression produces the target protein. In certain embodiments, the design of an antisense compound results in an antisense compound that can hybridize with the target nucleic acid molecule. In certain embodiments, the antisense compound is an antisense oligonucleotide or an antisense oligonucleoside. In certain embodiments, an antisense compound and a target nucleic acid are complementary to each other. In certain of said embodiments, an antisense compound is perfectly complementary to a target nucleic acid. In certain embodiments, an antisense compound includes erroneous pairing. In certain embodiments, an antisense compound includes two mismatches. In certain embodiments, an antisense compound includes three or more mismatches.

Modulation of the expression of a target nucleic acid can be achieved by altering any number of nucleic acid functions. In certain embodiments, the functions of the RNA to be modulated include, among others, translocation functions, which include, among others, translocation of the BNA to a protein translation site, translocation of the RNA to sites within the cell that are away from the site of RNA synthesis, and translation of proteins from RNA, RNA processing functions that can be modulated include, but are not limited to, RNA splicing to give one or more RNA species, plug the ends of RNA, 3 'maturation of RNA and catalytic activity or formation of complexes that involve RNA that can bind or be facilitated by RNA, Expression modulation can result in increased levels of one or more species of nucleic acid or the decrease in the levels of one or more nucleic acid species, either temporarily or at a net level in equilibrium. Therefore, in one embodiment, expression modulation may mean increasing or decreasing levels of RNA or target proteins. In another embodiment, expression modulation may mean increasing or decreasing one or more RNA splicing products or a change in the proportion of two or more splicing products.

In certain embodiments, expression of a target gene is modulated using an oligomeric compound comprising from about 8 to about 16, preferably from 9 to 15, more preferably from 9 to 14, more preferably from 10 to 14 monomers (i.e., from about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating the expression of a target gene using one or more antisense compounds of 8, 9, 10, 11, 12, 13, 14, 15 or 16 nucleotide bases.

In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 8 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 9 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 8 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 10 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 10 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 11 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 12 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 13 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 14 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 15 nucleotide bases in length. In certain embodiments, the methods of modulating a target gene comprise using a short antisense compound that is 16 nucleotide bases in length.

In certain embodiments, the methods of modulating the expression of a target gene comprise the use of a short antisense compound comprising 9 to 1-5 monomers. In certain embodiments, the methods of modulating the expression of a target gene comprise the use of a short antisense compound comprising 10 to 5 monomers. In certain embodiments, the methods of modulating the expression of a target gene comprise the use of a short antisense compound comprising 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of a target gene comprise the use of a short antisense compound comprising 12 or 14 nucleotides or nucleosides.

2. Hybridization

In certain embodiments, the antisense compounds hybridize specifically when there is a sufficient degree of complementarity to avoid nonspecific binding of the antisense compound with sequences of a non-target nucleic acid under conditions where specific binding is desired, i.e. under physiological conditions in the case. of in vivo tests or therapeutic treatment, and under the conditions under which the tests are performed in the case of in vitro tests.

As used herein, "stringent hybridization conditions" or "stringent conditions" refers to conditions in which an antisense compound hybridizes with its target sequence but with a minimum number of other sequences. The stringent conditions are sequence dependent and will be different under different circumstances and "stringent conditions" in which the antisense compounds hybridize with a target sequence are determined by the nature and composition of the antisense compounds and the assays in which They are investigating.

3.

 Complementarity

It is understood in the art that the incorporation of affinity modifications in the nucleotide can cause a greater number of mismatches in comparison to an unmodified compound. Similarly, certain oligonucleotide sequences may be more tolerant of mismatches than other oligonucleotide sequences. One skilled in the art is able to determine an appropriate number of mismatches between oligonucleotides or between an oligonucleotide and a target nucleic acid, such as by determining the melting temperature (Tf). Tf or Tf can be calculated using techniques familiar to a person skilled in the art. For example, the techniques described in Freier et al. (Nucleic Acids Research, 1997, 25, 22: 4429-4443) allow a person skilled in the art to evaluate in nucleotide modifications its ability to increase the melting temperature of an RNA: DNA duplex.

Four.

 Identity

The antisense compounds, or a portion thereof, may have a defined percentage of identity with a SEQ ID NO or a compound having a specific Isis number. As used herein, a sequence is identical to the sequence disclosed herein if it has the same nucleotide base mating ability. For example, an RNA that contains uracil instead of thymidine in the disclosed sequences of the compounds described herein would be considered identical, since both would mate with adenine. This identity may be along the entire length of the oligomeric compound or in a portion of the antisense compound

(eg, nucleotide bases 1-20 of a compound of 27 units can be compared with a compound of 20 units to determine the percent identity of the oligomeric compound with SEQ ID NO. Those skilled in the art understand that a compound antisense does not have to have an identical sequence to those described herein to function in a manner similar to the antisense compound described herein. Smaller versions of the antisense compounds taught herein are also disclosed non-identical document or versions of the antisense compounds taught herein The non-identical versions are those in which each base does not have the same pairing activity as the antisense compounds taught herein. The bases do not have the same activity of mating for being shorter or for having at least one absonic site. Alternatively, a v Non-identical version may include at least one substituted base with a different base with different mating activity (e.g. eg, G may be substituted by C, A or T). The percent identity is calculated according to the number of bases that have identical base pairing corresponding to SEQ ID NO or the antisense compound with which it is being compared. Non-identical bases may be adjacent, dispersed by the oligonucleotide or both.

For example, a 16-unit compound that has the same sequence as nucleotide bases 2-17 is 80% identical to the 20-unit compound. Alternatively, a 20 unit compound containing four nucleotide bases not identical to the 20 unit compound is also 80% identical to the 20 unit compound. A 14-unit compound having the same sequence as nucleotide bases 1-14 of an 18-unit compound is 78% identical to the 18-unit compound. Such calculations fall within the capacity of those skilled in the art.

The percent identity is based on the percentage of nucleotide bases in the original sequence present in a portion of the modified sequence. Thus, an antisense compound of 30 nucleotide bases comprising the complete sequence of the complement of an active target segment of 20 nucleotide bases would have a 100% identity portion with the complement of the active target segment of 20 nucleotide bases, while It also comprises an additional portion of 10 nucleotide bases. In the context of the present description, the complement of an active target segment may constitute a single portion. In preferred embodiments, the oligonucleotides disclosed herein are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99 % or 100% identical to at least a portion of the complement of the active target segments presented herein.

E. Nucleic acids, regions and target segments

In certain embodiments, short antisense compounds may be designed so that they are directed to any target nucleic acid. In certain embodiments, the target nucleic acid encodes a target that is clinically relevant. In such embodiments, the modulation of the target nucleic acid results in a clinical benefit. Certain target nucleic acids include, among others, the target nucleic acids illustrated in Table 1.

In certain embodiments, a nucleic acid is a nucleic acid molecule encoding ApoB. Nucleic acid molecules encoding ApoB include, without limitation, SEQ ID No. 1 and SEQ ID NO: 2.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes SGLT2. Nucleic acid molecules encoding SGLT2 include, without limitation, SEQ ID NO. 3.

In certain embodiments, a nucleic acid is a nucleic acid molecule encoding PCSK9. Nucleic acid molecules encoding PCSK9 include, without limitation, SEQ ID NO: 4.

5 In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes SOD1. Nucleic acid molecules encoding SOD1 include, without limitation, SEQ ID NO: 5.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes CRP. Nucleic acid molecules encoding CRP include, without limitation, SEQ ID NO. 6.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes GCCR. Nucleic acid molecules encoding GCCR include, without limitation, SEQ ID No. 7 and SEQ ID NO: 8.

In certain embodiments, a nucleic acid is a nucleic acid molecule encoding GCGR. Nucleic acid molecules encoding GCGR include, without limitation, SEQ ID NO. 9.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes DGAT2. Nucleic acid molecules encoding DGAT2 include, without limitation, SEQ ID NO. 10.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes PTP1B. Nucleic acid molecules encoding PTP1B include, without limitation, SEQ ID No. 11 and SEQ ID NO: 12.

In certain embodiments, a nucleic acid is a nucleic acid molecule that encodes PTEN. Nucleic acid molecules encoding PTEN include, without limitation, SEQ ID No. 14 or SEQ ID NO: 15.

Table 1: Certain target nucleic acids

Diana

Species GENBANK® registration number SEQ ID NO.

ApoB

Human being NM_000384.1 one

ApoB

Mouse XM_137955.5 2

SGLT2

Human being NM_003041.1 3

PCSK9

Human being NM_174936.2 4

SOD1

Human being X02317.1 5

CRP

Human being NM_000567.1 6

GCCR

Mouse BC031885.1 7

GCCR

Human being Nucleotides 1 to 10600 of AC012634 8

GCGR

Human being NM_000160.1 9

DGAT2

Human being NM_032564.2 10

PTP1B

Human being NM_002827.2 eleven

PTP1B

Human being Nucleotides 1417800 to 1425600 of NT 011362.9 12

PTEN

Mouse U92437.1 13

PTEN

Human being NM_000314.4 14

PTEN

Human being Nucleotides 8063255 to 8167140 of NT_033890.3 fifteen

The method of targeting a target includes the determination of at least one region, segment or target site within the target nucleic acid so that the antisense interaction occurs so that the desired effect takes place.

In certain embodiments, the 5 ′ plus nucleotide of a target region is the 5 ′ target site of a short antisense compound and the 3 ′ plus nucleotide of a target region is the 3 ′ target site of the same short antisense compound. In certain embodiments, the 5 'plus nucleotide of a target region is the 5' target site of a short antisense compound and the 3 'plus nucleotide of a target region is the 3' target site of a different short antisense compound. . In certain embodiments, a target region comprises a nucleotide sequence within 10, 15 or 20 nucleotides of a 5 'target site or a 3' target site.

In certain embodiments, a target region is a structurally defined region of the nucleic acid. For example, in certain of said embodiments, a target region may encompass a 3 'UTR, a 5' UTR, an exon, an intron, a coding region, a translation start region, a translation termination region or another defined nucleic acid region.

The locations on the target nucleic acid defined by having one or more target active short antisense compounds are called "active target segments." In certain embodiments, the target nucleic acid having one or more target active short antisense compounds is target RNA. When an active target segment is defined by multiple short antisense compounds, the compounds are preferably separated by no more than about 10 nucleotides on the target sequence, more preferably no more than about 5 nucleotides on the target sequence, even more preferably the short antisense compounds. they are contiguous, more preferably the short antisense compounds overlap. There may be a considerable variation in activity (eg, defined by the percentage of inhibition) of short antisense compounds within an active target segment. Active short antisense compounds are those that modulate the expression of their target nucleic acid, including, among others, a target RNA. Active short antisense compounds inhibit the expression of their target RNA by at least 10%, preferably 20%. In a preferred embodiment, at least about 50%, preferably about 70% of the short antisense compounds targeting the active target segment modulate the expression of their target RNA at least 40%. In a more preferred embodiment, the level of inhibition required to define an active short antisense compound is defined based on the screening results used to define the active target segments.

A suitable target segment is a portion of at least about 8 nucleotide bases of a target region to which an active short antisense compound is directed. The target segments may include DNA or RNA sequences comprising at least 8 consecutive nucleotide bases from the 5 'end of one of the illustrative target segments (the remaining nucleotide bases being a consecutive strip of the same DNA or RNA beginning immediately before the end 5 'of the target segment and continuing until the DNA or RNA comprises from about 8 to about 16 nucleotide bases). The target segments are also represented by DNA or RNA sequences comprising at least 8 consecutive nucleotide bases from the 3 'end of one of the illustrative target segments (the remaining nucleotide bases being a consecutive strip of the same DNA or RNA beginning immediately after from the 3 'end of the target segment and continuing until the DNA or RNA comprises from about 8 to about 16 nucleotide bases). It is understood that the antisense target segments may be represented by DNA or RNA sequences comprising at least 8 consecutive nucleotide bases of an internal portion of the sequence of an illustrative target segment and may extend in one or both directions until the short antisense compound comprises from about 8 to about 16 nucleotide bases. An expert in the art armed with the target segments illustrated herein may, without undue experimentation, identify other target segments.

Once one or more target regions, segments or sites have been identified, short antisense compounds are chosen that are sufficiently complementary to the target, that is, hybridize sufficiently well and with sufficient specificity, to give the desired effect.

Short antisense compounds may also be directed to regions of the target nucleotide sequence sequence comprising any consecutive nucleotide base of 8 to 16 nucleotide bases in length along the target nucleic acid molecule.

Target segments of 8 to 16 nucleotide bases in length comprising a strip of at least eight (8) consecutive nucleotide bases selected from within the illustrative target segments are also considered suitable as target. Thus, short antisense compounds may also encompass 8-16 nucleotide bases with the segments identified herein starting at a specific 5 ’target site. Any segment of, 9, 10, 11, or, more preferably, of 12, 13, 14, 15 or 16 contiguous nucleotide bases in a perimeter of 50, preferably 25, more preferably 16 nucleotide bases around these regions are also considered suitable as Diana

In another embodiment, the "suitable target segments" identified herein can be employed in a screen for additional short antisense compounds that modulate the expression of a target nucleic acid. "Modulators" are compounds that decrease or increase the expression of a target nucleic acid and that comprise at least a portion of 8 nucleotide bases that is complementary to a target segment. The screening method comprises the steps of contacting a target segment of a nucleic acid with one or more candidate modulators and selecting one or more candidate modulators that decreases or increases the expression of a target nucleic acid. Once it has been shown that the target candidate modulator or modulators are capable of modulating (e.g., decreasing or increasing) the expression of a target nucleic acid, the modulator can be used in additional research studies of the function or use as a research, diagnostic or therapeutic agent in accordance with the present disclosure.

For all short antisense compounds discussed herein, sequence, monomer, monomeric modification and monomeric bond can each be independently selected. In certain embodiments, short antisense compounds are described with a motive. In such embodiments, any motif may be used with any sequence, the sequence and / or the motif are specifically disclosed herein or not. In certain embodiments, short antisense compounds comprise modifications that are not suitable for describing with a motif (for example, short antisense compounds comprising several different modifications and / or bonds at various positions throughout the compound). Such combinations may be incorporated for any sequence, whether or not disclosed herein. The sequence listing that accompanies this presentation provides certain nucleic acid sequences independent of chemical modification. Although said list identifies each sequence as "RNA" or "DNA", as required, in reality said sequences can be modified with any combination of

15 chemical modifications and / or reasons.

In certain embodiments, short antisense compounds comprise at least one modified high affinity monomer. In certain embodiments, short antisense compounds targeting nucleic acid molecules encoding targets are disclosed, including but not limited to ApoB-100 (also known as APOB; Ag (x) antigen; apoB-48; apolipoprotein B; apolipoprotein B-100; apolipoprotein B-48). GCGR (also known as glucagon receptor, GR), CRP, DGAT2, GCCR, PCSK9, PTEN, PTP1B, SGLT2, and SOD1. In certain of said embodiments, said short antisense compounds are directed to a nucleic acid molecule encoding any of said targets.

F. Certain targets

In certain embodiments, short antisense compounds can be designed to modulate any target. In certain embodiments, the target is clinically relevant. In such embodiments, the modulation of the target results in a clinical benefit. Certain targets are preferably expressed in the kidney. Certain targets are preferably expressed in the liver. Certain targets are associated with a metabolic disorder. Certain targets are associated with a cardiovascular disorder. In certain embodiments, a target is selected from: ApoB, SGLT2, PCSK9, SOD1, CRP, GCCR, GCGR, DGAT2, PTP1B and PTEN. In certain embodiments, a target is selected from: ApoB, SGLT2, PCSK9, SOD1, CRP, GCCR, GCGR, DGAT2 and PTP1B. In certain embodiments, a target is any protein other than SGLT2.

In certain embodiments, short antisense compounds exhibit in vivo a reduction in kidney and liver specific target RNA. Said property makes said short antisense compounds particularly useful for the inhibition of many target RNAs involved in metabolic and cardiovascular diseases. Therefore, methods of treating metabolic and cardiovascular disorders by contacting said renal or hepatic tissues with short antisense compounds targeting RNA associated with such disorders are disclosed herein. So,

35 methods of improving any of several indications of metabolic or cardiovascular disease with the short antisense compounds of the present disclosure are also disclosed herein.

1. ApoB

ApoB (also known as apolipoprotein B-100; ApoB-100, apolipoprotein B-48; ApoB-48 and Ag (x) antigen) is a large glycoprotein that plays an indispensable role in the assembly and secretion of lipids and in transport and receptor-mediated uptake and release of different classes of lipoproteins. ApoB carries out various activities, from the absorption and processing of dietary lipids to the regulation of circulating levels of lipoprotein (Davidson and Shelness, Annu. Rev Nutr. 2000, 20, 169-193). This last property highlights its relevance in terms of susceptibility to atherosclerosis, which correlates considerably with the environmental concentration of lipoproteins containing ApoB (Davidson and Shelness, Annu. Rev. Nutr., 2000,20,169-193). ApoB-100 is the main

The protein component of LDL-C and contains the domain required for the interaction of this species of lipoprotein with the LDL receptor. Elevated LDL-C levels are a risk factor for cardiovascular disease, including atherosclerosis.

Definitions

"ApoB" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound.

"ApoB nucleic acid" means any nucleic acid encoding ApoB. For example, in certain embodiments, an ApoB nucleic acid includes, without limitation, a DNA sequence encoding ApoB, an RNA sequence transcribed from DNA encoding ApoB, and an mRNA sequence encoding ApoB.

"ApoB mRNA" means an mRNA encoding ApoB.

ApoB therapeutic indications

In certain embodiments, methods of modulating ApoB expression in an individual are disclosed herein, comprising administering a short antisense compound directed to an ApoB nucleic acid. In certain embodiments, methods of treating an individual are disclosed herein, comprising administering one or more pharmaceutical compositions comprising a short antisense compound directed to an ApoB nucleic acid. In certain embodiments, the individual has hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, history of coronary heart disease, coronary heart disease early onset, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, liver steatosis, nonalcoholic steatohepatitis or nonalcoholic fatty liver disease.

The guidelines for lipid-lowering therapies were established in 2001, in the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and were updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). The guidelines include obtaining a complete lipoprotein profile, usually after fasting for 9 to 12 hours, for the determination of the levels of LDL-C, total cholesterol and HDL-C. According to the most recently established guidelines, LDL-C levels of 130-159 mg / dl, 160-189 mg / dl and greater than or equal to 190 mg / dl are considered at the high, high and very high limit, respectively. Cholesterol levels of 200-239 and greater than or equal to 240 mg / dl are considered high and high limits, respectively. HCL-C levels below 40 mg / dl are considered low.

In certain embodiments, it has been identified that individuals need lipid lowering therapy. In certain of these embodiments, it has been identified that individuals need lipid-lowering therapy according to the guidelines established in 2001 by the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 190 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy has an LDL-C level greater than 160 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy has an LDL-C level greater than 130 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 100 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy should keep the LDLC level below 160 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy should keep the LDL-C level below 130 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy should keep the LDL-C level below 100 mg / dl. In certain of these embodiments, the individual must maintain the LDL-C level below 70 mg / dl.

In certain embodiments, procedures for reducing ApoB in an individual are disclosed herein. In certain embodiments, methods for reducing in an individual the levels of lipoproteins containing ApoB are disclosed in this document. In certain embodiments, procedures for reducing the level of LDL-C in an individual are disclosed herein. In certain embodiments, procedures for reducing the level of VLDL-C in an individual are disclosed in this document. In certain embodiments, This document discloses procedures to reduce the level of IDL-C in an individual. In certain embodiments, methods for reducing the level of non-HDL-C in an individual are disclosed herein. In certain embodiments, methods for reducing Lp (a) in an individual are disclosed herein. In certain embodiments, methods for reducing serum triglycerides in an individual are disclosed herein. In certain embodiments, methods for reducing liver triglycerides in an individual are disclosed herein. In certain embodiments, methods for reducing the level of Ox-LDL-C in an individual are disclosed herein. In certain embodiments, methods for reducing small LDL particles in an individual are disclosed herein. In certain embodiments, methods for reducing small VLDL particles in an individual are disclosed herein. In certain embodiments, methods for reducing phospholipids in an individual are disclosed herein. In certain embodiments, methods for reducing oxidized phospholipids in an individual are disclosed herein.

In certain embodiments, methods for reducing the concentration of Ox-LDL-C in a subject are disclosed herein. In certain of said embodiments, the reduction of ApoB, LDL-C, VLDL-C, IDL-C, total cholesterol, non-HDL-C, Lp (a), triglycerides or Ox-LDL-C is independently selected from at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 100%. In certain of said embodiments, the reduction of ApoB, LDL-C, VLDL-C, IDL-C, total cholesterol, non-HDL-C, Lp (a), triglycerides or Ox-LDL-C is independently selected from at least 20%, at least 30%, at least 40%, at least 50%, at least 60% and at least 70%. In certain of said embodiments, the reduction of ApoB, LDL-C, VLDL-C, IDL-C, total cholesterol, non-HDL-C, Lp (a), triglycerides or Ox-LDL-C is independently selected from at least 40%, at least 50%, at least 60%, and at least 70%.

In certain embodiments, methods for raising the concentration of HDL-C in a subject are disclosed herein.

In certain embodiments, the procedures disclosed herein do not reduce HDL-C levels. In certain embodiments, the procedures disclosed herein do not result in the accumulation of lipids in the liver. In certain embodiments, the procedures disclosed herein do not `produce hepatic steatosis.

In certain embodiments, methods for reducing the concentration of ApoB in a subject are disclosed herein while reducing the side effects associated with the treatment. In certain embodiments, a side effect is liver toxicity. In certain embodiments, a side effect is an abnormal liver function. In certain embodiments, a side effect is elevated levels of alanine aminotransferase (ALT). In certain embodiments, a side effect is elevated levels of aspartate aminotransferase (AST).

In certain embodiments, methods of reducing ApoB concentration in a subject that does not reach LDL-C target levels as a result of lipid-lowering therapy are disclosed herein. In certain of said embodiments, a short antisense compound directed to an ApoB nucleic acid is the only lipid lowering agent administered to the subject. In certain of said embodiments, the subject has not complied with the recommended lipid lowering therapy. In certain of said embodiments, a pharmaceutical composition of the disclosure is administered together with a different additional lipid-lowering therapy. In certain of said embodiments, an additional lipid-lowering therapy is LDL apheresis. In certain of said embodiments, an additional lipid-lowering therapy is a statin. In certain of said embodiments, an additional lipid-lowering therapy is ezetimibe.

In certain embodiments, methods for reducing the concentration of ApoB in a subject intolerant to statins are disclosed herein. In certain of said embodiments, the subject exhibits increases in creatine kinase concentration as a result of the administration of statins. In certain of said embodiments, the subject exhibits abnormal liver function as a result of the administration of statins. In certain of said embodiments, the subject exhibits muscle aches as a result of the administration of statins. In certain of said embodiments, the subject has side effects on the central nervous system as a result of the administration of statins. In certain embodiments, the subject has not complied with the recommended statin therapy.

In certain embodiments, methods for lowering triglyceride levels in the liver in a subject are disclosed herein. In certain of said embodiments, the subject has elevated levels of triglycerides in the liver. In certain of said embodiments, the subject has steatohepatitis. In certain of said embodiments, the subject has steatosis. In certain of said embodiments, liver triglyceride levels are measured by magnetic resonance imaging tests.

In certain embodiments, procedures for reducing the risk of coronary heart disease in a subject are disclosed herein. In certain embodiments, the procedures are to slow the progression of atherosclerosis in a subject. In certain of said embodiments, the procedures are to stop the progression of atherosclerosis in a subject. In certain of said embodiments, the procedures are to reduce the size and / or prevalence of atherosclerotic plaques in a subject. In certain embodiments, the procedures reduce a subject's risk of developing atherosclerosis.

In certain embodiments, the disclosed procedures improve the cardiovascular outcome in a subject. In certain of these embodiments, the improved cardiovascular outcome is the reduction of the risk of developing coronary heart disease. In certain of these embodiments, the improved cardiovascular outcome is a reduction in the occurrence of one or more major cardiovascular events, including, but not limited to, death, myocardial infarction, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest and dysrhythmia. handset. In certain of these embodiments, the improved cardiovascular outcome is evidenced by the improvement in the thickness of the intimate mean of the carotid. In certain of said embodiments, the improvement of the thickness of the intimate mean of the carotid is a decrease in thickness. In certain of said embodiments, the improvement of the thickness of the intimate carotid mean is a prevention of an increase in the thickness of the intimate mean.

In certain of said embodiments, a pharmaceutical composition comprising a short antisense compound directed to an ApoB nucleic acid is for use in therapy. In certain embodiments, the therapy is the reduction of LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp (a), serum triglycerides, liver triglycerides, Ox-LDL-C, particles small LDL, small VLDL, phospholipids or oxidized phospholipids in an individual. In certain embodiments, the therapy is the treatment of hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, coronary heart disease, coronary heart disease early, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, hepatic steatosis, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease. In further embodiments, therapy is the reduction of the risk of CPC. In certain, therapy is the prevention of atherosclerosis. In certain embodiments, therapy is the prevention of coronary heart disease.

In certain embodiments, a pharmaceutical composition comprising a short antisense compound targeting an ApoB nucleic acid is used for the preparation of a medicament to reduce levels of LDL-C, ApoB, VLDL-C, IDLC, non-HDL-C , Lp (a), serum triglycerides, liver triglycerides, Ox-LDL-C, small LDL particles, small VLDL, phospholipids or oxidized phospholipids in an individual. In certain embodiments, a pharmaceutical composition comprising a short antisense compound targeting an ApoB nucleic acid is used for the preparation of a medicament to reduce the risk of coronary heart disease. In certain embodiments, a short antisense compound targeting an ApoB nucleic acid is used for the preparation of a medicament for the treatment of hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, history of coronary heart disease, early-onset coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, hepatic steatosis, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

Combination therapies with ApoB

In certain embodiments, one or more pharmaceutical compositions comprising a short antisense compound directed to an ApoB nucleic acid are co-administered with one more different pharmaceutical agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical compositions of the present disclosure. In certain of said embodiments, the one plus pharmaceutical agents are lipid lowering agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat an undesired effect of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are prepared separately.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to an ApoB nucleic acid include lipid lowering agents. In certain of said embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, atorvastatin, simvastatin, rosuvastatin and ezetimibe. In certain of said embodiments, the lipid lowering agent is administered prior to the administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered after administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered at the same time as the pharmaceutical composition of the present disclosure. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is the same as the dose that would be administered if the lipid-lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid lowering agent is less than the dose that would be administered if the lipid lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is greater than the dose that would be administered if the lipid-lowering agent was administered alone.

In certain embodiments, a coadministered lipid lowering agent is an HMG-CoA reductase inhibitor. In certain of said embodiments, the HMG-CoA reductase inhibitor is a statin. In certain of said embodiments, the statin is selected from atorvastatin, simvastatin, pravastatin, fluvastatin and rosuvastatin.

In certain embodiments, a coadministered lipid lowering agent is a cholesterol absorption inhibitor. In certain of said embodiments, the cholesterol absorption inhibitor is ezetimibe.

In certain embodiments, a coadministered lipid-lowering agent is an HMG-CoA reductase inhibitor formulated in conjunction with a cholesterol absorption inhibitor. In certain of said embodiments, the jointly formulated lipid lowering agent is ezetimibe / simvastatin.

In certain embodiments, a co-administered lipid-lowering agent is a microsomal triglyceride transfer protein inhibitor.

In certain embodiments, a co-administered pharmaceutical agent is a bile acid sequestrant. In certain of said embodiments, the bile acid sequestrant is selected from cholestyramine, colestipol and colesevelam.

In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain of said embodiments, nicotinic acid is selected from nicotinic acid immediate release, nicotinic acid extended release and nicotinic acid sustained release.

In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain of said embodiments, the fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate and ciprofibrate.

Other examples of pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound targeting an ApoB nucleic acid include, among others, corticosteroids, including, but not limited to, prednisone; immunoglobulins, including, inter alia intravenous immunoglobulin (IVIG); analgesics (eg, acetaminophen); anti-inflammatory agents, including but not limited to non-steroidal anti-inflammatory drugs (eg, ibuprofen, COX-1 inhibitors and COX-2 inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (eg, biguanides, glucosidase inhibitors, insulins, sulfonylureas and thiazolidendiones); adrenergic modifiers; diuretics; hormones (eg, anabolic steroids, androgens, estrogens, calcitonin, progestin, somatostatin and thyroid hormones); immunomodulators; muscle relaxants; antihistamines, antiosteoporosis agents (eg, bisphosphonates, calcitonin and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; Atlantic poison oak or poison sumac; antibodies; and vaccines.

In certain of said embodiments, a pharmaceutical composition comprising a short antisense compound directed to an ApoB nucleic acid can be administered together with a lipid lowering therapy. In certain of these embodiments, a lipid lowering therapy is a therapeutic lifestyle change. In certain of these embodiments, a lipid-lowering therapy is LDL apheresis.

In one embodiment, the antisense compounds disclosed herein can be used to decrease the level of lipoproteins containing apolipoprotein B in a human subject. As used herein, "lipoprotein containing apolipoprotein B" refers to any lipoprotein that has apolipoprotein B as its protein component and is understood to include LDL, VLDL, IDL, and lipoprotein (a). Each of LDL, VLDL, IDL, and lipoprotein (a) contain an apolipoprotein B molecule, therefore the measurement of serum apolipoprotein B reflects the total number of these lipoproteins. As is known in the art, each of the aforementioned lipoproteins is atherogenic. Therefore, the reduction of one or more serum lipoproteins containing apolipoprotein B may provide a therapeutic benefit to a human subject. Small LDL particles are considered particularly atherogenic with respect to large LDL particles. Therefore, the reduction of small LDL particles can provide a therapeutic benefit to a human subject. Additional lipid parameters can also be determined in a subject. Reduction of the total cholesterol: HDL or LDL: HDL ratio is a clinically desirable improvement in the cholesterol ratio. Similarly, it is clinically desirable to reduce serum triglycerides in humans who exhibit elevated lipid levels.

Other indications of cardiovascular disease that can be measured in a subject include the size of the LDL particle; serum concentration of LDL cholesterol ester; the serum composition of LDL cholesterol ester; the extent of LDL polyunsaturation esters of serum cholesteryl; and serum levels of HDL cholesterol. As used herein, "serum LDL particle size" refers to the classification of serum LDL particle size, which can be very small, small, medium or large, and is usually expressed in g / µmol.

In the context of the present invention, "serum concentration of LDL cholesterol ester" means the amount of cholesterol ester present in the LDL particles and is usually measured in mg / dl. In the context of the present invention, "serum composition of LDL cholesterol ester" is a measure of the percentage of cholesterol esters of saturated, monounsaturated and polyunsaturated fatty acids present in serum LDL particles. "Polyunsaturation of cholesteryl esters in serum LDL" means the percentage of cholesteryl esters of polyunsaturated fatty acids in serum LDL particles.

Those skilled in the art are well aware of procedures for obtaining serum or plasma samples for analysis and procedures for preparing serum samples for analysis. With respect to the determinations of lipoproteins, cholesterol, triglycerides and cholesteryl esters, the terms "serum" and "plasma" are used interchangeably herein.

In another embodiment, the antisense compounds disclosed herein can be used to treat metabolic disorders. A variety of biomarkers can be used to assess metabolic disease. For example, a doctor, or even the patient, can determine blood glucose levels using a commonly available test kit or a blood glucose meter (for example, Ascensia ELITE ™, Ascensia (Bayer), Tarrytown NY, or Accucheck, Roche Diagnostics). The levels of glycated hemoglobin (HbA1c) can also be measured. HbA1c is a stable minor hemoglobin variant formed in vivo by post-translational modification of glucose and contains, mainly, β-chain glycated in NH2-terminal. There is a strong correlation between HbA1c levels and average blood glucose levels during the previous 3 months. Therefore, HbA1c is often seen as "the reference" for measuring sustained blood glucose control (Bunn, H.F. et al., 1978, Science. 200, 21-7). HbA1c can be measured by ion exchange HPLC or by immunoassay, a large quantity of home collection kit and its shipment for the determination of HbA1c is currently available. Fructosamine in

5 serum is another measure of stable glucose control and can be measured by a colorimetric procedure (Cobas Integra, Roche Diagnostics).

Certain short antisense compounds targeting an ApoB nucleic acid

In certain embodiments, the short antisense compounds are directed to an ApoB nucleic acid having the registration number sequence in GENBANK®. NM_000384.1, incorporated herein as SEQ ID 10 No. 1. In certain such embodiments, a short antisense compound directed to SEQ ID No. 1 is at least 90% complementary to SEQ ID No. 1. In certain cases. said embodiments, a short antisense compound directed to SEQ ID No. 1 is at least 95% complementary to SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to SEQ ID No. 1 EN 100% complementary to SEQ ID NO. 1. In certain embodiments, a short antisense compound directed to SEQ ID NO. 1 comprises a nucleotide sequence selected from the sequences.

15 nucleotides indicated in Table 2 and Table 3.

The nucleotide sequence indicated in each SEQ ID NO in Tables 2 and 3 is independent of any modification of a sugar moiety, a monomeric bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The antisense compounds described by the Isis Number (No. Isis) indicate a

20 combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside linkage or a nucleotide base.

Tables 2 and 3 illustrate examples of short antisense compounds directed to SEQ ID NO. 1. Table 2 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 1. Table 3 illustrates short antisense compounds having one or two. erroneous pairing with respect to SEQ ID NO. 1. The column called 25 "capper motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The links

30 internucleosides are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 2: Short antisense compounds directed to SEQ ID No. 1

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372816

263 278 CCGGAGGTGCTTGAAT 3-10-3 MOE 16

372894

264 277 CGGAGGTGCTTGAA 2-10-2 MOE 17

372817

428 443 GAAGCCATACACCTCT 3-10-3 MOE 18

372895

429 442 AAGCCATACACCTC 2-10-2 MOE 19

372818

431 446 GTTGAAGCCATACACC 3-10-3 MOE twenty

372896

432 445 TTGAAGCCATACAC 2-10-2 MOE twenty-one

372819

438 453 CCTCAGGGTTGAAGCC 3-10-3 MOE 22

372897

439 452 CTCAGGGTTGAAGC 2-10-2 MOE 2. 3

372820

443 458 TTTGCCCTCAGGGTTG  3-10-3 MOE 24

372898

444 457 TTGCCCTCAGGGTT 2-10-2 MOE 25

372821

468 483 AGTTCTTGGTTTTCTT 3-10-3 MOE 26

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372899

469 482 GTTCTTGGTTTTCT 2-10-2 MOE 27

372822

587 602 CCTCTTGATGTTCAGG 3-10-3 MOE 28

372900

588 601 CTCTTGATGTTCAG 2-10-2 MOE 29

372823

592 607 ATGCCCCTCTTGATGT 3-10-3 MOE 30

372901

593 606 TGCCCCTCTTGATG 2-10-2 MOE 31

346583

715 728 TGCCACATTGCCCT 3-8-3 MOE 32

346584

716 729 TTGCCACATTGCCC 3-8-3 MOE 33

346585

717 730 GTTGCCACATTGCC 3-8-3 MOE 3. 4

346586

718 731 TGTTGCCACATTGC 3-8-3 MOE 35

346587

719 732 CTGTTGCCACATTG 3-8-3 MOE 36

346588

720 733 TCTGTTGCCACATT 3-8-3 MOE 37

346589

721 734 TTCTGTTGCCACAT 3-8-3 MOE 38

346590

722 735 TTTCTGTTGCCACA  3-8-3 MOE 39

346591

723 736 ATTTCTGTTGCCAC  3-8-3 MOE 40

372824

929 944 GTAGGAGAAAGGCAGG 3-10-3 MOE 41

372902

930 943 TAGGAGAAAGGCAG 2-10-2 MOE 42

372825

1256 1271 GGCTTGTAAAGTGATG 3-10-3 MOE 43

372903

1257 1270 GCTTGTAAAGTGAT 2-10-2 MOE 44

372826

1304 1319 CCACTGGAGGATGTGA 3-10-3 MOE Four. Five

372904

1305 1318 CACTGGAGGATGTG 2-10-2 MOE 46

372829

2135 2150 TTTCAGCATGCTTTCT 3-10-3 MOE 47

372907

2136 2149 TTCAGCATGCTTTC  2-10-2 MOE 48

372832

2774 2789 CATATTTGTCACAAAC  3-10-3 MOE 49

372910

2775 2788 ATATTTGTCACAAA 2-10-2 MOE fifty

372833

2779 2794 ATGCCCATATTTGTCA  3-10-3 MOE 51

37291

2780 2793 TGCCCATATTTGTC  2-10-2 MOE 52

372835

2961 2976 TTTTGGTGGTAGAGAC  3-10-3 MOE 53

372913

2962 2975 TTTGGTGGTAGAGA 2-10-2 MOE 54

346592

3248 3261 TCTGCTTCGCACCT 3-8-3 MOE 55

346593

3249 3262 GTCTGCTTCGCACC 3-8-3 MOE 56

346594

3250 3263 AGTCTGCTTCGCAC 3-8-3 MOE 57

346595

3251 3264 CAGTCTGCTTCGCA 3-8-3 MOE 58

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

346596

3252 3265 TCAGTCTGCTTCGC 3-8-3 MOE 59

346597

3253 3266 CTCAGTCTGCTTCG 3-8-3 MOE 60

346598

3254 3267 CCTCAGTCTGCTTC 3-8-3 MOE 61

346599

3255 3268 GCCTCAGTCTGCTT 3-8-3 MOE 62

346600

3256 3269 AGCCTCAGTCTGCT 3-8-3 MOE 63

372836

3350 3365 AACTCTGAGGATTGTT 3-10-3 MOE 64

372914

3351 3364 ACTCTGAGGATTGT 2-10-2 MOE 65

372837

3355 3370 TCATTAACTCTGAGGA 3-10-3 MOE 66

372915

3356 3369 CATTAACTCTGAGG 2-10-2 MOE 67

372838

3360 3375 ATTCATCATTAACTCT 3-10-3 MOE 68

372916

3361 3374 TTCATCATTAACTC 2-10-2 MOE 69

372839

3409 3424 TTGTTCTGAATGTCCA 3-10-3 MOE 70

387461

3409 3424 TTGTTCTGAATGTCCA 3-10-3 Methyloxy BNA unmodified cytosines in the hollow 70

380147

3409 3424 TTGTTCTGAATGTCCA 3-10-3 Methylene BNA 70

372917

3410 3423 TGTTCTGAATGTCC 2-10-2 MOE 73

372840

3573 3588 CAGATGAGTCCATTTG  3-10-3 MOE 74

372918

3574 3587 AGATGAGTCCATTT 2-10-2 MOE 75

372841

3701 3716 ATCCACAGGGAAATTG 3-10-3 MOE 76

372919

3702 3715 TCCACAGGGAAATT 2-10-2 MOE 77

372843

4219 4234 CAGTTGTACAAGTTGC 3-10-3 MOE 78

372921

4220 4233 AGTTGTACAAGTTG 2-10-2 MOE 79

372844

4301 4316 CACAGAGTCAGCCTTC 3-10-3 MOE 80

372922

4302 4315 ACAGAGTCAGCCTT 2-10-2 MOE 81

372845

4308 4323 GGTCAACCACAGAGTC 3-10-3 MOE 82

372923

4309 4322 GTCAACCACAGAGT  2-10-2 MOE 83

346601

5588 5601 CAGCCACATGCAGC 3-8-3 MOE 84

346602

5589 5602 CCAGCCACATGCAG 3-8-3 MOE 85

346603

5590 5603 ACCAGCCACATGCA 3-8-3 MOE 86

346604

5591 5604 TACCAGCCACATGC 3-8-3 MOE 87

346605

5592 5605 TTACCAGCCACATG 3-8-3 MOE 88

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

346606

5593 5606 GTTACCAGCCACAT  3-8-3 MOE 89

346607

5594 5607 GGTTACCAGCCACA 3-8-3 MOE 90

346608

5595 5608 AGGTTACCAGCCAC 3-8-3 MOE 91

346609

5596 5609 TAGGTTACCAGCCA 3-8-3 MOE 92

372851

5924 5939 AGGTTCTGCTTTCAAC  3-10-3 MOE 93

372929

5925 5938 GGTTCTGCTTTCAA  2-10-2 MOE 94

372854

6664 6679 TACTGATCAAATTGTA 3-10-3 MOE 95

372932

6665 6678 ACTGATCAAATTGT 2-10-2 MOE 96

372855

6908 6923 TTTTTCTTGTATCTGG  3-10-3 MOE 97

372933

6909 6922 TTTTCTTGTATCTG  2-10-2 MOE 98

372856

7190 7205 ATCCATTAAAACCTGG 3-10-3 MOE 99

372934

7191 7204 TCCATTAAAACCTG 2-10-2 MOE 100

372858

7817 7832 ATATTGCTCTGCAAAG 3-10-3 MOE 101

372936

7818 7831 TATTGCTCTGCAAA 2-10-2 MOE 102

346610

7818 7831 TATTGCTCTGCAAA 3-8-3 MOE 102

346611

7819 7832 ATATTGCTCTGCAA 3-8-3 MOE 104

346612

7820 7833 AATATTGCTCTGCA 3-8-3 MOE 105

346613

7821 7834 GAATATTGCTCTGC 3-8-3 MOE 106

346614

7822 7835 AGAATATTGCTCTG 3-8-3 MOE 107

346615

7823 7836 TAGAATATTGCTCT 3-8-3 MOE 108

346616

7824 7837 ATAGAATATTGCTC 3-8-3 MOE 109

346617

7825 7838 GATAGAATATTGCT 3-8-3 MOE 110

346618

7826 7839 GGATAGAATATTGC 3-8-3 MOE 111

372859

7995 8010 ATGGAATCCTCAAATC 3-10-3 MOE 112

372937

7996 8009 TGGAATCCTCAAAT 2-10-2 MOE 113

372861

8336 8351 GAATTCTGGTATGTGA 3-10-3 MOE 114

372939

8337 8350 AATTCTGGTATGTG 2-10-2 MOE 115

372862

8341 8356 AGCTGGAATTCTGGTA 3-10-3 MOE 116

372940

8342 8355 GCTGGAATTCTGGT 2-10-2 MOE 117

372863

8539 8554 TGAAAATCAAAATTGA 3-10-3 MOE 118

372941

8540 8553 GAAAATCAAAATTG 2-10-2 MOE 119

372871

9344 9359 AAACAGTGCATAGTTA 3-10-3 MOE 120

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372949

9345 9358 AACAGTGCATAGTT 2-10-2 MOE 121

372872

9515 9530 TTCAGGAATTGTTAAA 3-10-3 MOE 122

372950

9516 9529 TCAGGAATTGTTAA 2-10-2 MOE 123

372875

9794 9809 TTTTGTTTCATTATAG  3-10-3 MOE 124

372953

9795 9808 TTTGTTTCATTATA  2-10-2 MOE 125

372877

10157 10172 GATGACACTTGATTTA  3-10-3 MOE 126

372955

10158 10171 ATGACACTTGATTT 2-10-2 MOE 127

372878

10161 10176 GTGTGATGACACTTGA 3-10-3- MOE 128

372956

10162 10175 TGTGATGACACTTG 2-10-2 MOE 129

372879

10167 10182 TATTCAGTGTGATGAC 3-10-3 MOE 130

372957

10168 10181 ATTCAGTGTGATGA 2-10-2 MOE 131

372880

10172 10187 ATTGGTATTCAGTGTG 3-10-3 MOE 132

372958

10173 10186 TTGGTATTCAGTGT 2-10-2 MOE 133

346619

10838 10851 CCTCTAGCTGTAAG 3-8-3 MOE 134

346620

10839 10852 CCCTCTAGCTGTAA 3-8-3 MOE 135

346621

10840 10853 GCCCTCTAGCTGTA 3-8-3 MOE 136

346622

10841 10854 GGCCCTCTAGCTGT 3-8-3 MOE 137

346623

10842 10855 AGGCCCTCTAGCTG 3-8-3 MOE 138

346624

10843 10856 GAGGCCCTCTAGCT 3-8-3 MOE 139

346625

10844 10857 AGAGGCCCTCTAGC 3-8-3 MOE 140

346626

10845 10858 AAGAGGCCCTCTAG 3-8-3 MOE 141

346627

10846 10859 AAAGAGGCCCTCTA 3-8-3 MOE 142

372890

13689 13704 GAATGGACAGGTCAAT 3-10-3 MOE 143

372968

13690 13703 AATGGACAGGTCAA 2-10-2 MOE 144

372891

13694 13709 GTTTTGAATGGACAGG  3-10-3 MOE 145

372969

13695 13708 TTTTGAATGGACAG  2-10-2 MOE 146

372892

13699 13714 TGGTAGTTTTGAATGG  3-10-3 MOE 147

372970

13700 13713 GGTAGTTTTGAATG  2-10-2 MOE 148

346628

13907 13920 TCACTGTATGGTTT 3-8-3 MOE 149

346629

13908 13921 CTCACTGTATGGTT 3-8-3 MOE 150

346630

13909 13922 GCTCACTGTATGGT 3-8-3 MOE 151

346631

13910 13923 GGCTCACTGTATGG 3-8-3 MOE 152

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

346632

13911 13924 TGGCTCACTGTATG 3-8-3 MOE 153

346633

13912 13925 CTGGCTCACTGTAT 3-8-3 MOE 154

346634

13913 13926 GCTGGCTCACTGTA 3-8-3 MOE 155

346635

13914 13927 GGCTGGCTCACTGT 3-8-3 MOE 156

346636

13915 13928 AGGCTGGCTCACTG 3-8-3 MOE 157

346637

13963 13976 CAGGTCCAGTTCAT 3-8-3 MOE 158

346638

13964 13977 GCAGGTCCAGTTCA 3-8-3 MOE 159

346639

13965 13978 TGCAGGTCCAGTTC 3-8-3 MOE 160

346640

13966 13979 GTGCAGGTCCAGTT 3-8-3 MOE 161

346641

13967 13980 GGTGCAGGTCCAGT 3-8-3 MOE 162

346642

13968 13981 TGGTGCAGGTCCAG 3-8-3 MOE 163

346643

13969 13982 TTGGTGCAGGTCCA 3-8-3 MOE 164

346644

13970 13983 TTTGGTGCAGGTCC 3-8-3 MOE 165

346645

13971 13984 CTTTGGTGCAGGTC 3-8-3 MOE 166

346646

14051 14064 TAACTCAGATCCTG 3-8-3 MOE 167

346647

14052 14065 ATAACTCAGATCCT 3-8-3 MOE 168

346648

14053 14066 AATAACTCAGATCC 3-8-3 MOE 169

346649

14054 14067 AAATAACTCAGATC 3-8-3 MOE 170

346650

14055 14068 AAAATAACTCAGAT 3-8-3 MOE 171

346651

14056 14069 CAAAATAACTCAGA 3-8-3 MOE 172

346652

14057 14070 GCAAAATAACTCAG 3-8-3 MOE 173

346653

14058 14071 AGCAAAATAACTCA 3-8-3 MOE 174

346654

14059 14072 TAGCAAAATAACTC 3-8-3 MOE 175

Table 3: Short antisense compounds directed to SEQ ID No. 1 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372894

771 784 CGGAGGTGCTTGAA 2-10-2 MOE 17

372905

1111 1124 CAGGGCCTGGAGAG 2-10-2 MOE 176

346628

1493 1506 TCACTGTATGGTTT 3-8-3 MOE 149

372828

2006 2021 TCTGAAGTCCATGATC 3-10-3 MOE 177

372906

2007 2020 CTGAAGTCCATGAT 2-10-2 MOE 178

372830

2382 2397 TGGGCATGATTCCATT 3-10-3 MOE 179

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372908

2383 2396 GGGCATGATTCCAT 2-10-2 MOE 180

346616

3162 3175 ATAGAATATTGCTC 3-8-3 MOE 109

346617

3163 3176 GATAGAATATTGCT 3-8-3 MOE 110

372929

3513 3526 GGTTCTGCTTTCAA  2-10-2 MOE 94

372946

3800 3813 TGGAGCCCACGTGC 2-10-2 MOE 181

372904

4040 4053 CACTGGAGGATGTG 2-10-2 MOE 46

372842

4084 4099 TTGAAGTTGAGGGCTG 3-10-3 MOE 182

372920

4085 4098 TGAAGTTGAGGGCT 2-10-2 MOE 183

346586

4778 4791 TGTTGCCACATTGC 3-8-3 MOE 35

372847

5030 5045 ACCAGTATTAATTTTG  3-10-3 MOE 184

372925

5031 5044 CCAGTATTAATTTT 2-10-2 MOE 185

372848

5192 5207 GTGTTCTTTGAAGCGG  3-10-3 MOE 186

372926

5193 5206 TGTTCTTTGAAGCG  2-10-2 MOE 187

372953

5625 5638 TTTGTTTCATTATA  2-10-2 MOE 125

372935

7585 7598 AGTTACTTTGGTGT  2-10-2 MOE 188

372860

8255 8270 TGGTACATGGAAGTCT 3-10-3 MOE 189

372938

8256 8269 GGTACATGGAAGTC 2-10-2 MOE 190

391260

8256 8269 GGTACATGGAAGTC 2-10-2 MOE 190

392068

8256 8269 GGTACATGGAAGTC 2-10-2 MOE 190

387462

8256 8269 GGTACATGGAAGTC 2-10-2 Methylene BNA 190

391872

8256 8269 GGTACATGGAAGTC 1-1-10-2 2 ’- (butylacetomide) -palmitamide Methylene oxy BNA / Methylene oxy BNA Unmodified cytosines 190

380148

8256 8269 GGTACATGGAAGTC 2-10-2 Methylene BNA 190

391871

8256 8269 GGTACATGGAAGTC 1-1-10-2 2 ’- (butylacetomide) -palmitamide / MOE / MOE Unmodified cytosines in the hole 190

391755

8256 8269 GGTACATGGAAGTC 2-10-2 ENA mC only on the wing 190

398296

8256 8269 GGTACATGGAAGTC 2-10-2 (6’S) -6’-methyl-methyloxy BNA Unmodified cytosines 190

372942

8455 8468 TCCATGCCATATGT 2-10-2 MOE 200

372865

8888 8903 CCCTGAAGAAGTCCAT  3-10-3 MOE 201

372943

8889 8902 CCTGAAGAAGTCCA 2-10-2 MOE 202

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372866

8908 8923 GCCCAGTTCCATGACC 3-10-3 MOE 203

372944

8909 8922 CCCAGTTCCATGAC 2-10-2 MOE 204

372867

9058 9073 TTGAGGAAGCCAGATT 3-10-3 MOE 205

372945

9059 9072 TGAGGAAGCCAGAT 2-10-2 MOE 206

372870

9261 9276 TGGATGCAGTAATCTC 3-10-3 MOE 207

372948

9262 9275 GGATGCAGTAATCT 2-10-2 MOE 208

372881

10185 10200 TATAAAGTCCAGCATT 3-10-3 MOE 209

372959

10186 10199 ATAAAGTCCAGCAT  2-10-2 MOE 210

372882

10445 10460 AAGTTCCTGCTTGAAG 3-10-3 MOE 211

372960

10446 10459 AGTTCCTGCTTGAA 2-10-2 MOE 212

372964

11451 11464 AATGGTGAAGTACT  2-10-2 MOE 213

346612

13459 13472 AATATTGCTCTGCA 3-8-3 MOE 105

346613

13460 13473 GAATATTGCTCTGC 3-8-3 MOE 106

In certain embodiments, a target region is nucleotides 263-278 of SEQ ID No. 1. In certain such embodiments, short antisense compounds directed to nucleotides 263-278 of SEQ ID No. 1 comprise a nucleotide sequence selected from SEQ ID NOS 16 or 17. In certain of said embodiments, a compound

Short antisense targeting nucleotides 263-278 of SEQ ID NO. 1 is selected from Isis No. 372816 or 372894.

In certain embodiments, a target region is nucleotides 428-483 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 428-483 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID Nos. 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27. In certain such embodiments, a short antisense compound directed to nucleotides 428-483 of SEQ ID NO: 1 is selected of the Nº

10 Isis 372817, 372895, 372818, 372896, 372819, 372897, 372820, 372898, 372821, or 372899.

In certain embodiments, a target region is nucleotides 428-458 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 428-458 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 18, 19, 20, 21, 22, 23, 24 or 25. In certain such embodiments, a short antisense compound directed to nucleotides 428-458 of SEQ ID No. 1 is selected from No.

15 Isis 372817, 372895, 372818, 372896, 372819, 372897, 372820 or 372898.

In certain embodiments, a target region is nucleotides 468-483 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 468-483 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 26 or 27. In certain such embodiments, a short antisense compound directed to nucleotides 468-483 of SEQ ID N ° 1 is selected from Isis No. 372821 or 372899.

In certain embodiments, a target region is nucleotides 587-607 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 587-607 of SEQ ID No. 1 comprises a selected nucleotide sequence. of SEQ ID NOS 28, 29, 30, or 31. In certain such embodiments, a short antisense compound directed to nucleotides 587-607 of SEQ ID N ° 1 is selected from Isis No. 372822, 372900, 372823 or 372901.

In certain embodiments, a target region is nucleotides 715-736 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 715-736 of SEQ ID No. 1 comprises a selected nucleotide sequence. of SEQ ID Nos. 32, 33, 34, 35, 36, 37, 38, 39 or 40. In certain such embodiments, a short antisense compound directed to nucleotides 715-736 of SEQ ID NO: 1 is selected from No. Isis 346583, 346584, 346585, 346586, 346587, 346588, 346589, 346590 or 346591.

In certain embodiments, a target region is nucleotides 929-944 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 929-944 of SEQ ID NO: 1 comprises a selected nucleotide sequence. of SEQ ID Nos. 41 or 42. In certain such embodiments, a short antisense compound directed to nucleotides 929-944 of SEQ ID NO: 1 is selected from Isis No. 372824 or 372902.

In certain embodiments, a target region is nucleotides 1256-1319 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 1256-1319 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NOS 43 44, 45, or 46. In certain such embodiments, a short antisense compound directed to nucleotides 1256-1319 of SEQ ID N ° 1 is selected from Isis No. 372825, 372903, 372826 or 372904.

In certain embodiments, a target region is nucleotides 1256-1271 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 1256-1271 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 43 or 44. In certain such embodiments, a short antisense compound directed to nucleotides 1256-1271 of SEQ ID NO. 1 is selected from Isis No. 372825 or 372903.

In certain embodiments, a target region is nucleotides 1304-1319 of SEQ ID No. 1. In certain of said embodiments, a short antisense compound directed to nucleotides 1304-1319 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID No. 45 or 46. In certain such embodiments, a short antisense compound directed to nucleotides 1304-1319 of SEQ ID No. 1 is selected from Isis No. 372826 or 372904.

In certain embodiments, a target region is nucleotides 2135-2150 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 2135-2150 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 47 or 48. In certain such embodiments, a short antisense compound directed to nucleotides 2135-2150 of SEQ ID NO. 1 is selected from Isis No. 372829 or 372907.

In certain embodiments, a target region is nucleotides 2774-2794 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 2774-2794 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID No. 49 50, 51, or 52. In certain such embodiments, a short antisense compound directed to nucleotides 2774-2794 of SEQ ID No. 1 is selected from No. Isis 372832, 372910, 372833 or 372911.

In certain embodiments, a target region is nucleotides 2961-2976 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 2961-2976 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 53 or 54. In certain of said embodiments, a short antisense compound directed to nucleotides 2961-2976 of SEQ ID NO. 1 is selected from Isis No. 372835 or 372913.

In certain embodiments, a target region is nucleotides 3248-3269 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 3248-3269 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 55, 56, 57, 58, 59, 60, 61, 62 or 63. In certain such embodiments, a short antisense compound directed to nucleotides 3248-3269 of SEQ ID NO. 1 is selected from No. Isis 346592, 346593, 346594, 346595, 346596, 346597, 346598, 346599 or 346600.

In certain embodiments, a target region is nucleotides 3350-3375 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 3350-3375 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID Nos. 64 65, 66, 67, 68 or 69. In certain such embodiments, a short antisense compound directed to nucleotides 3350-3375 of SEQ ID No. 1 is selected from Isis No. 372836, 372914, 372837, 372915, 372838, or 372916.

In certain embodiments, a target region is nucleotides 3409-3424 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 3409-3424 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 70 or 73. In certain such embodiments, a short antisense compound directed to nucleotides 3409-3424 of SEQ ID N ° 1 is selected from Isis No. 372839, 387461, 380147 or 372917.

In certain embodiments, a target region is nucleotides 3573-3588 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 3573-3588 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 74 or 75. In certain such embodiments, a short antisense compound directed to nucleotides 3573-3588 of SEQ ID NO. 1 is selected from Isis No. 372840 or 372918.

In certain embodiments, a target region is nucleotides 3701-3716 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 3701-3716 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID No. 76 or 77. In certain such embodiments, a short antisense compound directed to nucleotides 3701-3716 of SEQ ID No. 1 is selected from Isis No. 372841 or 372919.

In certain embodiments, a target region is nucleotides 4219-4234 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 4219-4234 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 78 or 79. In certain of said embodiments, a short antisense compound directed to nucleotides 4219-4234 of SEQ ID NO. 1 is selected from Isis No. 372843 or 372921.

In certain embodiments, a target region is nucleotides 4301-4323 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 4301-4323 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID No. 80 81, 82, or 83. In certain embodiments, a short antisense compound directed to nucleotides 4301-4323 of SEQ ID No. 1 is selected from No. Isis 372844, 372922, 372845 or 372923.

In certain embodiments, a target region is nucleotides 5588-5609 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 5588-5609 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS 84, 85, 86, 87, 88, 89, 90, 91 or 92. In certain such embodiments, a short antisense compound directed to nucleotides 5588-5609 of SEQ ID N ° 1 is selected from No. Isis 346601, 346602, 346603, 346604, 346605, 346606, 346607, 346608 or 346609.

In certain embodiments, a target region is nucleotides 5924-5939 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 5924-5939 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 93 or 94. In certain such embodiments, a short antisense compound directed to nucleotides 5924-5939 of SEQ ID NO. 1 is selected from Isis No. 372851 or 372929.

In certain embodiments, a target region is nucleotides 6664-6679 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 6664-6679 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS 95 or 96. In certain such embodiments, a short antisense compound directed to nucleotides 6664-6679 of SEQ ID N ° 1 is selected from Isis No. 372854 or 372932.

In certain embodiments, a target region is nucleotides 6908-6923 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 6908-6923 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NO. 97 or 98. In certain of said embodiments, a short antisense compound directed to nucleotides 6908-6923 of SEQ ID NO. 1 is selected from Isis No. 372855 or 372933.

In certain embodiments, a target region is nucleotides 7190-7205 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 7190-7205 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 99 or 100. In certain such embodiments, a short antisense compound directed to nucleotides 7190-7205 of SEQ ID NO. 1 is selected from Isis No. 372856 or 372934.

In certain embodiments, a target region is nucleotides 7817-7839 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 7817-7839 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID Nos. 101, 102, 104, 105, 106, 107, 108, 109, 110, or 111. In certain such embodiments, a short antisense compound directed to nucleotides 7817-7839 of SEQ ID NO: 1 is selected No. Isis 372858, 372936, 346610, 346611, 346612, 346613, 346614, 346615, 346616, 346617 or 346618.

In certain embodiments, a target region is nucleotides 7995-8010 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 7995-8010 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID Nos. 112 or 113. In certain such embodiments, a short antisense compound directed to nucleotides 7995-8010 of SEQ ID NO: 1 is selected from Isis No. 372859 or 372937.

In certain embodiments, a target region is nucleotides 8336-8356 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 8336-8356 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID Nos. 114 115, 116, or 117. In certain such embodiments, a short antisense compound directed to nucleotides 8336-8356 of SEQ ID No. 1 is selected from Isis No. 372861, 372939, 372862 or 372940.

In certain embodiments, a target region is nucleotides 8539-8554 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 8539-8554 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NOS 118 or 119. In certain such embodiments, a short antisense compound directed to nucleotides 8539-8554 of SEQ ID N ° 1 is selected from Isis No. 372863 or 372941.

In certain embodiments, a target region is nucleotides 9344-9359 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 9344-9359 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 120 or 121. In certain such embodiments, a short antisense compound directed to nucleotides 9344-9359 of SEQ ID N ° 1 is selected from Isis No. 372871 or 372949.

In certain embodiments, a target region is nucleotides 9515-9530 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 9515-9530 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS. 122 or 123. In certain such embodiments, a short antisense compound directed to nucleotides 9515-9530 of SEQ ID NO. 1 is selected from Isis No. 372872 or 372950.

In certain embodiments, a target region is nucleotides 9794-9809 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 9794-9809 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NO. 124 or 125. In certain such embodiments, a short antisense compound directed to nucleotides 9794-9809 of SEQ ID NO. 1 is selected from Isis No. 372875 or 372953.

In certain embodiments, a target region is nucleotides 10157-10187 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 10157-10187 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS 126, 127, 128, 129, 130, 131, 132 or 133. In certain such embodiments, a short antisense compound directed to nucleotides 10157-10187 of SEQ ID N ° 1 is selected from Isis No. 372877 , 372955, 372878, 372956, 372879, 372957, 372880 or 372958.

In certain embodiments, a target region is nucleotides 10838-10859 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 10838-10859 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NOS 134, 135, 136, 137, 138, 139, 140, 141 or 142. In certain such embodiments, a short antisense compound directed to nucleotides 10838-10859 of SEQ ID N ° 1 is selected from No. Isis 346619, 346620, 346621, 346622, 346623, 346624, 346625, 346626 or 346627.

In certain embodiments, a target region is nucleotides 13689-13714 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 13689-13714 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NOS 143 144, 145, 146, 147 or 148. In certain such embodiments, a short antisense compound directed to nucleotides 13689-13714 of SEQ ID N ° 1 is selected from Isis No. 372890, 372968, 372891, 372969, 372892, or 372970.

In certain embodiments, a target region is nucleotides 13907-13928 of SEQ ID NO. 1. In certain such embodiments, a short antisense compound directed to nucleotides 13907-13928 of SEQ ID NO: 1 comprises a nucleotide sequence selected from SEQ ID NOS 149, 150, 151, 152, 153, 154, 155, 156 or 157. In certain such embodiments, a short antisense compound directed to nucleotides 13907-13928 of SEQ ID N ° 1 is selected from No. Isis 346628, 346629, 346630, 346631, 346632, 346633, 346634, 346635 or 346636.

In certain embodiments, a target region is nucleotides 13963-13984 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 13963-13984 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS 158, 159, 160, 161, 162, 163, 164, 165 or 166. In certain such embodiments, a short antisense compound directed to nucleotides 13963-13984 of SEQ ID N ° 1 is selected from No. Isis 346637, 346638, 346639, 346640, 346641, 346642, 346643, 346644 or 346645.

In certain embodiments, a target region is nucleotides 14051-14072 of SEQ ID No. 1. In certain such embodiments, a short antisense compound directed to nucleotides 14051-14072 of SEQ ID No. 1 comprises a nucleotide sequence selected from SEQ ID NOS 167, 168, 169, 170, 171, 172, 173, 174 or 175. In certain such embodiments, a short antisense compound directed to nucleotides 14051-14072 of SEQ ID N ° 1 is selected from No. Isis 346646, 346647, 346648, 346649, 346650, 346651, 346652, 346653 or 346654.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are short captamers. In certain of said embodiments, short catheters directed to an ApoB nucleic acid comprise at least one high affinity modification on one or more wings of the compound. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from -L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-menyloxy (4'-CH2-O-2') BNA, ethylene (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid have a monomer length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of ApoB are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting an ApoB nucleic acid, wherein the short antisense compound targeting an ApoB nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating ApoB expression using one or more short antisense compounds targeting an ApoB nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 8 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 9 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 10 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 11 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 12 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 13 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 14 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 15 monomers in length. In certain embodiments, ApoB modulation methods comprise the use of a short antisense compound directed to an ApoB nucleic acid that is 16 monomers in length.

In certain embodiments, methods of modulating ApoB expression comprise the use of a short antisense compound targeting an ApoB nucleic acid comprising 9 to 15 monomers. In certain embodiments, methods of modulating ApoB expression comprise the use of a short antisense compound targeting an ApoB nucleic acid comprising 10 to 15 monomers. In certain embodiments, methods of modulating ApoB expression comprise the use of a short antisense compound targeting an ApoB nucleic acid comprising 12 to 14 monomers. In certain embodiments, methods of modulating ApoB expression comprise the use of a short antisense compound targeting an ApoB nucleic acid comprising 12 or 14 nucleotides or nucleosides.

In certain embodiments, short antisense compounds targeting an ApoB nucleic acid may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting an ApoB nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 28-2, 1-8-1, 3-6- 3 or 1-6-1, more preferably 1-10-1, 2-10-2, 3-10-3 and 1-9-2

2. SGLT-2

Sodium-dependent glucose transporter 2 (SGLT-2) is expressed in the epithelial cells of the proximal tubules of the kidney and works by reabsorbing glucose and preventing the loss of glucose in the urine. For the human genome, SGLT-2 is a member of a family of 11 members of sodium substrate cotransporters. Many of these family members share sequence homology, for example SGLT-1 shares approximately 59% sequence identity with SGLT-2 and approximately 70% sequence identity with SGLT-3. SGLT-1 is a glucose transporter found in the heart and the CNS. SGLT-3 is a glucose sensitive sodium channel in the small intestine. The separate safety patterns for these SGLTs are a point of distinction between homologous family members. (Handlon, AL, Expert Opin. Ther. Patents (2005) 15 (11): 15321540; Kanai et al., J. Clin. Invest., 1994, 93, 397-404; Wells et al., Am. J. Physiol, Endocrinol, Metab., 1992, 263, F459465).

In studies of human SGLT2 injected into xenopus oocytes it was shown that this protein participates in the sodium-dependent transport of D-glucose and alpha-methyl-D-glucopyranoside (alpha-MeGlc; a glucose analogue) with a value of Km 1.6 mM for alpha-MeGlc and a coupling ratio between sodium and glucose of 1: 1 (Kanai et al., J. Clin. Invest., 1994, 93, 397-404; You et al., J. Biol. Chem., 1995, 270, 29365-29371). This transport activity was suppressed by floricin, a plant glycoside that binds to the glucose site of SGLT, but is not transported and, therefore, inhibits the action of SGLT (You et al., J. Biol. Chem. , 1995, 270, 29365-29371).

Diabetes is a disorder characterized by hyperglycemia due to a deficient action of insulin. Chronic hyperglycemia is an important risk factor for complications associated with diabetes, including heart disease, retinopathy, nephropathy and neuropathy. Since the kidneys play a fundamental role in regulating plasma glucose levels, renal glucose transporters are becoming attractive pharmacological targets (Wright, Am. J. Physiol. Renal Physiol., 2001, 280, F10- 18). Diabetic nephropathy is the most common cause of terminal nephropathy that develops in many patients with diabetes. Glucotoxicity, which is the result of long-term hyperglycemia, induces tissue-dependent insulin resistance in diabetic patients (Nawano et al., Am. J. Physiol. Endocrinol. Metab., 2000, 278, E535-543) .

Definitions

"Sodium dependent glucose transporter 2" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound. In general, sodium-dependent glucose transporter 2 is called SGLT2, but it can also be referred to as SLC5A2; sodium-glucose transporter 2; low-affinity sodium-glucose cotransporter; sodium-glucose cotransporter, renal; solute transporter family 5 (sodium / glucose cotransporter), member 2; SL52.

"SGLT2 nucleic acid" means any nucleic acid encoding SGLT2. For example, in certain embodiments, an SGLT2 nucleic acid includes, without limitation, a DNA sequence encoding SGLT2, an RNA sequence transcribed from DNA encoding SGLT2, and an mRNA sequence encoding SGLT2. "SGLT2 mRNA" means an mRNA that encodes an SGLT2 protein.

Therapeutic indications

In certain embodiments, short antisense compounds are used to modulate the expression of SGLT-2 and related proteins. In certain embodiments, said modulation is achieved by providing short antisense compounds that hybridize with one or more target nucleic acid molecules encoding SGLT-2, including, but not limited to, SGLT2, SL52, SLCSA2, sodium-glucose cotransporter, sodium cotransporter- low affinity renal glucose, sodium-glucose cotransporter 2 and sodium / glucose co-transporter member 2 of the family of solute transporters. Methods of treatment of diseases and metabolic and / or cardiovascular disorders as described herein are also disclosed. In certain embodiments, short antisense compounds that inhibit SOLT2 expression are used in procedures for reducing blood glucose levels in an animal and procedures for delaying or preventing the onset of type 2 diabetes. Such procedures comprise administering a therapeutically or prophylactically effective amount of one or more of the compounds of the disclosure to the animal that the treatment may need. The one or more of the compounds may be a short antisense compound directed to a nucleic acid encoding SGLT2. This document discloses methods of enhancing the inhibition of SGLT2 expression in renal cells or renal tissues, which comprises contacting the cells or tissues with one or more of the compounds of the disclosure, such as short antisense compounds directed to a nucleic acid encoding SGLT2.

Although certain compounds, compositions and procedures have been described with specificity according to certain embodiments, the following examples only serve to illustrate the compounds of the disclosure and are not intended to limit it.

In certain embodiments, short antisense compounds are chimeric oligomeric compounds having mixed skeletons of phosphorothioate and phosphodiester. Certain short mixed skeleton antisense compounds have a central recess comprising at least 5 contiguous 2'-deoxy nucleosides flanked by two wings, each of which comprises at least one 2'-O-methoxyethyl nucleoside. In certain embodiments, the internucleoside bonds of the mixed skeleton compounds are phosphorothioate bonds in the hollow and phosphodiester bonds in the two wings. In certain embodiments, the mixed skeleton compounds have phosphorothioate bonds on the wings, except for a phosphodiester bond at one or both 5 ’and 3’ ends of the oligonucleotide. In certain embodiments, the short antisense compounds targeting SGLT2 have a motif (wing-deoxy-wing) selected from 3-10-3, 2-10-3, 2-10-2, 1-10-1,1- 10-2, 28-2, 1-9-2, 1-8-1, 3-6-3 or 1-6-1. In certain embodiments, short antisense compounds targeting SGLT2 have a motif (wing-deoxy-wing) selected from 1-10-1, 1-10-2, 2-8-2, 1-9-2, 1- 8-1, 3-6-3 or 1-6-1.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid and having a mixed skeleton are efficiently released into the kidney. In certain embodiments, administration of short antisense compounds directed to an SGLT2 nucleic acid and having a mixed skeleton results in modulation of kidney gene expression in the kidney. In certain of said embodiments, there is little or no renal toxicity. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid and having a mixed skeleton are more potent in reducing SGLT-2 mRNA and have a faster onset compared to a short antisense compound that does not have a mixed skeleton but, otherwise, be identical. In certain of said embodiments, said increase in potency and / or lower toxicity is in mouse and / or rat. In certain of said embodiments, said increase in potency and / or less toxicity is in a human being.

By way of example, and for illustrative purposes only, ISIS 145733, which comprises uniform phosphorothioate bonds, and ISIS 257016, which comprises phosphodiester bond on the wings and phosphorothioate bonds in the hollow are otherwise identical. Both comprise the sequence GAAGTAGCCACCAACTGTGC (SEQ ID No. 1572). Both oligonucleotides further comprise a gap consisting of ten 2’-deoxynucleotides, flanked on each side by “2’methoxyethyl (2’-MOE) nucleotides of five nucleotides. All citidine residues are 5-methylcytidines. The mixed skeleton compound ISIS 257016 was approximately 50 times more potent in reducing the mRNA of SGLT-2 compared to the non-mixed parental compound, ISIS 145733 (see EXAMPLE 9)

Pharmacokinetic studies of a certain mixed skeleton compound ISIS 257016 indicate that, in certain embodiments, the compound acts as a prodrug that is metabolized to a 12-nucleotide base pharmacophore. Studies with ISIS 370717, a short antisense compound of 12 nucleotide bases corresponding to ISIS 257016, show that the compound has a pharmacological profile similar to ISIS 257016, but with a faster onset of action. ISIS 370717 is an antisense oligonucleotide of 12 nucleotide bases directed to SGLT-2, which comprises the sequence TAGCCACCAACT (SEQ ID No. 1554), which also comprises a gap consisting of a ten 2'-deoxynucleotides, flanked at both ends by wings of a nucleotide. The wings are composed of 2’-methoxyethyl (2’MOE) nucleotides. All citidine residues are 5-methylcytidines. The internucleoside bonds are phosphorothioate (P = S) along the oligonucleotide. The similarity of the pharmacological activity of ISIS 257016 and ISIS 370717 supports the pharmacokinetic studies that indicate that ISIS 257016 was a prodrug that has a 12 nucleotide pharmacophore (see EXAMPLE 10). In addition, studies with stabilized versions (with hoods at the ends) of ISIS 257016 show a spectacular loss of activity.

In certain embodiments, short antisense compounds comprising 2 'MOE monomers in the wings are efficiently released in the kidney and treatment with said compounds results in efficient modulation of expression of a target gene in the kidney without liver toxicity. or renal Here, it is also shown that, in certain embodiments, short antisense compounds are more potent in the reduction of SGLT-2 mRNA and have a faster onset compared to parental oligonucleotides targeting SGLT-2 mRNA in mouse and rat This document shows 2’MOE shortmeros in the hole to improve potency and bioavailability above parental compounds.

By way of example, and for illustrative purposes only, studies with ISIS 370717 reveal a significantly greater accumulation of the short antisense compound in renal tissue (approximately 500 micrograms per gram of tissue) compared to the longer parent. In addition, the SGLT-2 mRNA was reduced by more than 80% over controls (see EXAMPLE 11). 1-10-1 ISIS 370717 was used as a template to make oligos related to the sequence with various motifs. Studies in which variations in the wing, gap and total length around the oligonucleotide of 12 ISIS 370717 units can be seen in EXAMPLE 12. Certain motifs evaluated included 110-1, 2-8-2, 1 -8-1, 3-6-3, and 1-6-1 (see Table 60 in EXAMPLE 12). The compounds were analyzed according to their effect on the SGLT2 RNM levels. All motifs inhibited the expression of SGLT2 in vivo in a dose-dependent manner. It was found that 1-10-1, 2-8-2 and 1-8-1 cathamers were particularly potent. SGLT-2 mRNA was reduced by more than 80% over controls using these motifs.

In certain embodiments, the disclosure provides short antisense compounds targeting an SGLT2 nucleic acid and having a motif selected from: 1-10-1 and 1-10-2 MOE. (See Table 62 in EXAMPLE 13). Certain of these compounds were analyzed according to their effect on the levels of SGLT2 mRNA in rat. The results in Table 63 illustrate that 1-10-1 and 1-10-2 MOE cathamers inhibit the expression of SGLT2 in vivo in a dose-dependent manner and a reduction of more than 80% mRNA was achieved. SGLT-2

Certain additional 1-10-1 and 2-8-2 MOE catheters were evaluated in in vivo mouse and rat models (see, for example, EXAMPLE 14 and 15). With many of the 1-10-1 and 2-8-2 MOE cathamers, a greater than 80% reduction in SGLT-2 mRNA was achieved at relatively low oligo concentrations and in the absence of toxic effects.

In another non-limiting example, the effect of ISIS 388625 on SGLT2 mRNA levels in dogs was also analyzed. Studies in dogs illustrate that an inhibition of more than 80% of SGLT2 expression can be achieved at a dose of 1 mg / kg / week. An even greater inhibition can be achieved at slightly higher doses. It was also shown that the administration of ISIS 388625 improved glucose tolerance. Maximum plasma glucose levels decreased by more than 50% on average and the subsequent decrease in glucose was reduced compared to saline controls in a conventional glucose tolerance test (see EXAMPLE 17). Also, in a rat diabetes model, short antisense compounds were shown to significantly decrease plasma glucose and HbA1C levels over time, compared to animals treated with PBS and with control (see Example 16).

In animals of all studies toxicity was also evaluated. For example, total body weight, liver, spleen and kidney weight were evaluated. Significant changes in the weight of the liver, spleen or body may indicate that a specific compound produces toxic effects. It was found that all changes were within the margin of error. No significant changes in body weight were observed during treatment or at the end of the study. Nor were significant changes in liver or spleen weight observed.

Certain short antisense compounds targeting an SGLT2 nucleic acid

In certain embodiments, the short antisense compounds are directed to an SGLT2 nucleic acid having the registration number sequence in GENBANK® NM_003041.1, incorporated herein as SEQ ID NO.

2.

 In certain of said embodiments, a short antisense compound directed to SEQ ID No. 3 is at least 90% complementary to SEQ ID No. 3. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 3 is at minus 95% complementary to SEQ ID NO.

3.

 In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 3 IS 100% complementary to SEQ ID NO. 1. In certain embodiments, a short antisense compound directed to SEQ ID NO. 3 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Tables 4 and 5.

The nucleotide sequence indicated in each SEQ ID NO in Tables 4 and 5 is independent of any modification of a sugar moiety, a monomeric bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

Tables 4 and 5 illustrate examples of short antisense compounds directed to SEQ ID NO. 3. Table 4 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 3. Table 5 illustrates short antisense compounds having one or two. erroneous pairing with respect to SEQ ID NO. 3. The column called "catheter motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 4: Short antisense compounds directed to SEQ ID No. 3

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

379684

84 95 TGTCAGCAGGAT 1-10-1 MOE 214

405193

113 124 CAGCAGGAAATA 2-8-2 MOE 215

405194

114 125 CCAGCAGGAAAT 2-8-2 MOE 216

405195

115 126 ACCAGCAGGAAA 2-8-2 MOE 217

405196

116 127 GACCAGCAGGAA 2-8-2 MOE 218

405197

117 128 TGACCAGCAGGA 2-8-2 MOE 219

3796855

117 128 TGACCAGCAGGA 1-10-1 MOE 219

405198

118 129 ATGACCAGCAGG 2-8-2 MOE 221

405199

119 130 AATGACCAGCAG 2-8-2 MOE 222

405200

120 131 CAATGACCAGCA 2-8-2 MOE 223

405201

121 132 CCAATGACCAGC 2-8-2 MOE 224

379686

135 146 ACCACAAGCCAA 1-10-1 MOE 225

379711

172 183 TAGCCGCCCACA 1-10-1 MOE 226

388628

172 183 TAGCCGCCCACA 2-8-2 MOE 226

405202

207 218 CCGGCCACCACA 2-8-2 MOE 228

405203

208 219 ACCGGCCACCAC 2-8-2 MOE 229

405204

236 247 GATGTTGCTGGC 2-8-2 MOE 230

379687

236 247 GATGTTGCTGGC 1-10-1 MOE 230

405205

237 248 CGATGTTGCTGG 2-8-2 MOE 232

405206

238 249 CCGATGTTGCTG 2-8-2 MOE 233

405207

239 250 GCCGATGTTGCT 2-8-2 MOE 2. 3. 4

405208

240 251 TGCCGATGTTGC 2-8-2 MOE 235

405209

241 252 CTGCCGATGTTG 2-8-2 MOE 236

405210

260 271 CAGGCCCACAAA 2-8-2 MOE 237

405211

261 272 CCAGGCCCACAA 2-8-2 MOE 238

405212

262 273 GCCAGGCCCACA 2-8-2 MOE 239

379688

288 299 CCAAGCCACTTG 1-10-1 MOE 240

379689

318 329 AGAGCGCATTCC 1-10-1 MOE 241

379690

435 446 ACAGGTAGAGGC 1-10-1 MOE 242

405248

474 485 AGATCTTGGTGA 2-8-2 MOE 243

379691

474 485 AGATCTTGGTGA 1-10-1 MOE 243

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

382676

527 539 TGTTCCAGCCCAG 1-10-2 MOE 245

388625

528 539 TGTTCCAGCCCA 2-8-2 MOE 246

389780

528 539 TGTTCCAGCCCA 1-9-2 MOE 246

379692

528 539 TGTTCCAGCCCA 1-10-1 MOE 246

392170

528 539 TGTTCCAGCCCA 1-10-1 Methylene BNA 246

392173

528 539 TGTTCCAGCCCA 2-8-2 Methylene BNA 246

405213

529 540 ATGTTCCAGCCC 2-8-2 MOE 251

405214

564 575 TGGTGATGCCCA 2-8-2 MOE 252

405215

565 576 ATGGTGATGCCC 2-8-2 MOE 253

405216

566 577 CATGGTGATGCC 2-8-2 MOE 254

379693

566 577 CATGGTGATGCC 1-10-1 MOE 254

405217

567 578 TCATGGTGATGC 2-8-2 MOE 256

405218

568 579 ATCATGGTGATG 2-8-2.MOE 257

405219

587 598 CCCTCCTGTCAC 2-8-2 MOE 258

405220

588 599 GCCCTCCTGTCA 2-8-2 MOE 259

405221

589 600 AGCCCTCCTGTC 2-8-2 MOE 260

405222

590 601 CAGCCCTCCTGT 2-8-2 MOE 261

405223

591 602 CCAGCCCTCCTG 2-8-2 MOE 262

405224

592 603 GCCAGCCCTCCT 2-8-2 MOE 263

379694

629 640 GACGAAGGTCTG 1-10-1 MOE 264

405225

707 718 GTATTTGTCGAA  2-8-2 MOE 265

379695

737 748 GGACACCGTCAG 1-10-1 MOE 266

379696

974 985 CAGCTTCAGGTA 1-10-1 MOE 267

405226

998 1009 CATGACCATGAG 2-8-2 MOE 268

405227

999 1010 GCATGACCATGA 2-8-2 MOE 269

405228

1000 1011 GGCATGACCATG 2-8-2 MOE 270

405229

1001 1012 TGGCATGACCAT 2-8-2 MOE 271

405230

1002 1013 CTGGCATGACCA 2-8-2 MOE 272

379697

1002 1013 CTGGCATGACCA 1-10-1 MOE 272

405231

1003 1014 CCTGGCATGACC 2-8-2 MOE 274

379698

1091 1102 GCAGCCCACCTC 1-10-1 MOE 275

405232

1092 1103 AGCAGCCCACCT 2-8-2 MOE 276

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

405233

1093 1104 GAGCAGCCCACC 2-8-2 MOE 277

405234

1130 1141 CATGAGCTTCAC 2-8-2 MOE 278

405235

1131 1142 GCATGAGCTTCA 2-8-2 MOE 279

382677

1131 1143 GGCATGAGCTTCA 1-10-2 MOE 280

388626

1132 1143 GGCATGAGCTTC 2-8-2 MOE 281

379699

1132 1143 GGCATGAGCTTC 1-10-1 MOE 281

405236

1133 1144 GGGCATGAGCTT 2-8-2 MOE 283

405237

1157 1168 CAGCATGAGTCC 2-8-2 MOE 284

405238

1158 1169 CCAGCATGAGTC 2-8-2 MOE 285

379700

1158 1169 CCAGCATGAGTC 1-10-1 MOE 285

405239

1159 1170 GCCAGCATGAGT 2-8-2 MOE 287

379701

1230 1241 CCATGGTGAAGA 1-10-1 MOE 288

405240

1542 1553 CACAGCTGCCCG 2-8-2 MOE 289

405241

1543 1554 ACACAGCTGCCC 2-8-2 MOE 290

405242

1544 1555 CACACAGCTGCC 2-8-2 MOE 291

382678

1544 1556 GCACACAGCTGCC 1-10-2 MOE 292

388627

1545 1556 GCACACAGCTGC 2-8-2 MOE 293

379702

1545 1556 GCACACAGCTGC 1-10-1 MOE 293

379703

1701 1712 GCCGGAGACTGA 1-10-1 MOE 295

405243

1976 1987 ATTGAGGTTGAC 2-8-2 MOE 296

405244

1977 1988 CATTGAGGTTGA 2-8-2 MOE 297

405245

1978 1989 GCATTGAGGTTG 2-8-2 MOE 298

405246

1979 1990 GGCATTGAGGTT 2-8-2 MOE 299

405247

1980 1991 GGGCATTGAGGT 2-8-2 MOE 300

Table 5: Short antisense compounds directed to SEQ ID No. 3 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

405200

96 107 CAATGACCAGCA 2-8-2 MOE 223

405215

382 393 ATGGTGATGCCC 2-8-2 MOE 253

405216

383 394 CATGGTGATGCC 2-8-2 MOE 254

379693

383 394 CATGGTGATGCC 1-10-1 MOE 254

379701

471 482 CCATGGTGAAGA 1-10-1 MOE 288

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

405218

472 483 ATCATGGTGATG 2-8-2 MOE 257

405246

536 547 GGCATTGAGGTT 2-8-2 MOE 299

405248

570 581 AGATCTTGGTGA 2-8-2 MOE 243

379691

570 581 AGATCTTGGTGA 1-10-1 MOE 243

379698

683 694 GCAGCCCACCTC 1-10-1 MOE 275

405232

684 695 AGCAGCCCACCT 2-8-2 MOE 276

379711

685 696 TAGCCGCCCACA 1-10-1 MOE 226

388628

685 696 TAGCCGCCCACA 2-8-2 MOE 226

379698

950 961 GCAGCCCACCTC 1-10-1 MOE 275

405232

95l 962 AGCAGCCCACCT 2-8-2 MOE 276

405235

978 989 GCATGAGCTTCA 2-8-2 MOE 279

382677

978 990 GGCATGAGCTTCA 1-10-2 MOE 280

388626

979 990 GGCATGAGCTTC 2-8-2 MOE 281

379699

979 990 GGCATGAGCTTC 1-10-1 MOE 281

405236

980 991 GGGCATGAGCTT 2-8-2 MOE 283

379698

1043 1054 GCAGCCCACCTC 1-10-1 MOE 275

405239

1171 1182 GCCAGCATGAGT 2-8-2 MOE 287

405209

1213 1224 CTGCCGATGTTG  2-8-2 MOE 236

405233

1364 1375 GAGCAGCCCACC 2-8-2 MOE 277

405240

1366 1377 CACAGCTGCCCG 2-8-2 MOE 289

405211

1500 1511 CCAGGCCCACAA 2-8-2 MOE 238

405212

1501 1512 GCCAGGCCCACA 2-8-2 MOE 239

379695

1643 1654 GGACACCGTCAG 1-10-1 MOE 266

379698

1875 1886 GCAGCCCACCTC 1-10-1 MOE 275

405239

1993 2004 GCCAGCATGAGT 2-8-2 MOE 287

405211

2210 2221 CCAGGCCCACAA 2-8-2 MOE 238

405212

2211 2222 GCCAGGCCCACA 2-8-2 MOE 239

In certain embodiments, a target region is nucleotides 85-184 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 85-184 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 85-184 comprises a nucleotide sequence selected from SEQ ID NOS: 214, 215, 216, 217, 218, 219, 221, 222, 223, 224, 225 or 227. In certain of said embodiments, a compound Short antisense targeting nucleotides 85-184 of SEQ ID NO: 3 is selected from No. Isis 379684, 405193, 405194, 405195, 405196, 405197, 379685, 405198, 405199, 405200 or 405201, 379686, 379711 or 388628.

In certain embodiments, a target region is nucleotides 113-132 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 113-132 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 113-132 comprises a nucleotide sequence selected from SEQ ID Nos. 215, 216, 217, 218, 219, 221, 222, 223 or 224. In certain such embodiments, a short antisense compound directed to nucleotides 113-132 of SEQ ID NO. 3 is selected from No. Isis 405193, 405194, 405195, 405196, 405197, 379685, 405198, 405199, 405200 or 405201.

In certain embodiments, a target region is nucleotides 207-329 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 207-329 of SEQ ID No. 3. In certain embodiments, a short antisense compound. Nucleotide targeting 207-329 comprises a nucleotide sequence selected from SEQ ID NO: 228, 229, 230, 232, 233, 234, 235, 236, 237, 238, 239, 240 or 241. In certain such embodiments, A short antisense compound targeting nucleotides 207-329 of SEQ ID NO: 3 is selected from No. Isis 405202, 405203, 405204, 379687, 405205, 405206, 405207, 405208, 405209, 405210, 405211, 405212, 379688 or 379689 .

In certain embodiments, a target region is nucleotides 207-273 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 207-273 of SEQ ID No. 3. In certain embodiments, a short antisense compound. Nucleotide targeting 207-273 comprises a nucleotide sequence selected from SEQ ID Nos. 228, 229, 230, 232, 233, 234, 235, 236, 237, 238 or 239. In certain such embodiments, a short antisense compound targeting nucleotides 207-273 of SEQ ID NO. 3 is selected from No. Isis 405202, 405203, 405204, 379687, 405205, 405206, 405207, 405208, 405209, 405210, 405211 or 405212.

In certain embodiments, a target region is nucleotides 207-219 of SEQ ID NO. 3. In certain embodiments, a short antisense compound directed to nucleotides 207-219 of SEQ ID NO. 3. In certain embodiments, a short antisense compound. Nucleotide targeting 207-219 comprises a nucleotide sequence selected from SEQ ID NO. 228 or 229. In certain such embodiments, a short antisense compound targeting nucleotides 207-219 of SEQ ID NO. 3 is selected from No. Isis 405202 or 405203.

In certain embodiments, a target region is nucleotides 236-252 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 236-252 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 236-252 comprises a nucleotide sequence selected from SEQ ID Nos. 230, 232, 233, 234, 235 or 236. In certain such embodiments, a short antisense compound directed to nucleotides 236-252 of SEC ID No. 3 is selected from No. Isis 405204, 379687, 405205, 405206, 405207, 405208 or 405209.

In certain embodiments, a target region is nucleotides 260-273 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 260-273 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 260-273 comprises a nucleotide sequence selected from SEQ ID NO: 237, 238 or 239. In certain of said embodiments, a short antisense compound directed to nucleotides 260-273 of SEQ ID NO: 3 is selected from No. Isis 405210, 405211 or 405212.

In certain embodiments, a target region is nucleotides 435-640 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 435-640 of SEQ ID No. 3. In certain embodiments, a short antisense compound. Nucleotide targeting 435-640 comprises a nucleotide sequence selected from SEQ ID NO: 242, 243, 245, 246, 251, 252, 253, 254, 256, 257, 258, 259, 260, 261, 262, 263 or 264. In certain of said embodiments, a short antisense compound directed to nucleotides 435-640 of SEQ ID NO: 3 is selected from No. Isis 379690, 405248, 379691, 389780, 379692, 382676, 388625, 392170, 392173, 405213 , 405214, 405215, 405216, 379693, 405217, 405218, 405219, 405220, 405221, 405222, 405223, 405224 or 379694.

In certain embodiments, a target region is nucleotides 527-540 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 527-540 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 527-540 comprises a nucleotide sequence selected from SEQ ID NO. 245, 246 or 251. In certain such embodiments, a short antisense compound directed to nucleotides 527-540 of SEQ ID NO: 3 is selected from No. Isis 389780, 379692, 382676, 388626, 392170, 392173 or 405213.

In certain embodiments, a target region is nucleotides 564-603 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 564-603 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 564-603 comprises a nucleotide sequence selected from SEQ ID NO: 252, 253, 254, 256, 257, 258, 259, 260, 261, 262 or 263. In certain of said embodiments, a short antisense compound addressed to nucleotides 564-603 of SEQ ID NO. 3 is selected from No. Isis 405214, 405215, 405216, 379693, 405217, 405218, 405219, 405220, 405221, 405222, 405223 or 405224.

In certain embodiments, a target region is nucleotides 564-579 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 564-579 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 564-579 comprises a nucleotide sequence selected from SEQ ID NO: 252, 253, 254, 256 or 257. In certain such embodiments, a short antisense compound directed to nucleotides 564-579 of SEQ ID NO. 3 is selected from No. Isis 405214, 405215, 405216, 379693, 405217 or 405218.

In certain embodiments, a target region is nucleotides 587-603 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 587-603 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 587-603 comprises a nucleotide sequence selected from SEQ ID NO: 258, 259, 260, 261, 262 or 263. In certain such embodiments, a short antisense compound directed to nucleotides 587-603 of SEC ID No. 3 is selected from No. Isis 405219, 405220, 05221, 405222, 405223 or 405224.

In certain embodiments, a target region is nucleotides 974-1014 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 974-1014 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 974-1014 comprises a nucleotide sequence selected from SEQ ID Nos. 267, 268, 269, 270, 271, 272 or 274. In certain such embodiments, a short antisense compound directed to nucleotides 974-1014 of SEQ ID NO. 3 is selected from No. Isis 379696, 405226, 405227, 405228, 405229, 405230, 379697 or 405231.

In certain embodiments, a target region is nucleotides 998-1014 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 998-1014 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 998-1014 comprises a nucleotide sequence selected from SEQ ID Nos. 268, 269, 270, 271, 272 or 274. In certain such embodiments, a short antisense compound directed to nucleotides 998-1014 of SEC ID No. 3 is selected from No. Isis 405226, 405227, 405228, 405229, 405230, 379697 or 405231.

In certain embodiments, a target region is nucleotides 1091-1170 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 1091-1170 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 1091-1170 comprises a nucleotide sequence selected from SEQ ID Nos. 275, 276, 277, 278, 279, 280, 281, 283, 284, 285, 286 or 287. In certain of said embodiments, a compound Short antisense targeting nucleotides 1091-1170 of SEQ ID NO: 3 is selected from No. Isis 379698, 405232, 405233, 405234, 405235, 388626, 379699, 382677, 405236, 405237, 405238, 379700, or 405239.

In certain embodiments, a target region is nucleotides 1091-1104 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 1091-1104 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 1091-1104 comprises a nucleotide sequence selected from SEQ ID NO: 275, 276 or 277. In certain such embodiments, a short antisense compound directed to nucleotides 1091-1104 of SEQ ID NO: 3 is selected from No. Isis 379698, 405232 or 405233.

In certain embodiments, a target region is nucleotides 1130-1144 of SEQ ID NO. 3. In certain embodiments, a short antisense compound directed to nucleotides 1130-1144 of SEQ ID NO. 3. In certain embodiments, a short antisense compound. directed to nucleotides 1130-1144 comprises a nucleotide sequence selected from SEQ ID NO. 278, 279, 280, 281 or 283. In certain such embodiments, a short antisense compound directed to nucleotides 1130-1144 of SEQ ID NO. 3 is selected from No. Isis 405234, 405235, 388626,379699,382677 or 405236.

In certain embodiments, a target region is nucleotides 1157-1170 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 1157-1170 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 1157-1170 comprises a nucleotide sequence selected from SEQ ID NO: 284, 285 or 287. In certain such embodiments, a short antisense compound directed to nucleotides 1157-1170 of SEQ ID NO: 3 is selected from No. Isis 405237, 405238, 379700 or 405239.

In certain embodiments, a target region is nucleotides 1542-1556 of SEQ ID No. 3. In certain embodiments, a short antisense compound directed to nucleotides 1542-1556 of SEQ ID No. 3. In certain embodiments, a short antisense compound. directed to nucleotides 1542-1556 comprises a nucleotide sequence selected from SEQ ID NO: 289, 290, 291, 292 or 293. In certain such embodiments, a short antisense compound directed to nucleotides 1542-1556 of SEQ ID NO. 3 is selected from No. Isis 405240, 405241, 405242, 388629, 379702 or 382678. In certain embodiments, a target region is nucleotides 1976-1991 of SEQ ID NO. 3. In certain embodiments, a short antisense compound directed at 1976-1991 nucleotides of SEQ ID NO. 3. In certain embodiments, a short antisense compound directed to nucleotides 1976-1991 comprises a nucleotide sequence selected from SEQ ID NO: 296, 297, 298, 299 or 300. In certain of said embodiments, a short antisense compound directed to nucleotides 1976-1991 of SEQ ID NO: 3 is selected from Isis No. 405243, 405244, 405245, 405246 or 405247.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are short captamers. In certain of said embodiments, short captamers directed to an SGLT2 nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds targeting a nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from -Lmethyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA. In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl.

In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to an SGLT2 nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to an SGLT2 nucleic acid have a monomer length. In certain embodiments, short antisense compounds directed to an SGLT2 nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to an SGLT2 nucleic acid are 16 6 monomers in length. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds targeting an SGLT2 nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of SGLT2 are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting an SGLT2 nucleic acid, wherein the short antisense compound targeting an SGLT2 nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating ApoB expression using one or more short antisense compounds targeting an SGLT2 nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, the methods of modulating SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid having a length of 8 monomers. In certain embodiments, SGLT2 modulation processes comprise the use of a short antisense compound directed to an SGLT2 nucleic acid that is 9 monomers in length. In certain embodiments, the methods of modulating SGLT2 comprise the use of a short antisense compound targeting an SGLT2 nucleic acid that is 10 monomers in length. In certain embodiments, the methods of modulating SGLT2 comprise the use of a short antisense compound targeting an SGLT2 nucleic acid that is 11 monomers in length. In certain embodiments, the methods of modulating SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid that is 12 monomers in length. In certain embodiments, the methods of modulating SGLT2 comprise the use of a short antisense compound targeting an SGLT2 nucleic acid that is 13 monomers in length. In certain embodiments, SGLT2 modulation processes comprise the use of a short antisense compound directed to an SGLT2 nucleic acid that is 14 monomers in length. In certain embodiments, the SGLT2 modulation processes comprise the use of a short antisense compound directed to an SGLT2 nucleic acid that is 15 monomers in length. In certain embodiments, SGLT2 modulation processes comprise the use of a short antisense compound directed to an SGLT2 nucleic acid that is 16 monomers in length.

In certain embodiments, the methods of modulating the expression of SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating the expression of SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid comprising 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of SGLT2 comprise the use of a short antisense compound directed to an SGLT2 nucleic acid comprising 12 or 14 nucleotides or nucleosides.

3. PCSK9

In individuals with autosomal dominant hypercholesterolemia (HAD), elevated levels of LDL-C have been linked to mutations in the genes encoding the LDL receptor (LDL-R), apolipoprotein B (apon) or proprotein convertase subtilisin / quexin type 9 (PCSK9) (Abifadel et al., Nat. Genet., 2003, 34: 154-156). PCSK9 was identified as a third locus associated with ADH when function gain mutations in PCSK9 were found to be linked to elevated levels of LDL-C. ApoB participates in the intracellular assembly and secretion of triglyceride-rich lipoproteins and is a ligand for LDL-R. It has been proposed that PCSK9 reduces levels of LDL-R expression in the liver. Reduced LDL-R expression results in reduced hepatic uptake of circulating ApoB-containing lipoproteins, which, in turn, leads to elevated cholesterol levels.

Definitions

"PCSK9" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound.

"PCSK9 nucleic acid" means any nucleic acid encoding PCSK9. For example, in certain embodiments, a PCSK9 nucleic acid includes, without limitation, a DNA sequence encoding PCSK9, an RNA sequence transcribed from DNA encoding PCSK9, and an mRNA sequence encoding PCSK9.

"PCSK9 mRNA" means an mRNA encoding PCSK9.

Therapeutic indications of PCSK9

In certain embodiments, methods of modulating the expression of PCSK9 in an individual are disclosed herein, comprising administering a short antisense compound directed to a PCSK9 nucleic acid. In certain embodiments, methods of treating an individual are disclosed herein, comprising administering one or more pharmaceutical compositions than of the present invention. In certain embodiments, the individual has hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early coronary heart disease, one or more risk factors for coronary heart disease, type II diabetes, diabetes Type II with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, liver steatosis, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

The guidelines for lipid-lowering therapies were established in 2001, in the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and were updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). The guidelines include obtaining a complete lipoprotein profile, usually after fasting for 9 to 12 hours, for the determination of the levels of LDL-C, total cholesterol and HDL-C. According to the most recently established guidelines, LDL-C levels of 134-159 mg / dl, 160-189 mg / dl and greater than or equal to 190 mg / dl are considered at the high, high and very high limit, respectively. Cholesterol levels of 200-239 and greater than or equal to 240 mg / dl are considered high and high limits, respectively. HCL-C levels below 40 mg / dl are considered low.

In certain embodiments, individuals have been identified as needing lipid lowering therapy. In certain of these embodiments, it has been identified that individuals need lipid-lowering therapy according to the guidelines established in 2001 by the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 190 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy has an LDL-C level greater than 160 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy has an LDL-C level greater than 130 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 100 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy should keep the LDLC level below 160 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy should keep the LDL-C level below 130 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy should keep the LDL-C level below 100 mg / dl. In certain of these embodiments, the individual must maintain the LDL-C level below 70 mg / dl.

In certain embodiments, procedures for reducing ApoB in an individual are disclosed herein. In certain embodiments, methods for reducing in an individual the levels of lipoproteins containing ApoB are disclosed in this document. In certain embodiments, procedures for reducing the level of LDL-C in an individual are disclosed herein. In certain embodiments, procedures for reducing the level of VLDL-C in an individual are disclosed in this document. In certain embodiments, This document discloses procedures to reduce the level of IDL-C in an individual. In certain embodiments, methods for reducing the level of non-HDL-C in an individual are disclosed herein. In certain embodiments, methods for reducing Lp (a) in an individual are disclosed herein. In certain embodiments, methods for reducing serum triglycerides in an individual are disclosed herein. In certain embodiments, methods for reducing liver triglycerides in an individual are disclosed herein. In certain embodiments, methods for reducing the level of Ox-LDL-C in an individual are disclosed herein. In certain embodiments, methods for reducing the level of small LDL particles in an individual are disclosed herein. In certain embodiments, methods for reducing the level of small VLDL particles in an individual are disclosed herein. In certain embodiments, methods for reducing phospholipids in an individual are disclosed herein. In certain embodiments, methods for reducing oxidized phospholipids in an individual are disclosed herein.

In certain embodiments, the procedures disclosed herein do not reduce HDL-C levels. In certain embodiments, the procedures disclosed herein do not result in the accumulation of lipids in the liver.

In certain of said embodiments, a pharmaceutical composition comprising a short antisense compound directed to a PCSK9 nucleic acid is for use in therapy. In certain embodiments, the therapy is the reduction of LDL-C, ApoB, VLDL-C, IDL-C, non-HDL-C, Lp (a), serum triglycerides, liver triglycerides, Ox-LDL-C, particles small LDL, small VLDL, phospholipids or oxidized phospholipids in an individual. In certain embodiments, therapy is the treatment of hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease, type diabetes. II, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, hepatic steatosis, nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. In further embodiments, therapy is the reduction of the risk of CPC. In certain, therapy is the prevention of atherosclerosis. In certain embodiments, therapy is the prevention of coronary heart disease.

In certain embodiments, a pharmaceutical composition comprising a short antisense compound targeting a PCSK9 nucleic acid is used for the preparation of a medicament to reduce the levels of LDL-C, ApoB, VLDL-C, IDL-C, non-HDL. -C, Lp (a), serum triglycerides, liver triglycerides, Ox-LDL-C, small LDL particles, small VLDL, phospholipids or oxidized phospholipids in an individual. In certain embodiments, a pharmaceutical composition comprising a short antisense compound directed to a PCKS9 is used for the preparation of a medicament to reduce the risk of coronary heart disease. In certain embodiments, a short antisense compound targeting a PCSK9 nucleic acid is used for the preparation of a medicament for the treatment of hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, coronary heart disease. early onset, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, fatty hyperacidemia, liver steatosis, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

Combination therapies with PCSK9

In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with one or more other pharmaceutical agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition different from that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat an undesired effect of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions herein and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one

or more different pharmaceutical agents are prepared separately.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include lipid lowering agents. In certain of said embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, atorvastatin, simvastatin, rosuvastatin and ezetimibe. In certain of said embodiments, the lipid lowering agent is administered prior to the administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered after administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered at the same time as the pharmaceutical composition of the present disclosure. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is the same as the dose that would be administered if the lipid-lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid lowering agent is less than the dose that would be administered if the lipid lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is greater than the dose that would be administered if the lipid-lowering agent was administered alone.

In certain embodiments, a coadministered lipid lowering agent is an HMG-CoA reductase inhibitor. In certain of said embodiments, the HMG-CoA reductase inhibitor is a statin. In certain of said embodiments, the statin is selected from atorvastatin, simvastatin, pravastatin, fluvastatin and rosuvastatin.

In certain embodiments, a coadministered lipid lowering agent is a cholesterol absorption inhibitor. In certain of said embodiments, the cholesterol absorption inhibitor is ezetimibe.

In certain embodiments, a coadministered lipid-lowering agent is an HMG-CoA reductase inhibitor formulated in conjunction with a cholesterol absorption inhibitor. In certain of said embodiments, the jointly formulated lipid lowering agent is ezetimibe / simvastatin.

In certain embodiments, a co-administered lipid-lowering agent is a microsomal triglyceride transfer protein inhibitor.

In certain embodiments, a co-administered lipid-lowering agent is an oligonucleotide directed to an ApoB nucleic acid.

In certain embodiments, a co-administered pharmaceutical agent is a bile acid sequestrant. In certain of said embodiments, the bile acid sequestrant is selected from cholestyramine, colestipol and colesevelam.

In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain of said embodiments, nicotinic acid is selected from nicotinic acid immediate release, nicotinic acid extended release and nicotinic acid sustained release.

In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain of said embodiments, the fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate and ciprofibrate.

Other examples of pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, corticosteroids, including, but not limited to, prednisone; immunoglobulins, including, inter alia intravenous immunoglobulin (IVIG); analgesics (eg, acetaminophen); anti-inflammatory agents, including but not limited to non-steroidal anti-inflammatory drugs (eg, ibuprofen, COX-1 inhibitors and COX-2 inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (eg, biguanides, glucosidase inhibitors, insulins, sulfonylureas and thiazolidendiones); adrenergic modifiers; diuretics; hormones (eg, anabolic steroids, androgens, estrogens, calcitonin, progestin, somatostatin and thyroid hormones); immunomodulators; muscle relaxants; antihistamines, antiosteoporosis agents (eg, bisphosphonates, calcitonin and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; Atlantic oak and poison sumac products; antibodies; and vaccines.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be co-administered with a lipid lowering therapy. In certain of these embodiments, a lipid lowering therapy is a therapeutic lifestyle change. In certain of these embodiments, a lipid-lowering therapy is LDL apheresis.

Certain short antisense compounds targeting a PCSK9 nucleic acid

In certain embodiments, the short antisense compounds are directed to a PCSK9 nucleic acid having the registration number sequence in GENBANK® NM_174936.2, incorporated herein as SEQ ID NO.

4. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 4 is at least 90% complementary to SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to SEQ ID No. 4 it is at least 95% complementary to SEQ ID NO. 4. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 4 IS 100% complementary to SEQ ID NO. 4. In certain embodiments, a short antisense compound. directed to SEQ ID NO: 4 comprises a nucleotide sequence selected from the sequences

5 nucleotides indicated in Table 6 or Table 7.

The nucleotide sequence indicated in each SEQ ID NO in Tables 6 and 7 is independent of any modification of a sugar moiety, an internucleoside linkage or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The short antisense compounds described by the Isis Number (No.

10 Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside linkage or a nucleotide base.

Tables 6 and 7 illustrate examples of short antisense compounds directed to SEQ ID NO. 4. Table 6 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 4. Table 7 illustrates short antisense compounds having one or two. erroneous pairing with respect to SEQ ID NO. 4. The column called 15 "capper motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The links

20 internucleosides are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 6: Short antisense compounds directed to SEQ ID No. 4

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

400297

695 708  ATGGGGCAACTTCA 2-10-2 MOE 329

400298

696 709  CATGGGGCAACTTC 2-10-2 MOE 330

400299

697 710  ACATGGGGCAACTT 2-10-2 MOE 331

400300

742 755  GGGATGCTCTGGGC 2-10-2 MOE 332

400301

757 770  CGCTCCAGGTTCCA 2-10-2 MOE 333

400302

828 841  GATACACCTCCACC 2-10-2 MOE 334

400303

829 842  AGATACACCTCCAC 2-10-2 MOE 335

400304

830 843  GAGATACACCTCCA 2-10-2 MOE 336

400305

937 950  GCCTGTCTGTGGAA 2-10-2 MOE 337

400306

952 965  CTGTCACACTTGCT 2-10-2 MOE 338

400307

988 1001  CGGCCGCTGACCAC 2-10-2 MOE 339

400308

989 1002  CCGGCCGCTGACCA 2-10-2 MOE 340

400309

990 1003  CCCGGCCGCTGACC 2-10-2 MOE 341

400310

991 1004  TCCCGGCCGCTGAC 2-10-2 MOE 342

400311

992 1005  ATCCCGGCCGCTGA 2-10-2 MOE 343

400312

993 1006  CATCCCGGCCGCTG 2-10-2 MOE 344

400313

994 1007  GCATCCCGGCCGCT 2-10-2 MOE 3. 4. 5

400314

1057 1070  GTGCCCTTCCCTTG 2-10-2 MOE 346

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

400315

1075 1088  ATGAGGGTGCCGCT 2-10-2 MOE 347

400316

1076 1089  TATGAGGGTGCCGC 2-10-2 MOE 348

400317

1077 1090  CTATGAGGGTGCCG 2-10-2 MOE 349

400318

1078 1091  CCTATGAGGGTGCC 2-10-2 MOE 350

400319

1093 1106  CGAATAAACTCCAG 2-10-2 MOE 351

400320

1094 1107  CCGAATAAACTCCA 2-10-2 MOE 352

400321

1095 1108  TCCGAATAAACTCC 2-10-2 MOE 353

400322

1096 1109  TTCCGAATAAACTC 2-10-2 MOE 354

400323

1147 1160 GCCAGGGGCAGCAG 2-10-2 MOE 355

400324

1255 1268  GAGTAGAGGCAGGC 2-10-2 MOE 356

400325

1334 1347  CCCCAAAGTCCCCA 2-10-2 MOE 357

400326

1335 1348  TCCCCAAAGTCCCC 2-10-2 MOE 358

400327

1336 1349  GTCCCCAAAGTCCC 2-10-2 MOE 359

400328

1453 1466  ACGTGGGCAGCAGC 2-10-2 MOE 360

400329

1454 1467  CACGTGGGCAGCAG 2-10-2 MOE 361

400330

1455 1468  CCACGTGGGCAGCA 2-10-2 MOE 362

400331

1456 1469  GCCACGTGGGCAGC 2-10-2 MOE 363

400332

1569 1582 CAGGGAACCAGGCC 2-10-2 MOE 364

400333

1570 1583  TCAGGGAACCAGGC 2-10-2 MOE 365

400334

1571 1584  CTCAGGGAACCAGG 2-10-2 MOE 366

400335

1572 1585  CCTCAGGGAACCAG 2-10-2 MOE 367

400336

1573 1586  TCCTCAGGGAACCA 2-10-2 MOE 368

400337

1574 1587  GTCCTCAGGGAACC 2-10-2 MOE 369

400338

1575 1588  GGTCCTCAGGGAAC 2-10-2 MOE 370

400339

1576 1589  TGGTCCTCAGGGAA 2-10-2 MOE 371

400340

1577 1590  CTGGTCCTCAGGGA 2-10-2 MOE 372

400341

1578 1591  GCTGGTCCTCAGGG 2-10-2 MOE 373

400342

1621 1634 GTGCTGGGGGGCAG 2-10-2 MOE 374

400343

1622 1635 GGTGCTGGGGGGCA 2-10-2 MOE 375

400344

1623 1636 GGGTGCTGGGGGGC 2-10-2 MOE 376

400345

1624 1637 TGGGTGCTGGGGGG 2-10-2 MOE 377

400346

1738 1751  GAGCAGCTCAGCAG 2-10-2 MOE 378

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

400347

1739 1752  GGAGCAGCTCAGCA 2-10-2 MOE 379

400348

1740 1753  TGGAGCAGCTCAGC 2-10-2 MOE 380

400349

1741 1754  CTGGAGCAGCTCAG 2-10-2 MOE 381

400350

1834 1847  CCCTCACCCCCAAA 2-10-2 MOE 382

400351

1835 1848  ACCCTCACCCCCAA 2-10-2 MOE 383

400352

1836 1849  CACCCTCACCCCCA 2-10-2 MOE 384

400353

1837 1850  ACACCCTCACCCCC 2-10-2 MOE 385

400354

1838 1851  GACACCCTCACCCC 2-10-2 MOE 386

400355

1839 1852  AGACACCCTCACCC 2-10-2 MOE 387

400356

1840 1853  TAGACACCCTCACC 2-10-2 MOE 388

400357

2083 2096  TGGCAGCAGGAAGC 2-10-2 MOE 389

400358

2084 2097  ATGGCAGCAGGAAG 2-10-2 MOE 390

400359

2085 2098  CATGGCAGCAGGAA 2-10-2 MOE 391

400360

2086 2099  GCATGGCAGCAGGA 2-10-2 MOE 392

400361

2316 2329  GGCAGCAGATGGCA 2-10-2 MOE 393

400362

2317 2330  CGGCAGCAGATGGC 2-10-2 MOE 394

400363

2318 2331  CCGGCAGCAGATGG 2-10-2 MOE 395

400364

2319 2332  TCCGGCAGCAGATG 2-10-2 MOE 396

400365

2320 2333  CTCCGGCAGCAGAT 2-10-2 MOE 397

400366

2321 2334  GCTCCGGCAGCAGA 2-10-2 MOE 398

400367

2322 2335  GGCTCCGGCAGCAG 2-10-2 MOE 399

400368

2323 2336  CGGCTCCGGCAGCA 2-10-2 MOE 400

400369

2324 2337  CCGGCTCCGGCAGC 2-10-2 MOE 401

400370

2325 2338  GCCGGCTCCGGCAG 2-10-2 MOE 402

400371

3543 3556  AGTTACAAAAGCAA 2-10-2 MOE 403

403739

988 1001  CGGCCGCTGACCAC 2-10-2 (6’S) -6’-methyl-Methyloxy BNA 339

403740

1455 1468  CCACGTGGGCAGCA 2-10-2 (6’S) -6’-methyl-Methyloxy BNA 362

Table 7: Short antisense compounds directed to SEQ ID No. 4 and having 1 or 2 mismatches

ISIS Nº

 Target site in 5 ’  Target site in 3 ’  Sequence (5’-3 ’)  Gápmero motive  SEQ ID NO.

400323

349 362 GCCAGGGGCAGCAG 2-10-2 MOE 355

400370

679 692  GCCGGCTCCGGCAG 2-10-2 MOE 402

400361

1860 1873  GGCAGCAGATGGCA 2-10-2 MOE 393

400323

1873 1886 GCCAGGGGCAGCAG 2-10-2 MOE 355

400310

2257 2270  TCCCGGCCGCTGAC 2-10-2 MOE 342

400361

2653 2666  GGCAGCAGATGGCA 2-10-2 MOE 393

400350

2811 2824  CCCTCACCCCCAAA 2-10-2 MOE 382

400351

2812 2825  ACCCTCACCCCCAA 2-10-2 MOE 383

400352

2813 2826  CACCCTCACCCCCA 2-10-2 MOE 384

400353

2814 2827  ACACCCTCACCCCC 2-10-2 MOE 385

400334

2966 2979  CTCAGGGAACCAGG 2-10-2 MOE 366

400332

3379 3392 CAGGGAACCAGGCC 2-10-2 MOE 364

400340

3448 3461  CTGGTCCTCAGGGA 2-10-2 MOE 372

400341

3449 3462  GCTGGTCCTCAGGG 2-10-2 MOE 373

In certain embodiments, a target region is nucleotides 695-710 of SEQ ID No. 4. In certain such embodiments, short antisense compounds directed to nucleotides 695-710 of SEQ ID No. 4 comprise a

5 nucleotide sequence selected from SEQ ID Nos. 329, 330 or 331. In certain such embodiments, a short antisense compound directed to nucleotides 695-710 of SEQ ID No. 4 is selected from Isis No. 400297, 400298 or 400299 .

In certain embodiments, a target region is nucleotides 742-770 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 742-770 of SEQ ID No. 4 comprises a

10 nucleotide sequence selected from SEQ ID No. 332 or 333. In certain such embodiments, a short antisense compound directed to nucleotides 742-770 of SEQ ID No. 4 is selected from Isis No. 400300 or 400301.

In certain embodiments, a target region is nucleotides 828-843 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 828-843 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 334, 335 or 336. In certain of said embodiments, a

Short antisense compound targeting nucleotides 828-843 of SEQ ID NO: 4 is selected from Isis No. 400302, 400303 or 400304.

In certain embodiments, a target region is nucleotides 937-1007 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 937-1007 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 337, 338, 339, 340, 341, 342, 343, 344 or 345. In certain of

20 said embodiments, a short antisense compound directed to nucleotides 937-1007 of SEQ ID NO: 4 is selected from No. Isis 400305, 400306, 400307, 400308, 400309, 400310, 400311, 400312, 400313, or 403739.

In certain embodiments, a target region is nucleotides 937-965 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 937-965 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 337 or 338. In certain of said embodiments, a compound

Short antisense directed to nucleotides 937-965 of SEQ ID No. 4 is selected from Isis No. 400305 or 400306.

In certain embodiments, a target region is nucleotides 988-1007 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 988-1007 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 339 340, 341, 342, 343, 344 or 345. In certain such embodiments, a short antisense compound directed to nucleotides 937-1007 of SEQ ID No. 4 is selected from Isis No. 400307, 400308, 400309, 400310, 400311, 400312, 4003313 or 403739.

In certain embodiments, a target region is nucleotides 1057-1160 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1160 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 346, 347, 348, 349, 350, 351, 352, 353, 354, or 355. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1160 of SEQ ID NO: 4 is selected No. Isis 400314, 400315, 400316, 400317, 400318, 400319, 400320, 400321, 400322, or 400323.

In certain embodiments, a target region is nucleotides 1057-1109 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1109 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 346, 347, 348, 349, 350, 351, 352, 353 or 354. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1109 of SEQ ID No. 4 is selected from No. Isis 400314, 400315, 400316, 400317, 400318, 400319, 400320, 400321 or 400322.

In certain embodiments, a target region is nucleotides 1057-1091 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1091 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 346 347, 348, 349 or 350. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1091 of SEQ ID No. 4 is selected from Isis No. 400314, 400315, 400316 or 400317 or 400318

In certain embodiments, a target region is nucleotides 1093-1109 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1093-1109 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 351 352, 353, or 354. In certain such embodiments, a short antisense compound directed to nucleotides 1057-1109 of SEQ ID NO: 4 is selected from Isis No. 400319, 400320, 400321 or 400322.

In certain embodiments, a target region is nucleotides 1334-1349 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1334-1349 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 357, 358 or 359. In certain such embodiments, a short antisense compound directed to nucleotides 1334-1349 of SEQ ID N ° 4 is selected from Isis No. 400325, 400326 or 400327.

In certain embodiments, a target region is nucleotides 1453-1469 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1453-1469 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID No. 360 361, 362, or 363. In certain such embodiments, a short antisense compound directed to nucleotides 1453-1469 of SEQ ID No. 4 is selected from Isis No. 400328, 400329, 400330, 400331 or 403470 .

In certain embodiments, a target region is nucleotides 1569-1591 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1569-1591 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 364, 365, 366, 367, 368, 369, 370, 371, 372, or 373. In certain such embodiments, a short antisense compound directed to nucleotides 1569-1591 of SEQ ID N ° 4 is selected No. Isis 400332, 400333, 400334, 400335, 400336, 400337, 400338, 400339, 400340, or 400341.

In certain embodiments, a target region is nucleotides 1621-1637 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1621-1637 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 374 375, 376, or 377. In certain such embodiments, a short antisense compound directed to nucleotides 1621-1637 of SEQ ID N ° 4 is selected from Isis No. 400342, 400343, 400344 or 400345.

In certain embodiments, a target region is nucleotides 1738-1754 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1738-1754 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 378 379, 380, or 381. In certain such embodiments, a short antisense compound directed to nucleotides 1738-1754 of SEQ ID N ° 4 is selected from Isis No. 400346, 400347, 400348 or 400349.

In certain embodiments, a target region is nucleotides 1834-1853 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 1834-1853 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID Nos. 382 383, 384, 385, 386, 387 or 388. In certain embodiments, a short antisense compound targeting nucleotides 1834-1853 of SEQ ID NO: 4 is selected from Isis No. 400350, 400351, 400352, 400353, 400354, 400355 or 400356.

In certain embodiments, a target region is nucleotides 2083-2099 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 2083-2099 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 389 390, 391, or 392. In certain such embodiments, a short antisense compound targeting nucleotides 2083-2099 of SEQ ID N ° 4 is selected from Isis No. 400357, 400358, 400359 or 400360.

In certain embodiments, a target region is nucleotides 2316-2338 of SEQ ID No. 4. In certain such embodiments, a short antisense compound directed to nucleotides 2316-2338 of SEQ ID No. 4 comprises a nucleotide sequence selected from SEQ ID NOS 393, 394, 395, 396, 397, 398, 399, 400, 401, or 402. In certain such embodiments, a short antisense compound directed to nucleotides 2316-2338 of SEQ ID N ° 4 is selected No. Isis 400361, 400362, 400363, 400364, 400365, 400366, 400367, 400368, 400369, or 400370.

In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, the short antisense compounds targeted to a PCSK9 nucleic acid are short captamers. In certain of said embodiments, the short catometers directed to a PCSK9 nucleic acid comprise at least one high affinity modification on one or more wings of the compound. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from -L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-menyloxy (4'-CH2-O-2') BNA, ethylene (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid comprise a gap between the 5 ′ wing and the 3 ′ wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides.

In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid have a motif (deoxid-wing hollow) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3,2-82, 1-8-1,3-6- 3 or 1-6-1, more preferably 1-10-1, 2-10-2,3-10-3 and 1-9-2.

In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid have a monomer length. In certain embodiments, short antisense compounds targeting a PCSK9 nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to a PCSK9 nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of PCSK9 are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a PCSK9 nucleic acid, wherein the short antisense compound targeting a PCSK9 nucleic acid has a

5 length from about 8 to about 16, preferably from 9 to 15, more preferably from 9 to 14, more preferably from 10 to 14 monomers (ie, from about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating ApoB expression using one or more short antisense compounds targeting a PCSK9 nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, PCSK9 modulation processes comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 8 monomers in length. In certain embodiments, PCSK9 modulation processes comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 9 monomers in length. In certain embodiments, the PCSK9 modulation procedures comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 10 monomers in length. In certain embodiments, PCSK9 modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 11 monomers in length. In certain embodiments, the PCSK9 modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 12 monomers in length. In certain embodiments, PCSK9 modulation processes comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 13 monomers in length. In certain embodiments, PCSK9 modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 14 monomers in length. In certain embodiments, PCSK9 modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid that is 15 monomers in length. In certain embodiments, PCSK9 modulation procedures comprise the use of a short antisense compound.

25 directed to a PCSK9 nucleic acid having a length of 16 monomers.

In certain embodiments, PCSK9 expression modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating the expression of PCSK9 comprise the use of a short antisense compound directed to a PCSK9 nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of PCSK9 comprise the use of a short antisense compound directed to a PCSK9 nucleic acid comprising from 12 to 14 monomers. In certain embodiments, PCSK9 expression modulation methods comprise the use of a short antisense compound directed to a PCSK9 nucleic acid comprising 12 or 14 nucleotides or nucleosides.

4. Enzyme superoxide dismutase 1 (SOD1)

35 Enzymes known as superoxide dismutases (SOD) provide defense against the oxidative damage of biomolecules by catalyzing the dismutation of superoxide into hydrogen peroxide (H2O2) (Fridovich, Annu. Rev. Biochem., 1995, 64, 97-112). There are two main classes of superoxide dismutases. One consists of a group of enzymes with active sites that contain copper and zinc, while the other class has manganese or iron in the active site (Fridovich, Annu. Rev. Biochem., 1995, 64, 97-112).

Mutations in the superoxide dismutase I gene are associated with a dominant inheritance form of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), a disorder characterized by selective degeneration of the upper and lower motor neurons (Cleveland and Liu, Nat. Med., 2000, 6, 1320-1321). The detrimental effects of several mutations in superoxide dismutase I are most likely mediated by a gain in toxic function rather than by a loss of activity of superoxide dismutase I, since

45 that the complete absence of superoxide dismutase I in mice or decrease life does not cause symptomatic disease (Al-Chalabi and Leigh, Curr. Opin. Neurol., 2000, 13, 397-405; Alisky and Davidson, Hum. Gene Ther ., 2000, 11, 2315-2329).

More than 100 mutations of the human SDO1 gene have been identified and, together, they represent approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS). Some mutations, such as the most common A4V mutation in the US, are very lethal and result in a survival of only nine months from the onset of disease symptoms - Other mutations of SOD1 manifest themselves in one more course Slow disease.

Definitions

"SOD1" means the gene product or protein whose expression is to be modulated by the administration of a short antisense compound.

"SOD1 nucleic acid" means any nucleic acid encoding SOD1. For example, in certain embodiments, an SOD1 nucleic acid includes, without limitation, a DNA sequence encoding SOD1, an RNA sequence transcribed from DNA encoding SOD1, and an mRNA sequence encoding SOD1.

"SOD1 mRNA" means an mRNA encoding SOD1.

Therapeutic indications of SOD1

It has been found that antisense inhibition of superoxide dismutase 1 (SOD1) in an animal model of familial ALS reduces mRNA and SOD1 protein levels, and also results in a slowing of disease progression and, a fact important, an increase in survival time. Accordingly, in certain embodiments, methods for slowing the progression of the disease in an individual suffering from familial ALS are disclosed herein, administering to said individual a short antisense compound directed to an SOD1 nucleic acid. In certain of said embodiments, a short antisense compound directed to SOD1 is released directly into the cerebrospinal fluid of the individual. In certain of said embodiments, the procedures further comprise increasing the survival time of an individual suffering from familial ALS. The slowdown of disease progression is indicated by an improvement in one or more indicators of the progression of ALS disease, which includes, among others, the revised scale of functional ALS score, lung function tests and strength measurements muscular.

Combination therapies with SOD1

In certain embodiments, one or more pharmaceutical compositions comprising a short antisense compound directed to an SOD1 nucleic acid are co-administered with one more different pharmaceutical agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat an undesired effect of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are prepared separately.

In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain of said embodiments, nicotinic acid is selected from nicotinic acid immediate release, nicotinic acid extended release and nicotinic acid sustained release.

In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain of said embodiments, the fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate and ciprofibrate.

Other examples of pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound targeting an ApoB nucleic acid include, among others, corticosteroids, including, but not limited to, prednisone; immunoglobulins, including, inter alia intravenous immunoglobulin (IVIG); analgesics (eg, acetaminophen); anti-inflammatory agents, including but not limited to non-steroidal anti-inflammatory drugs (eg, ibuprofen, COX-1 inhibitors and COX-2 inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (eg, biguanides, glucosidase inhibitors, insulins, sulfonylureas and thiazolidendiones); adrenergic modifiers; diuretics; hormones (eg, anabolic steroids, androgens, estrogens, calcitonin, progestin, somatostatin and thyroid hormones); immunomodulators; muscle relaxants; antihistamines, antiosteoporosis agents (eg, bisphosphonates, calcitonin and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; Atlantic poisonous oak or poison sumac products; antibodies; and vaccines.

Certain short antisense compounds targeting an SOD1 nucleic acid

In certain embodiments, the short antisense compounds are directed to an SOD1 nucleic acid having the registration number sequence in GENBANK® NM_X02317.1, incorporated herein as SEQ ID NO.

5. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 5 is at least 90% complementary to SEQ ID No. 5. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 5 it is at least 95% complementary to SEQ ID NO. 5. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 5 IS 100% complementary to SEQ ID NO. 5. In certain embodiments, a short antisense compound. directed to SEQ ID NO. 5 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Table 8 or Table 9.

The nucleotide sequence indicated in each SEQ ID No. in Tables 8 and 9 is independent of any modification of

5 a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The short antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

10 Tables 8 illustrates examples of short antisense compounds directed to SEQ ID NO. 5. Table 8 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 5. The column labeled "rubber motif" indicates the hollow motif. -ala of each short antisense compound. The hollow segment comprises 2'-deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, ‘2-10-2 MOE’ means a 2-10-2 track motive, in which

A gap segment of ten 2’-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2’-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in the hollow" indicates that the hollow segment has 5-methylcytosines, while the

20 wing segments have unmodified cytosines.

In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1, 1-1-10-2,2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 2-8

25 2, 1-8-1, 3-6-3 or 1-6-1, more preferably 1-10-1, 2-10-2, 3-10-3 and 1-9-2.

Table 8: Short antisense compounds directed to SEQ ID No. 5

ISIS Nº

 Target site in 5 ’  Target site in 3 ’  Sequence (5’-3 ’)  Gápmero motive  SEQ ID NO.

387541

85 100  GTCGCCCTTCAGCACG 3-10-3 MOE 406

387540

86 99  TCGCCCTTCAGCAC 2-10-2 MOE 407

387539

87 98  CGCCCTTCAGCA 1-10-1 MOE 408

In certain embodiments, a target region is nucleotides 85-100 of SEQ ID No. 5. In certain such embodiments, short antisense compounds directed to nucleotides 85-100 of SEQ ID No. 5 comprise a sequence of

30 nucleotides selected from SEQ ID No. 406, 407 or 408. In certain such embodiments, a short antisense compound directed to nucleotides 85-100 of SEQ ID No. 5 is selected from Isis No. 387541, 387540 or 387539.

In certain embodiments, short antisense compounds directed to a SOD1 nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid have a

35 length of 9 to 14 nucleotides. In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid are short captamers. In certain of said embodiments, the short catheters directed to an SOD1 nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from α-L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-O

45 N (R) -2 ’) BNA and oxyamino (4’-CH2-N (R) -O-2’) BNA. In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting an SOD1 nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a SOD1 nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a SOD1 nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid have a monomer length. In certain embodiments, short antisense compounds directed to a SOD1 nucleic acid are 13 monomers in length. In certain embodiments, the short antisense compounds directed to an SOD1 nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a SOD1 nucleic acid are 15 monomers in length. In certain embodiments, the short antisense compounds directed to an SOD1 nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to an SOD1 nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of SOD1 are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting an SOD1 nucleic acid, wherein the short antisense compound targeting an SOD1 nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, from 9 to 14, from 10 to 14 monomers (that is, from about 8 to about 16 monomers attached). One skilled in the art will appreciate that this comprises methods of modulating the expression of SOD1 using one or more short antisense compounds targeting an SOD1 nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 8 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 9 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 10 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 11 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 12 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 13 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 14 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 15 monomers. In certain embodiments, the methods of modulating SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 having a length of 16 monomers.

In certain embodiments, the methods of modulating the expression of SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 comprising 9 to 15 monomers. In certain embodiments, the methods of modulating the expression of SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 comprising 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of SOD1 comprise the use of a short antisense compound directed to a nucleic acid of SOD1 comprising 12 or 14 nucleotides or nucleosides.

5. CRP

CRP (also known as C-reactive protein and PTX1) is an essential human acute phase reactant produced in the liver in response to various inflammatory cytokines. The protein, first identified in 1930, is highly conserved and is considered to be an early indicator of infectious or inflammatory conditions. Plasma CRP levels are multiplied by 1000 in response to infection, ischemia, trauma, burns and inflammatory conditions. In clinical trials in which patients receive lipid-lowering therapy, such as statin therapy, it has been shown that patients with reductions in LDL-C and CRP levels have a lower risk of future coronary events compared to patients who experience only reductions. in LDL-C levels.

Definitions

"CRP" means the gene product or protein whose expression is to be modulated by a short antisense compound.

"CRP nucleic acid" means any nucleic acid encoding the CRP. For example, in certain embodiments, a CRP nucleic acid includes, without limitation, a DNA sequence encoding CRP, an RNA sequence transcribed from DNA encoding CRP, and an mRNA sequence encoding CRP.

"CRP mRNA" means an mRNA encoding the CRP.

Therapeutic indications of CRP

In certain embodiments, methods of modulating the expression of CRP in an individual are disclosed herein, comprising administering a short antisense compound directed to a CRP nucleic acid. In certain embodiments, methods of treating an individual are disclosed herein, comprising administering one or more pharmaceutical compositions comprising a short antisense compound directed to a CRP nucleic acid. In certain embodiments, the individual has hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, history of coronary heart disease, coronary heart disease early onset, one or more risk factors for coronary heart disease. In certain embodiments, the individual has acute coronary syndrome, vascular injury, arterial occlusion, unstable angina, postperipheral vascular disease, myocardial infarction (MI), thrombosis, deep venous thrombosis, terminal nephropathy (TPN), chronic renal failure, complement activation , congestive heart failure or systemic vasculitis. In certain embodiments, the individual has suffered a stroke.

In certain embodiments, the individual has undergone a selected procedure of programmed stent placement, angioplasty, percutaneous transluminal angioplasty (PTCA), renal dialysis cardiac transplantation or cardiopulmonary bypass.

In certain embodiments, the individual has an inflammatory disease. In certain of said embodiments, the inflammatory disease is selected from inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis or osteoarthritis.

The guidelines for lipid-lowering therapies were established in 2001, in the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and were updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). The guidelines include obtaining a complete lipoprotein profile, usually after fasting for 9 to 12 hours, for the determination of the levels of LDL-C, total cholesterol and HDL-C. According to the most recently established guidelines, LDL-C levels of 130-159 mg / dl, 160-189 mg / dl and greater than or equal to 190 mg / dl are considered at the high, high and very high limit, respectively. Cholesterol levels of 200-239 and greater than or equal to 240 mg / dl are considered high and high limits, respectively. HCL-C levels below 40 mg / dl are considered low.

In certain embodiments, individuals have been identified as needing lipid lowering therapy. In certain of these embodiments, it has been identified that individuals need lipid-lowering therapy according to the guidelines established in 2001 by the Adult Treatment Panel III (ATP III) of the US National Cholesterol Education Program. (NCEP) and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 190 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy has an LDL-C level greater than 160 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy has an LDL-C level greater than 130 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy has an LDL-C level greater than 100 mg / dl. In certain of these embodiments, the individual in need of lipid lowering therapy should keep the LDLC level below 160 mg / dl. In certain of these embodiments, the individual in need of lipid-lowering therapy should keep the LDL-C level below 130 mg / dl. In certain of these embodiments, the individual who needs lipid-lowering therapy should keep the LDL-C level below 100 mg / dl. In certain of these embodiments, the individual must maintain the LDL-C level below 70 mg / dl.

In certain embodiments, procedures for reducing CRP in an individual are disclosed herein. In certain embodiments, the CRP reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35% , of at least 40%, of at least 45%, of at least 50%, of at least 55%, of at least 60%, of at least 65%, of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 100%.

In certain embodiments, the procedures disclosed herein do not reduce HDL-C levels. In certain embodiments, the procedures disclosed herein do not result in the accumulation of lipids in the liver. In certain embodiments, the procedures disclosed herein do not `produce hepatic steatosis.

In certain embodiments, methods for reducing the concentration of CRP in a subject are disclosed herein while reducing the side effects associated with the treatment. In certain embodiments, a side effect is liver toxicity. In certain embodiments, a side effect is an abnormal liver function. In certain embodiments, a side effect is elevated levels of alanine aminotransferase (ALT). In certain embodiments, a side effect is elevated levels of aspartate aminotransferase (AST).

In certain embodiments, methods for reducing the concentration of CRP in a subject that does not reach LDL-C target levels as a result of lipid lowering therapy are disclosed herein. In certain of said embodiments, a short antisense compound directed to a CRP nucleic acid is the only pharmaceutical agent administered to the subject. In certain of said embodiments, the subject has not complied with the recommended lipid lowering therapy. In certain of said embodiments, a pharmaceutical composition of the disclosure is administered together with a different additional lipid-lowering therapy. In certain of said embodiments, an additional lipid-lowering therapy is LDL apheresis. In certain of said embodiments, an additional lipid-lowering therapy is a statin. In certain of said embodiments, an additional lipid-lowering therapy is ezetimibe.

In certain embodiments, methods for reducing the concentration of CRP in a subject intolerant to statins are disclosed herein. In certain of said embodiments, the subject exhibits increases in creatine kinase concentration as a result of the administration of statins. In certain of said embodiments, the subject exhibits abnormal liver function as a result of the administration of statins. In certain of said embodiments, the subject exhibits muscle aches as a result of the administration of statins. In certain of said embodiments, the subject has side effects on the central nervous system as a result of the administration of statins. In certain embodiments, the subject has not complied with the recommended statin therapy.

In certain embodiments, procedures for reducing the risk of coronary heart disease in a subject are disclosed herein. In certain embodiments, methods for slowing the progression of atherosclerosis in a subject are disclosed herein. In certain of said embodiments, methods for stopping the progression of atherosclerosis in a subject are disclosed herein. In certain of said embodiments, methods for reducing the size and / or prevalence of atherosclerotic plaques in a subject are disclosed herein. In certain embodiments, the procedures reduce a subject's risk of developing atherosclerosis.

In certain embodiments, the procedures improve the cardiovascular outcome in a subject. In certain of these embodiments, the improved cardiovascular outcome is the reduction of the risk of developing coronary heart disease. In certain of these embodiments, the improved cardiovascular outcome is a reduction in the occurrence of one or more major cardiovascular events, including, but not limited to, death, myocardial infarction, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest and dysrhythmia. handset. In certain of these embodiments, the improved cardiovascular outcome is evidenced by the improvement in the thickness of the intimate mean of the carotid. In certain of said embodiments, the improvement of the thickness of the intimate mean of the carotid is a decrease in thickness. In certain of said embodiments, the improvement of the thickness of the intimate carotid mean is a prevention of an increase in the thickness of the intimate mean.

In certain of said embodiments, a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid is for use in therapy. In certain embodiments, therapy is the reduction of CRP in an individual. In certain embodiments, the therapy is the treatment of hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, coronary heart disease, coronary heart disease early, precocious, premature. In further embodiments, therapy is the reduction of the risk of CPC. In certain, therapy is the prevention of atherosclerosis. In certain embodiments, therapy is the prevention of coronary heart disease. In certain embodiments, the therapy is the treatment of acute coronary syndrome, chronic renal failure, vascular injury, arterial occlusion, atherothrombosis, unstable angina, postperipheral vascular disease, myocardial post-infarction (MI), thrombosis, deep vein thrombosis, terminal kidney disease (TPN). ), complement activation, congestive heart failure or systemic vasculitis. In certain embodiments, the therapy is the treatment of an individual has undergone a selected procedure of programmed stent placement, angioplasty, percutaneous transluminal angioplasty (PTCA), renal dialysis cardiac transplantation or cardiopulmonary bypass.

In certain embodiments, therapy is the treatment of an inflammatory disorder.

In certain embodiments, a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament to reduce CRP levels in an individual. In certain embodiments, a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament to reduce the risk of coronary heart disease. In certain embodiments, the short antisense compound targeting a CRP nucleic acid is used for the preparation of a medicament for the treatment of hypercholesterolemia, unfamiliar hypercholesterolemia, familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, one or more risk factors for coronary heart disease.

In certain embodiments, a short antisense compound targeting a CRP nucleic acid is used for the preparation of a medicament for the treatment of acute coronary syndrome, chronic renal failure, vascular injury, arterial occlusion, atherothrombosis, unstable angina, postperipheral vascular disease, post-myocardial infarction (MI), thrombosis, deep vein thrombosis, terminal nephropathy (TPN), complement activation, congestive heart failure or systemic vasculitis. In certain embodiments, a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament for the treatment of an individual who has suffered a stroke.

In certain embodiments, a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament for the treatment of an individual who has undergone a selected procedure of programmed stent placement, angioplasty, percutaneous transluminal angioplasty (PTCA ), renal dialysis or cardiopulmonary bypass transplant.

In certain embodiments, a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament for the treatment of an inflammatory disease. In certain of said embodiments, a short antisense compound directed to a CRP nucleic acid is used for the preparation of a medicament for the treatment of inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis or osteoarthritis.

Combination therapies with CRP

In certain embodiments, one or more pharmaceutical compositions comprising a short antisense compound directed to a CRP nucleic acid are co-administered with one more different pharmaceutical agents. In certain of said embodiments, the one plus pharmaceutical agents are lipid lowering agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition different from that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat an undesired effect of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are prepared separately.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid include lipid lowering agents. In certain of said embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, atorvastatin, simvastatin, rosuvastatin and ezetimibe. In certain of said embodiments, the lipid lowering agent is administered prior to the administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered after administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered at the same time as the pharmaceutical composition of the present disclosure. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is the same as the dose that would be administered if the lipid-lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid lowering agent is less than the dose that would be administered if the lipid lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is greater than the dose that would be administered if the lipid-lowering agent was administered alone.

In certain embodiments, a coadministered lipid lowering agent is an HMG-CoA reductase inhibitor. In certain of said embodiments, the HMG-CoA reductase inhibitor is a statin. In certain of said embodiments, the statin is selected from atorvastatin, simvastatin, pravastatin, fluvastatin and rosuvastatin.

In certain embodiments, a co-administered lipid lowering agent is ISIS 301012.

In certain embodiments, a coadministered lipid lowering agent is a cholesterol absorption inhibitor. In certain of said embodiments, the cholesterol absorption inhibitor is ezetimibe.

In certain embodiments, a coadministered lipid-lowering agent is an HMG-CoA reductase inhibitor formulated in conjunction with a cholesterol absorption inhibitor. In certain of said embodiments, the jointly formulated lipid lowering agent is ezetimibe / simvastatin.

In certain embodiments, a co-administered lipid-lowering agent is a microsomal triglyceride transfer protein inhibitor.

In certain embodiments, a co-administered pharmaceutical agent is a bile acid sequestrant. In certain of said embodiments, the bile acid sequestrant is selected from cholestyramine, colestipol and colesevelam.

In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain of said embodiments, nicotinic acid is selected from nicotinic acid immediate release, nicotinic acid extended release and nicotinic acid sustained release.

In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain of said embodiments, the fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate and ciprofibrate.

Other examples of pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid include, among others, corticosteroids, including, but not limited to, prednisone; immunoglobulins, including, inter alia intravenous immunoglobulin (IVIG); analgesics (eg, acetaminophen); anti-inflammatory agents, including but not limited to non-steroidal anti-inflammatory drugs (eg, ibuprofen, COX-1 inhibitors and COX-2 inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (eg, biguanides, glucosidase inhibitors, insulins, sulfonylureas and thiazolidendiones); adrenergic modifiers; diuretics; hormones (eg, anabolic steroids, androgens, estrogens, calcitonin, progestin, somatostatin and thyroid hormones); immunomodulators; muscle relaxants; antihistamines, antiosteoporosis agents (eg, bisphosphonates, calcitonin and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; Atlantic poisonous oak or poison sumac products; antibodies; and vaccines.

In certain of said embodiments, a pharmaceutical composition comprising a short antisense compound directed to a CRP nucleic acid can be administered together with a lipid lowering therapy. In certain of these embodiments, a lipid lowering therapy is a therapeutic lifestyle change. In certain of these embodiments, a lipid-lowering therapy is LDL apheresis.

Certain short antisense compounds targeting a CRP nucleic acid

In certain embodiments, short antisense compounds are directed to a CRP nucleic acid having the registration number sequence in GENBANK® NM_000567.1, incorporated herein as SEQ ID NO.

6. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 6 is at least 90% complementary to SEQ ID No. 6. In certain such embodiments, a short antisense compound directed to SEQ ID No. 6 it is at least 95% complementary to SEQ ID No. 6. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 6 IS 100% complementary to SEQ ID No. 6. In certain embodiments, a short antisense compound directed to SEQ ID NO. 6 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Table 9.

The nucleotide sequence indicated in each SEQ ID NO in Table 9 is independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The short antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

Tables 9 illustrates examples of short antisense compounds directed to SEQ ID NO. 6. Table 9 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 6. The column labeled "rubber motif" indicates the wing-hollow motif. wing of each short antisense compound. The hollow segment comprises 2'-deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in the hollow" indicates that the hollow segment has 5-methylcytosines, while the

5 wing segments have unmodified cytosines.

In certain embodiments, short antisense compounds directed to a CRP nucleic acid may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a CRP nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 2

10 8-2, 1-8-1, 3-6-3 or 1-6-1, more preferably 1-10-1, 2-10-2, 3-10-3 and 1-9-2

Table 9: Short antisense compounds directed to SEQ ID No. 6

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

353506

1257 1272  ACTCTGGACCCAAACC 3-10-3 MOE 409

353507

1258 1271  CTCTGGACCCAAAC 2-10-2 MOE 410

353484

1305 1320 CCATTTCAGGAGACCT 3-10-3 MOE 411

353485

1306 1319 CATTTCAGGAGACC 2-10-2 MOE 412

In certain embodiments, a target region is nucleotides 1305-1320 of NM_000567. In certain of said embodiments, short antisense compounds directed to nucleotides 1305-1320 of NM_000567.1 comprise a

A nucleotide sequence selected from SEQ ID Nos. 1305 or 1306. In certain such embodiments, a short antisense compound directed to nucleotides 263-278 of NM_000567.1 is selected from No. Isis 353484 or 353485.

In certain embodiments, a target region is nucleotides 1257-1272 of NM_000567. In certain embodiments, a short antisense compound directed to nucleotides 1257-1272 of NM_000567 comprises a nucleotide sequence selected from SEQ ID NOS 1257 or 1258. In certain such embodiments, an antisense compound

Short 20 directed to nucleotides 428-483 of NM_000567.1 is selected from No. Isis 353506 or 353507.

In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a CRP nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeted to a nucleic acid of

25 CRPs have a length of 10 to 14 nucleotides. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting a CRP nucleic acid are short captamers. In certain of said embodiments, short cappules directed to a CRP nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds directed to a CRP nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from -L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-menyloxy (4'-CH2-O-2') BNA, ethylene (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a

Substituent at the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O-CH3, 2'-O (CH2) 2SCH3 , O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), in which each Rm and Rn is, independently, H or C1-C10 alkyl substituted or unsubstituted. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a CRP nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven,

40 twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds directed to a CRP nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a CRP nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a CRP nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a CRP nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to a CRP nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to a CRP nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of CRP are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a CRP nucleic acid, wherein the short antisense compound targeting a CRP nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating CRP expression using one or more short antisense compounds targeting a CRP nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 8 monomers in length. In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 9 monomers in length. In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 10 monomers in length. In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 11 monomers in length. In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 12 monomers in length. In certain embodiments, the CRP modulation procedures comprise the use of a short antisense compound directed to a CRP nucleic acid that is 13 monomers in length. In certain embodiments, the CRP modulation methods comprise the use of a short antisense compound directed to a CRP nucleic acid that is 14 monomers in length. In certain embodiments, the CRP modulation methods comprise the use of a short antisense compound directed to a CRP nucleic acid that is 15 monomers in length. In certain embodiments, the CRP modulation methods comprise the use of a short antisense compound directed to a CRP nucleic acid that is 16 monomers in length.

In certain embodiments, the methods of modulating CRP expression comprise the use of a short antisense compound directed to a CRP nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating CRP expression comprise the use of a short antisense compound directed to a CRP nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of CRP comprise the use of a short antisense compound directed to a CRP nucleic acid comprising from 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of CRP comprise the use of a short antisense compound directed to a CRP nucleic acid comprising 12

or 14 nucleotides or nucleosides.

6. Glucocorticoid receptor s (GCCR)

Glucocorticoids were among the first steroid hormones that were identified and are responsible for a multitude of physiological functions, including stimulation of gluconeogenesis, decreased glucose uptake and use in peripheral tissues, increased glycogen deposition, suppression of immune and inflammatory responses, inhibition of cytokine synthesis and acceleration of various developmental events. Glucocorticoids are also especially important for fighting stress. The increased synthesis and release of stress-induced glucocorticoids leads to, among other responses, increased ventricular workload, inhibition of inflammatory mediators, inhibition of cytokine synthesis and increased glucose production (Karin, Cell , 1998, 93,487-490).

Natural glucocorticoids and their synthetic derivatives exert their action through the glucocorticoid receptor, a cytoplasmic member expressed ubiquitously from the nuclear hormone receptor superfamily. The human glucocorticoid receptor is also known as nuclear receptor subfamily 3, group C, member 1; NR3C1; GCCR; GCR; GRL; glucocorticoid receptor, lymphocyte. The gene is located on the human chromosome 5q11-q13 and consists of a 9 exons (Encio and Detera-Wadleigh, J Biol Chem, 1991, 266, 7182-7188; Gehring et al., Proc Natl Acad Sci USA, 1985, 82 , 3751-3755). There are multiple forms of human glucocorticoid receptor mRNA: a cDNA containing exons 1-8 and exon 9a of the human 5.5 glucocorticoid receptor; a cDNA containing exons 1-8 and exon 9β of the human 4.3 glucocorticoid β receptor; and a cDNA containing exons 1-8 and all exon 9, which includes exon 9a, exon 9ß and "region J", which is flanked by exons 9a and 9ß of the human glucocorticoid receptor 7.0 kb (Hollenberg et al., Nature, 1985, 318, 635-641; Oakley et al., J Biol Chem, 1996, 271, 9550-9559). The human glucocorticoid receptor is the predominant isoform of the receptor and the one that exhibits steroid binding activity (Hollenberg et al., Nature, 1985, 318, 635-641). Additionally, by using three different promoters three different variants of exon 1 can be transcribed and alternative splicing of a variant of exon 1 can result in three different versions of this exon. Thus, the human glucocorticoid receptor mRNA may contain 5 different variants of exon 1 (Breslin et al., Mol Endocrinol, 2001, 15, 13811395).

Analysis of the expression patterns of the a and β isoforms of the human glucocorticoid receptor mRNA reveals that the isoform is expressed more abundantly. Both isoforms are expressed in similar tissues and cell types, including lung, kidney, heart, liver, skeletal muscle, macrophages, neutrophils and peripheral blood mononuclear cells.

Only the human glucocorticoid receptor is expressed in the colon. At the protein level, while isoform a is detected in all tissues analyzed, the β isoform is undetectable, suggesting that, under physiological conditions, the default splicing pathway is one that produces isoform a (Pujols and col., Am J Physiol Cell Physiol, 2002, 283, C1324-1331). The β isoform of the glucocorticoid receptor does not bind a glucocorticoid agonist or an antagonist. In addition, the β isoform is primarily located in the nucleus of transfected cells, independent of hormonal stimulation. When both isoforms are expressed in the same cell, the β glucocorticoid receptor inhibits hormone-mediated glucocorticoid receptor stimulation of gene expression, suggesting that the β isoform functions as an inhibitor of the a receptor activity. glucocorticoids (Oakley et al., J Biol Chem, 1996, 271, 9550-9559). Unless otherwise indicated, the human glucocorticoid receptor described herein is defined as the ubiquitous product (s) of the gene located on chromosome 5q11-q13.

Cell lines transfected with an antisense RNA strand complementary to the glucocorticoid receptor exhibited a reduction in glucocorticoid receptor mRNA levels and a decreased response to the dexamethasone glucocorticoid receptor agonist (Pepin and Barden, Mol Cell Biol, 1991 , 11, 1647-1653). Transgenic mice carrying an antisense glucocorticoid receptor gene construct were used to study the effect of glucocorticoid feedback on the hypothalamic-pituitary-adrenal axis (Pepin et al., Nature, 1992, 355, 725-728). In another study of similarly engineered mice, the intake and energy expenditure, the lipoprotein lipase activity in the vastus lateralis muscle and the norepinephrine of the brown and cardiac adipose tissue were lower than in the control animals. On the contrary, the fat content and total body energy were significantly higher than in the control animals. These results suggest that a defective glucocorticoid receptor system can affect energy balance by increasing energy efficiency and emphasizes the modulating effects of changes in the hypothalamic-pituitary-adrenal axis on the activity of muscle lipoprotein lipase ( Richard et al., Am J Physiol. 1993, 265, R146-150).

The behavioral effects of glucocorticoid receptor antagonists have been measured in animal models designed to assess anxiety, learning and memory. Reduction of glucocorticoid receptor expression in rats that were infused intracerebro-ventricularly in the long term antisense oligodeoxynucleotides targeting the glucocorticoid receptor mRNA did not interfere with space navigation in the Morris water maze test (Engelmann et al., Eur J Pharmacol, 1998, 361, 17-26). Bilateral infusion of an antisense oligodeoxynucleotide targeting the glucocorticoid receptor mRNA in the dentate gyrus of the rat hippocampus reduced the immobility of the rats in the Porsolt forced swimming test (Korte et al., Eur J Pharmacol. 1996, 301 , 19-25).

Glucocorticoids are frequently used for their immunosuppressive, anti-inflammatory effects and the treatment of diseases such as allergies, asthma, rheumatoid arthritis, AIDS, systemic lupus erythematosus and degenerative osteoarthritis. It has been proposed that the negative regulation of gene expression, such as that caused by the interaction of the glucocorticoid receptor with NF-kB, is, at least in part, responsible for the anti-inflammatory action of glucocorticoids in vivo. Interleukin 6, tumor necrosis factor and interleukin 1 are the three cytokines responsible for most of the stimulation of the hypothalamus-pituitary-adrenal axis (HPA) during inflammation stress. The HPA axis and the systemic sympathetic and supramedullary system are the peripheral components of the stress system, responsible for maintaining baseline and stress-related homeostasis. Glucocorticoids, the final products of the HPA axis, inhibit the production of the three inflammatory cytokines and also inhibit their effects on target tissues, with the exception of interleukin 6, which acts synergistically with glucocorticoids to stimulate the production of reactants from acute phase Treatment with glucocorticoids decreases the activity of the HPA axis (Chrousos, N Engl J Med, 1995, 332, 1351-1362).

In some cases, patients are resistant to glucocorticoid treatment. One reason for this steroid resistance lies in the mutations or polymorphisms present in the glucocorticoid receptor gene. A total of 15 missense mutations, three nonsense, three frame shifting, one splice site and two alternative splicing sites, as well as 16 polymorphisms, have been reported in the NR3C1 gene in association with resistance to glucocorticoids (Bray and Cotton, Hum Mutat, 2003, 21, 557-568). Additional studies in humans have suggested a possible association between the incidence and progression of the metabolic syndrome with the alleles in the glucocorticoid receptor (GR) gene (Rosmond, Obes Res, 2002, 10, 1078-1086).

Other cases of glucocorticoid insensitivity are associated with impaired expression of glucocorticoid receptor isoforms. A study of mRNA expression of the human glucocorticoid receptor β isoform in patients with glucocorticoid-resistant ulcerative colitis revealed that the presence of this mRNA was significantly higher than in glucocorticoid-sensitive patients, suggesting that mRNA expression of the ß isoform of the human glucocorticoid receptor in peripheral blood mononuclear cells can serve as a predictor of the response to glucocorticoids in patients with ulcerative colitis (Honda et al., Gastroenterology, 2000, 118, 859-866). An increase in glucocorticoid β receptor expression is also observed in a significantly high number of asthma patients insensitive to glucocorticoids. Additionally, cytokine-induced abnormalities in the ability to bind to the glucocorticoid receptor DNA were found in peripheral blood mononuclear cells of transfection of asthma patients insensitive to glucocorticoids and HepG2 cells with the β-glucocorticoid receptor gene resulted in a significant reduction in the ability to bind to the  glucocorticoid receptor DNA (Leung et al., J Exp Med, 1997, 186, 1567-1574). Dexamethasone binding studies demonstrate that the human β glucocorticoid receptor does not alter the affinity of the  receptor for hormonal ligands, but is its ability to bind to GRE (Bamberger et al., J Clin Invest, 1995, 95, 2435- 2441). Together, these results illustrate that the β glucocorticoid receptor, through competition with the glucocorticoid receptor a for the GRE target sites, can function as an endogenous physiological and pathophysiologically relevant inhibitor of glucocorticoid action.

In the liver, glucocorticoid agonists increase the production of hepatic glucose by activating the glucocorticoid receptor, which subsequently leads to increased expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase. Through gluconeogenesis glucose is formed by non-hexose precursors, such as lactate, pyruvate and alanine (Link, Curr Opin Investig Drugs, 2003, 4, 421-429). Steroidal glucocorticoid receptor antagonists, such as RU 486, have been analyzed in rodent diabetes models. Mice deficient in the leptin receptor gene, called db / db mice, are genetically obese, diabetic and hyperinsulinemic. Treatment of hyperglycemic db / db mice with RU 486 lowered glucose levels by approximately 49%, without affecting plasma insulin levels. Additionally, treatment with RU 486 reduced the expression of the PEPCK glucocorticoid receptor responsive genes, glucose-6-phosphatase, type 2 glucose transporter and tyrosine aminotransferase in db / db mice compared to untreated animals (Friedman and col., J Biol Chem, 1997, 272, 31475-31481). RU 486 also improves diabetes in ob / ob mice with diabetes, obesity and hyperinsulinemia, through a reduction in serum insulin and blood glucose levels (Gettys et al., Int J Obes Relat Metab Disord, 1997, 21,865-873).

Since the increase in gluconeogenesis is considered the main source of increased glucose production in diabetes, numerous therapeutic targets have been investigated for the inhibition of hepatic glucose production. Due to the ability of glucocorticoid receptor antagonists to improve diabetes in animal models, such compounds are among the possible therapies being explored. However, there are harmful systemic effects of glucocorticoid receptor antagonists, including activation of the HPA axis (Link, Curr Opin Investig Drugs, 2003, 4, 421-429). The increased activity of the HPA axis is associated with the suppression of the inflammatory action related to the immune system, which can increase susceptibility to infectious agents and neoplasms. Conditions associated with suppressing inflammation mediated by the immune system through defects in the HPA axis, or its target tissues, include Cushing syndrome, chronic stress, chronic alcoholism and melancholic depression ((Chrousos, N Engl J Med, 1995, 332, 1351-1362) Therefore, the development of liver-specific glucocorticoid receptor antagonists is of great value Steroidal glucocorticoid receptor antagonists have been conjugated to bile acids in order to direct them to the liver (Apelqvist et al., 2000.) Currently, no known therapeutic agents targeting glucocorticoid receptors are undesirable peripheral effects (Link, Curr Opin Investig Drugs, 2003, 4, 421-429). need for agents capable of effectively inhibiting the hepatic glucocorticoid receptor.

Definitions

"Glucocorticoid receptor" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound. In general, the glucocorticoid receptor is called GCCR.

"GCCR nucleic acid" means any nucleic acid encoding the GCCR. For example, in certain embodiments, a GCCR nucleic acid includes, without limitation, a DNA sequence encoding GCCR, an RNA sequence transcribed from DNA encoding GCCR and an mRNA sequence encoding the GCCR. "GCCR mRNA" means an mRNA that encodes the GCCR.

Therapeutic indications

Antisense technology is an effective means to reduce the expression of one or more specific gene products and, therefore, is useful in a number of therapeutic, diagnostic and research applications for the modulation of glucocorticoid receptor expression. In addition, in certain embodiments, the liver is one of the tissues in which the highest concentrations of antisense oligonucleotides are found after administration (Geary et al., Curr. Opin. Investig. Drugs, 2001, 2, 562-573) . Therefore, in certain embodiments, the antisense technology represents an attractive procedure for specific liver inhibition of glucocorticoid receptors.

In certain embodiments, short antisense compounds targeting a nucleic acid encoding the glucocorticoid receptor are preferably distributed in the liver. In certain embodiments, short antisense compounds have greater potency in the liver when compared to a longer parental compound. In certain embodiments, the target RNA is predominantly expressed in the liver.

For therapeutics, a subject suspected of having a disease or disorder, which can be treated by modulating the expression of GCCR is treated by administering one or more short antisense compounds. In a non-limiting example, the methods comprise the step of administering to a animal a therapeutically effective amount of a short antisense compound. Certain short antisense compounds inhibit GCCR activity and / or inhibit GCCR expression. In certain embodiments, the activity or expression of GCCR in a subject is inhibited by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in at least 95%, at least 98%, at least 99%, or 100%. In certain embodiments, the activity or expression of GCCR in a subject is inhibited by at least 30%. In certain embodiments, the activity or expression of GCCR in a subject is inhibited by at least 50% or more.

The reduction of GCCR expression can be measured in, for example, blood, plasma, serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. In certain embodiments, the cells contained within said fluids, tissues or organs being analyzed comprise nucleic acids encoding GCCR and / or contain the GCCR protein itself.

Certain pharmaceutical and other compositions comprising short antisense compounds are also disclosed herein. In certain embodiments, short antisense compounds are used in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have a motif (detoxifying wing) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3- 10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 2-8-2, 1-8-1, 36-3 or 1-6-1. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have a motif (wing-deoxy-wing) selected from 1-10-1, 2-10-2, 3-10-3 and 1-9- 2. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have a motif (wing-deoxy-wing) selected from 3-10-3, 2-10-3, 2-10-2, 1-10- 1, 1-10-2, 2-8-2, 1-8-1, 3-6-3 or 1-6-1, more preferably 2-10-2 and 2-8-2.

In certain embodiments, methods of treating an individual by administering one are disclosed herein.

or short antisense compounds directed to a GCCR nucleic acid or a pharmaceutical composition comprising said compound. Methods of treating an individual suffering from a disease or condition associated with the activity of GCCR are also disclosed by administering a short antisense compound directed to a GCCR nucleic acid. In addition to diabetes, particularly type 2 diabetes, diseases and conditions associated with GCCR include, but are not limited to, obsessed, metabolic syndrome X, Cushing syndrome, Addison's disease, inflammatory diseases such as asthma, rhinitis and arthritis, allergy, autoimmune disease , immunodeficiency, anorexia, cachexia, bone loss or bone fragility and wound healing. Metabolic syndrome, metabolic syndrome X or simply syndrome X refers to a group of risk factors that include obesity, dyslipidemia, particularly elevated blood triglyceride levels, glucose intolerance, elevated blood sugar levels and hypertension. In certain embodiments, short antisense compounds targeting GCCR are used to improve hyperglycemia induced by systemic steroid therapy. In addition, antisense technology provides a means of inhibiting the expression of the β isoform of the glucocorticoid receptor, which has been shown to be overexpressed in patients resistant to

glucocorticoid treatment.

In certain embodiments, short antisense compounds directed to a nucleic acid encoding GCCR and modulating glucocorticoid receptor expression are disclosed herein. Pharmaceutical and other compositions comprising the compounds of the disclosure are also disclosed. Five methods of selective detection of glucocorticoid receptor modulators and methods of modulating glucocorticoid receptor expression in cells, tissues or animals, comprising contacting said cells, tissues or animals with one or more of the compounds are also disclosed. or compositions of the disclosure. This document also indicates procedures for treating an animal, particularly a human being, suspected of having, or is susceptible to, a disease or condition associated with the expression of recipients of

10 glucocorticoids Such procedures comprise administering a therapeutically or prophylactically effective amount of one or more of the compounds or compositions of the disclosure to the person in need of the treatment.

Certain short antisense compounds targeting a GCCR nucleic acid

In certain embodiments, the short antisense compounds are directed to a GCCR nucleic acid having the nucleotide sequence 1 to 106000 of registration number in GENBANK® AC012634, incorporated herein as SEQ ID NO. 8. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 8 is at least 90% complementary to SEQ ID NO. 8. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 8 is at least 95%. complementary to SEQ ID NO. 8. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 8 IS 100% complementary to SEQ ID NO. 8. In certain embodiments, a short antisense compound directed to SEQ ID NO. 8 includes a selected nucleotide sequence

20 of the nucleotide sequences indicated in Tables 10 and 11.

The nucleotide sequence indicated in each SEQ ID NO in Tables 10 and 11 is independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The short antisense compounds described by the Isis Number (No.

25 Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a catheter motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a 2-10-2 cathamer motif.

30 Tables 10 and 11 illustrate examples of short antisense compounds directed to SEQ ID NO. 8. Table 10 illustrates short antisense compounds that are 100% complementary to SEQ ID NO. 8. Table 11 illustrates short antisense compounds having one or more two mismatches with respect to SEQ ID NO. 8. The column called "catheter motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar

35 modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the gimer motif, in which case the

40 cytosines indicated are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 10: Short antisense compounds directed to SEQ ID NO. 8

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

371644

88142 88155 TTTGGGAGGTGGTC 2-10-2 MOE 413

371645

88156 88169 CACACCAGGCAGAG 2-10-2 MOE 414

371649

88212 88225 CTITACAGCTTCCA 2-10-2 MOE 415

371651

88242 88255 CACTACCTTCCACT 2-10-2 MOE 416

371652

88248 88261 AACACACACTACCT 2-10-2 MOE 417

371653

88256 88269 CTCTTCAAAACACA 2-10-2 MOE 418

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

371665

92037 92050 GTAATTGTGCTGTC 2-10-2 MOE 419

371669

92086 92099 OTTTTTCTTCGAATT 2-10-2 MOE 420

371671

92114 92127 CATTTTCGATAGCG  2-10-2 MOE 421

371673

92142 92155 ACCTTCCAGGTTCA 2-10-2 MOE 422

Table 11: Short antisense compounds directed to SEQ ID No. 8 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

371638

2039 2052 ATAGGAAGCATAAA 2-10-2 MOE 423

371650

4949 4962 TCTTTTAAAGAAGA 2-10-2 MOE 424

371673

10187 10200 ACCTTCCAGGTTCA 2-10-2 MOE 422

371660

13465 13478 AAGGATATTTTAAA 2-10-2 MOE 425

371660

14428 14441 AAGGATATTTTAAA 2-10-2 MOE 425

371654

15486 15499 GAACAAAAATTAAA 2-10-2 MOE 427

371661

16638 16651 TTCCACAGATCTGT 2-10-2 MOE 428

371653

17892 17905 CTCTTCAAAACACA 2-10-2 MOE 418

371679

18444 18457 TTTATAAAGTAAAG 2-10-2 MOE 429

371645

19816 19829 CACACCAGGCAGAG 2-10-2 MOE 414

371638

21555 21568 ATAGGAAGCATAAA 2-10-2 MOE 423

371650

21775 21788 TCTTTTAAAGAAGA 2-10-2 MOE 424

371679

21902 21915 TTTATAAAGTAAAG 2-10-2 MOE 429

371655

22507 22520 TACTGTGAGAAATA 2-10-2 MOE 433

371655

22722 22735 TACTGTGAGAAATA 2-10-2 MOE 433

371672

25662 25675 TTCCAGCTTGAAGA 2-10-2 MOE 435

371678

25926 25939 GATCAGTTCTCATG 2-10-2 MOE 436

371655

26041 26054 TACTGTGAGAAATA 2-10-2 MOE 433

371638

29770 29783 ATAGGAAGCATAAA 2-10-2 MOE 423

371668

30551 30564 TTATCAATGATGCA 2-10-2 MOE 439

371670

40584 40597 GCATGCTGGACAGT 2-10-2 MOE 440

371654

43331 43344 GAACAAAAATTAAA 2-10-2 MOE 427

371650

46024 46037 TCTTTTAAAGAAGA 2-10-2 MOE 424

371659

50372 50385 TTGCACCTGAACTA 2-10-2 MOE 443

371634

50565 50578 CAGAATATATTTCT 2-10-2 MOE 444

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

371673

56942 56955 ACCTTCCAGGTTCA 2-10-2 MOE 422

371654

62372 62385 GAACAAAAATTAAA 2-10-2 MOE 427

371679

63537 63550 TTTATAAAGTAAAG 2-10-2 MOE 429

371654

64908 64921 GAACAAAAATTAAA 2-10-2 MOE 427

371661

65795 65808 TTCCACAGATCTGT 2-10-2 MOE 428

371645

70997 71010 CACACCAGGCAGAG 2-10-2 MOE 414

371661

77400 77413 TTCCACAGATCTGT 2-10-2 MOE 428

371663

82329 82342 ATAAGAGATTAAAA 2-10-2 MOE 450

371633

83426 83439 TCCCCCTTCTCATT 2-10-2 MOE 451

371662

85873 85886 GGGCATTGTTAAAA 2-10-2 MOE 452

371654

86476 86489 GAACAAAAATTAAA 2-10-2 MOE 427

371679

86516 86529 TTTATAAAGTAAAG 2-10-2 MOE 429

371641

88097 88110 AGAACTCACATCTG 2-10-2 MOE 455

371642

88111 88124 GAGCTGGACGGAGG 2-10-2 MOE 456

371646

88170 88183 AAGCTTCATCGGAG 2-10-2 MOE 457

371647

88184 88197 ATAATGGCATCCCG 2-10-2 MOE 458

371650

88226 88239 TCTTTTAAAGAAGA 2-10-2 MOE 424

371673

91493 91506 ACCTTCCAGGTTCA 2-10-2 MOE 422

371664

92030 92043 TGCTGTCCTATAAG 2-10-2 MOE 460

371666

92044 92057 CACAAAGGTAATTG 2-10-2 MOE 461

371667

92058 92071 ATCATTTCTTCCAG  2-10-2 MOE 462

371668

92072 92085 TTATCAATGATGCA 2-10-2 MOE 463

371670

92100 92113 GCATGCTGGACAGT 2-10-2 MOE 440

371672

92128 92141 TTCCAGCTTGAAGA 2-10-2 MOE 435

371674

92147 92160 CCATTACCTTCCAG 2-10-2 MOE 466

371637

92983 92996 GCATAAACAGGGTT 2-10-2 MOE 467

371654

93928 93941 GAACAAAAATTAAA 2-10-2 MOE 427

371641

99772 99785 AGAACTCACATCTG 2-10-2 MOE 455

371679

99883 99896 TTTATAAAGTAAAG 2-10-2 MOE 429

371660

99933 99946 AAGGATATTTTAAA 2-10-2 MOE 425

371635

105004 105017 TATGAAAGGAATGT 2-10-2 MOE 472

371654

105028 105041 GAACAAAAATTAAA 2-10-2 MOE 427

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

371676

106482 106495 TTCCTTAAGCTTCC 2-10-2 MOE 474

371650

107838 107851 TCTTTTAAAGAAGA 2-10-2 MOE 424

371673

110922 110935 ACCTTCCAGGTTCA 2-10-2 MOE 422

371673

111580 111593 ACCTTCCAGGTTCA 2-10-2 MOE 422

371634

114608 114621 CAGAATATATTTCT 2-10-2 MOE 444

371638

115040 115053 ATAGGAAGCATAAA 2-10-2 MOE 423

371660

116244 116257 AAGGATATTTTAAA 2-10-2 MOE 425

371663

116657 116670 ATAAGAGATTAAAA 2-10-2 MOE 450

371673

118068 118081 ACCTTCCAGGTTCA 2-10-2 MOE 422

371666

118834 118847 CACAAAGGTAATTG 2-10-2 MOE 461

371660

119858 119871 AAGGATATTTTAAA 2-10-2 MOE 425

371660

120210 120223 AAGGATATTTTAAA 2-10-2 MOE 425

371662

120876 120889 GGGCATTGTTAAAA 2-10-2 MOE 452

371655

124004 124017 TACTGTGAGAAATA 2-10-2 MOE 433

371656

124170 124183 GAACAGTTAAACAT 2-10-2 MOE 485

In certain embodiments, a target region is nucleotides 88142-88269 of SEQ ID NO. 8. In certain embodiments, a short antisense compound targeting nucleotides 88142-88269 of SEQ ID NO. 8. In certain embodiments, a short antisense compound. directed to nucleotides 88142-88269 comprises a nucleotide sequence

5 selected from SEQ ID Nos. 413, 414, 415, 416, 417 or 418. In certain such embodiments, an antisense compound directed to nucleotides 88142-88269 of SEQ ID NO: 8 is selected from No. Isis 371644, 371645 , 371649, 371651, 371652 or 371653.

In certain embodiments, a target region is nucleotides 88142-88169 of SEQ ID NO. 8. In certain embodiments, a short antisense compound directed to nucleotides 88142-88169 of SEQ ID NO. 8. In certain embodiments, a

The short antisense compound directed to nucleotides 88142-88169 comprises a nucleotide sequence selected from SEQ ID NO: 413 or 414. In certain such embodiments, an antisense compound directed to nucleotides 88142-88169 of SEQ ID NO: 8 is selected. No. Isis 371644 or 371645.

In certain embodiments, a target region is nucleotides 88242-88269 of SEQ ID NO. 8. In certain embodiments, a short antisense compound directed to nucleotides 88242-88269 of SEQ ID NO. 8. In certain embodiments, a

The short antisense compound targeting nucleotides 88242-88269 comprises a nucleotide sequence selected from SEQ ID NO: 416, 417 or 418. In certain such embodiments, an antisense compound targeting nucleotides 88242-88269 of SEQ ID NO: 8 is selected from No. Isis 371651, 371652 or 371653.

In certain embodiments, a target region is nucleotides 92037-92155 of SEQ ID NO. 8. In certain embodiments, a short antisense compound directed to nucleotides 92037-92155 of SEQ ID NO. 8. In certain embodiments, a

The short antisense compound directed to nucleotides 92037-92155 comprises a nucleotide sequence selected from SEQ ID NOS 419, 420, 421 or 422. In certain such embodiments, an antisense compound directed to nucleotides 92037-92155 of SEQ ID No. 8 is selected from No. Isis 371665, 371669, 371671 or 171673.

In certain embodiments, a target region is nucleotides 92114-92155 of SEQ ID No. 8. In certain embodiments, a short antisense compound directed to nucleotides 92114-92155 of SEQ ID No. 8. In certain embodiments, a

The short antisense compound directed to nucleotides 92114-92155 comprises a nucleotide sequence selected from SEQ ID NO: 421 or 422. In certain such embodiments, an antisense compound directed to nucleotides 92114-92155 of SEQ ID NO: 8 is selected. No. Isis 371671 or 171673.

In certain embodiments, short antisense compounds directed to a GCCR nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are short captamers. In certain of said embodiments, short cappules directed to a GCCR nucleic acid comprise at least one high affinity modification on one or more wings of the compound. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from α-L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a GCCR nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid have a monomer length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a GCCR nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a GCCR nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of GCCR are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a GCCR nucleic acid, wherein the short antisense compound targeting a GCCR nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating GCCR expression using one

or more short antisense compounds directed to a GCCR nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers.

In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 8 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 9 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 10 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 11 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 12 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 13 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 14 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 15 monomers in length. In certain embodiments, the GCCR modulation methods comprise the use of a short antisense compound directed to a GCCR nucleic acid that is 16 monomers in length.

In certain embodiments, the methods of modulating the expression of GCCR comprise the use of a short antisense compound directed to a GCCR nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating the expression of GCCR comprise the use of a short antisense compound directed to a GCCR nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of GCCR comprise the use of a short antisense compound directed to a GCCR nucleic acid comprising from 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of GCCR comprise the use of a short antisense compound directed to a GCCR nucleic acid comprising 12 or 14 nucleotides or nucleosides.

7. Glucagon receptor (GCGR)

The maintenance of normal blood glucose is a carefully regulated metabolic event. Glucagon, a 29-amino acid peptide responsible for maintaining blood glucose levels in the post-absorption state, increases the release of glucose from the liver by activating hepatic glycogenolysis, gluconeogenesis, stimulating lipolysis in adipose tissue and stimulating insulin secretion. . During elevated blood glucose levels, insulin reverses the potentiation of glycogenolysis and glucagon-mediated glycogenolysis. In patients with diabetes, insulin is either unavailable or not completely effective. Although the treatment of diabetes has traditionally focused on increasing insulin levels, antagonism of glucagon function has been considered an alternative therapy. Since glucagon exerts its physiological effects by signaling through the glucagon receptor, the glucagon receptor has been proposed as a possible therapeutic target for diabetes (Madsen et al., Curr. Pharm. Des., 1999, 5, 683 -691).

The glucagon receptor belongs to the superfamily of G-protein coupled receptors that has seven transmembrane domains. It is also a member of the smaller subfamily of homologous receptors that bind peptides that are structurally similar to glucagon. The gene encoding the human glucagon receptor was cloned in 1994 and genomic sequence analysis revealed multiple introns and an 82% identity with the rat glucagon receptor gene ((Lok et al., Gene, 1994, 140 , 203-209 .; MacNeil et al., Biochem. Biophys. Res. Commun., 1994, 198, 328-334.) Cloning of the rat glucagon receptor gene has also led to the description of multiple alternative variants of splicing (Maget et al., FEBS Lett., 1994, 351, 271-275). The human glucagon receptor gene is located on chromosome 17q25 (Menzel et al., Genomics, 1994, 20, 327-328 ) A missense mutation of Gly to Ser in codon 40 of the glucagon receptor gene leads to an affinity 3 times lower for glucagon (Fujisawa et al., Diabetologia, 1995, 38, 983-985) and this mutation It has been linked to several disease states, including non-insulin dependent diabetes mellitus (Fujisawa et al., Diabeto lodge, 1995, 38, 983-985), hypertension (Chambers and Morris, Nat. Genet., 1996, 12, 122) and central adiposity (Siani et al., Obes. Res., 2001, 9, 722-726).

Definitions

"Glucagon receptor" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound.

In general, the glucagon receptor is called GCGR, but it can also be called GR, GGR, MGC138246, MGC93090.

"GCGR nucleic acid" means any nucleic acid encoding the GCGR. For example, in certain embodiments, a GCGR nucleic acid includes, without limitation, a sequence encoding GCGR, an RNA sequence transcribed from DNA encoding GCGR and an mRNA sequence encoding GCGR. "GCGR mRNA" means an mRNA that encodes a GCGR protein.

Therapeutic indications

Antisense technology is an effective means of reducing glucagon receptor expression (GCGR) and has been shown to be unique in its usefulness in a number of therapeutic, diagnostic and research applications. As such, in certain embodiments, short antisense compounds directed to a nucleic acid encoding the glucagon receptor and modulating glucagon receptor expression are disclosed herein. Short antisense compounds capable of inhibiting GCGR expression are also disclosed herein. Methods of treating an individual are also disclosed herein, which comprises administering one or more pharmaceutical compositions comprising a short antisense compound directed to a GCGR nucleic acid. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid inhibit GCGR expression. Methods of treating an individual suffering from a disease or condition associated with GCGR activity by administering one or more pharmaceutical compositions comprising a short antisense compound directed to a GCGR nucleic acid are disclosed herein. For example, methods of treating a subject having elevated blood glucose levels, hyperglycemia, prediabetes, diabetes, type 2 diabetes, metabolic syndrome, obesity and / or insulin resistance are disclosed herein.

Pharmaceutical compositions comprising one or more short antisense compounds targeting GCGR and, optionally, a pharmaceutically acceptable carrier, diluent, enhancer or excipient are also contemplated herein. Certain compounds of the disclosure can also be used in the manufacture of a medicament for the treatment of diseases and disorders related to the effects of GCGR-mediated glucagon.

Certain embodiments of the present disclosure include methods of reducing GCGR expression in tissues or cells, which comprise contacting said cells or tissues with a short antisense compound directed to a nucleic acid encoding GCGR or the pharmaceutical composition comprising said antisense compound. short. In certain of said embodiments, methods of lowering blood glucose levels, blood triglyceride levels or blood cholesterol levels are disclosed herein in a subject, comprising administering to the subject a short antisense compound or A pharmaceutical composition Blood levels can be plasma levels or serum levels. Also contemplated are methods of improving insulin sensitivity, methods of increasing GLP-1 levels and methods of inhibiting hepatic glucose expenditure in an animal comprising administering to said animal an antisense oligonucleotide or a pharmaceutical composition of the disclosure. An improvement in insulin sensitivity can be indicated by a reduction in circulating insulin levels.

In certain embodiments, methods of treating a subject having a disease or condition associated with glucagon activity by GCGR are disclosed herein comprising administering to the subject a therapeutically or prophylactically effective amount of a short antisense compound or a pharmaceutical composition. In certain embodiments, said disease or condition may be a metabolic disease or condition. In certain embodiments, the metabolic disease or condition is diabetes, hyperglycemia, hyperlipidemia, metabolic syndrome X, obesity, primary hyperglycagonemia, insulin deficiency or insulin resistance. In some embodiments, diabetes is type 2 diabetes. In some embodiments, obesity is diet induced. In some embodiments, hyperlipidemia is associated with elevated blood lipid levels. Lipids include cholesterol and triglycerides. In one embodiment, the condition is hepatic steatosis. In some embodiments, the steatosis is steatohepatitis or non-alcoholic steatohepatitis.

In certain embodiments, methods of preventing or delaying the onset of high blood glucose levels in an animal are disclosed herein, as well as methods of preserving the function of beta cells in an animal used the oligomeric compounds indicated herein. document.

Certain short antisense compounds targeting GCGR can be used to modulate GCGR expression in a subject in need, such as an animal, including, but not limited to, a human being. In certain embodiments, said methods comprise the step of administering to said animal an effective amount of a short antisense compound that reduces the expression of GCGR RNA. In certain embodiments, short antisense compounds effectively reduce GCGR RNA levels or function. Since the reduction of GCGR mRNA levels can lead to the alteration of GCGR expression protein products as well, such resulting alterations can also be measured. Certain short antisense compounds that effectively reduce the levels or function of GCGR RNA or protein expression products are considered an active antisense compound. In certain embodiments, short antisense compounds reduce GCGR expression, resulting in a reduction of RNA by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%.

Methods of selective detection of glucagon receptor modulators and methods of modulation of glucagon receptor expression in cells, tissues or animals are also disclosed, comprising contacting said cells, tissues or animals with one or more of the antisense compounds. Shorts directed to GCGR or with compositions comprising said compounds. This document also indicates procedures for treating an animal, particularly a human being, suspected of having, or is susceptible to, a disease or condition associated with the expression of glucagon receptors. Certain procedures comprise administering a therapeutically or prophylactically effective amount of one or more of the compounds or compositions of the disclosure to the person in need of the treatment.

The reduction of glucagon receptor expression can be measured in, for example, blood, plasma, serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. Preferably, the cells contained within said fluids, tissues or organs being analyzed contain a nucleic acid molecule that encodes the glucagon receptor protein and / or the glucagon receptor protein itself.

Pharmaceutical and other compositions comprising short antisense compounds are also disclosed. In certain embodiments, short antisense compounds targeting a nucleic acid encoding GCGR are used in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier.

Short antisense compounds directed to a GCGR nucleic acid may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid have a motif (detoxifying alahueco) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3- 10-3, 2-10-3, 2-10-2,1-10-1,1-10-2, 3-8-3, 2-8-2, 1-8-1, 36-3 or 1-6-1. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1,2-10-2, 3-10-3,3-8- 3, 1-1-10-2.

Certain short antisense compounds targeting a GCGR nucleic acid

In certain embodiments, the short antisense compounds are directed to a GCGR nucleic acid having the registration number sequence in GENBANK® NM_000160.1, incorporated herein as SEQ ID NO.

9. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 9 is at least 90% complementary to SEQ ID No. 9. In certain such embodiments, a short antisense compound directed to SEQ ID No. 9 it is at least 95% complementary to SEQ ID NO. 9. In certain of said embodiments, a short antisense compound directed to SEQ ID NO. 9 IS 100% complementary to SEQ ID NO. 9. In certain embodiments, a short antisense compound. directed to SEQ ID NO. 9 includes a nucleotide sequence selected from the nucleotide sequences indicated in Tables 12 and 13.

The nucleotide sequences indicated in each SEQ ID NO in Tables 12 and 13 are independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds defined by SEQ ID NO. May independently comprise one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base. The short antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a catheter motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a 3-10-3 cathator motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a catheter motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a 3-8-3 cathamer motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a catheter motif. In certain embodiments, short antisense compounds targeting a GCCR nucleic acid comprise a 2-10-2 cathamer motif.

Tables 12 and 13 illustrate examples of short antisense compounds directed to SEQ ID No. 9. Table 12 illustrates short antisense compounds that are 100% complementary to SEQ ID No. 9. Table 13 illustrates short antisense compounds having one or two. erroneous pairing with respect to SEQ ID NO. 9. The column called "catheter motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methyl-cytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 12: Short antisense compounds directed to SEQ ID No. 9

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338463

378 393  TAGAGCTTCCACTTCT 3-10-3 MOE 486

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338534

378 391  GAGCTTCCACTTCT 3-8-3 MOE 487

327130

499 512  TGTTGGCCGTGGTA 3-8-3 MOE 488

327131

500 513  ATGTTGGCCGTGGT 3-8-3 MOE 489

327132

501 514  GATGTTGGCCGTGG 3-8-3 MOE 490

327133

502 515 AGATGTTGGCCGTG 3-8-3 MOE 491

327134

503 516  GAGATGTTGGCCGT 3-8-3 MOE 492

327135

504 517  GGAGATGTTGGCCG 3-8-3 MOE 493

327136

505 518  AGGAGATGTTGGCC 3-8-3 MOE 494

327137

506 519  CAGGAGATGTTGGC 3-8-3 MOE 495

327138

507 520  GCAGGAGATGTTGG 3-8-3 MOE 496

327139

508 521  GGCAGGAGATGTTG 3-8-3 MOE 497

327140

531 544  GTGGTGCCAAGGCA 3-8-3 MOE 498

327141

532 545  TGTGGTGCCAAGGC 3-8-3 MOE 499

327142

533 546  TTGTGGTGCCAAGG 3-8-3 MOE 500

327143

534 547 TTTGTGGTGCCAAG 3-8-3 MOE 501

327144

535 548 CTTTGTGGTGCCAA 3-8-3 MOE 502

327145

536 549 ACTTTGTGGTGCCA 3-8-3 MOE 503

327146

537 550 CACTTTGTGGTGCC 3-8-3 MOE 504

327147

538 551 GCACTTTGTGGTGC 3-8-3 MOE 505

327148

539 552 TGCACTTTGTGGTG 3-8-3 MOE 506

327149

540 553 TTGCACTTTGTGGT 3-8-3 MOE 507

327150

545 558 CGGTGTTGCACTTT 3-8-3 MOE 508

327151

546 559  GCGGTGTTGCACTT 3-8-3 MOE 509

327152

547 560  AGCGGTGTTGCACT 3-8-3 MOE 510

327153

548 561  AAGCGGTGTTGCAC 3-8-3 MOE 511

327154

549 562  GAAGCGGTGTTGCA 3-8-3 MOE 512

327155

550 563  CGAAGCGGTGTTGC 3-8-3 MOE 513

327156

551 564  ACGAAGCGGTGTTG 3-8-3 MOE 514

327157

552 565  CACGAAGCGGTGTT 3-8-3 MOE 515

327158

553 566  ACACGAAGCGGTGT 3-8-3 MOE 516

327159

554 567  AACACGAAGCGGTG 3-8-3 MOE 517

345897

684 697  GCTGCTGTACATCT 2-10-2 MOE 518

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

327160

684 697  GCTGCTGTACATCT 3-8-3 MOE 518

327161

685 698  AGCTGCTGTACATC 3-8-3 MOE 520

327162

686 699  AAGCTGCTGTACAT 3-8-3 MOE 521

327163

687 700  GAAGCTGCTGTACA 3-8-3 MOE 522

327164

688 701  GGAAGCTGCTGTAC 3-8-3 MOE 523

327165

689 702  TGGAAGCTGCTGTA 3-8-3 MOE 524

327166

690 703  CTGGAAGCTGCTGT 3-8-3 MOE 525

327167

691 704  CCTGGAAGCTGCTG 3-8-3 MOE 526

327168

692 705  ACCTGGAAGCTGCT 3-8-3 MOE 527

327169

693 706  CACCTGGAAGCTGC 3-8-3 MOE 528

327170

694 707  TCACCTGGAAGCTG 3-8-3 MOE 529

327171

695 708  ATCACCTGGAAGCT 3-8-3 MOE 530

327172

696 709  CATCACCTGGAAGC 3-8-3 MOE 531

327173

697 710  ACATCACCTGGAAG 3-8-3 MOE 532

327174

698 711  TACATCACCTGGAA 3-8-3 MOE 533

327175

699 712  GTACATCACCTGGA 3-8-3 MOE 534

327176

700 713  TGTACATCACCTGG 3-8-3 MOE 535

327177

701 714  GTGTACATCACCTG 3-8-3 MOE 536

327178

869 882  TAGCGGGTCCTGAG 3-8-3 MOE 537

327179

870 883  GTAGCGGGTCCTGA 3-8-3 MOE 538

327180

871 884  TGTAGCGGGTCCTG 3-8-3 MOE 539

327181

872 885  CTGTAGCGGGTCCT 3-8-3 MOE 540

327182

873 886  GCTGTAGCGGGTCC 3-8-3 MOE 541

327183

874 887  GGCTGTAGCGGGTC 3-8-3 MOE 542

327184

875 888  TGGCTGTAGCGGGT 3-8-3 MOE 543

327185

876 889  CTGGCTGTAGCGGG 3-8-3 MOE 544

327186

877 890  TCTGGCTGTAGCGG 3-8-3 MOE 545

327187

878 891  TTCTGGCTGTAGCG 3-8-3 MOE 546

327188

955 968  TGAACACCGCGGCC 3-8-3 MOE 547

327189

956 969  ATGAACACCGCGGC 3-8-3 MOE 548

327190

957 970  CATGAACACCGCGG 3-8-3 MOE 549

327191

958 971  GCATGAACACCGCG 3-8-3 MOE 550

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

327192

959 972  TGCATGAACACCGC 3-8-3 MOE 551

327193

960 973  TTGCATGAACACCG 3-8-3 MOE 552

327194

961 974  ATTGCATGAACACC 3-8-3 MOE 553

327195

962 975  TATTGCATGAACAC 3-8-3 MOE 554

327196

963 976  ATATTGCATGAACA 3-8-3 MOE 555

327197

964 977  CATATTGCATGAAC 3-8-3 MOE 556

327198

1019 1032  AGGTTGTGCAGGTA 3-8-3 MOE 557

327199

1020 1033  CAGGTTGTGCAGGT 3-8-3 MOE 558

327200

1021 1034  GCAGGTTGTGCAGG 3-8-3 MOE 559

327201

1022 1035  AGCAGGTTGTGCAG 3-8-3 MOE 560

327202

1023 1036  CAGCAGGTTGTGCA 3-8-3 MOE 561

327203

1024 1037  CCAGCAGGTTGTGC 3-8-3 MOE 562

327204

1025 1038  CCCAGCAGGTTGTG 3-8-3 MOE 563

327205

1026 1039  GCCCAGCAGGTTGT 3-8-3 MOE 564

327206

1027 1040  GGCCCAGCAGGTTG 3-8-3 MOE 565

327207

1028 1041  AGGCCCAGCAGGTT 3-8-3 MOE 566

338491

1160 1175  TGTCATTGCTGGTCCA 3-10-3 MOE 567

338562

1160 1173  TCATTGCTGGTCCA 3-8-3 MOE 568

338498

1307 1322  TGGCCAGCCGGAACTT 3-10-3 MOE 569

338569

1307 1320 GCCAGCCGGAACTT 3-8-3 MOE 570

338499

1329 1344  GGGATGAGGGTCAGCG 3-10-3 MOE 571

338570

1329 1342  GATGAGGGTCAGCG 3-8-3 MOE 572

385067

1364 1377 AAGGCAAAGACCAC 3-8-3 MOE 573

338573

1401 1414  GGAGCGCAGGGTGC 3-8-3 MOE 574

338580

1487 1500  TGCACCTCCTTGTT 3-8-3 MOE 575

Table 13: Short antisense compounds directed to SEQ ID No. 1 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338577

158 171 CAGCAGACCCTGGA 3-8-3 MOE 576

338458

237 252 ACATCTGGCAGAGGTT 3-10-3 MOE 577

338529

237 250 ATCTGGCAGAGGTT 3-8-3 MOE 578

338466

318 333 CAGGCCAGCAGGAGTA 3-10-3 MOE 579

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338537

318 331 GGCCAGCAGGAGTA 3-8-3 MOE 580

338533

364 377 CAAACAAAAAGTCC 3-8-3 MOE 582

338462

364 379 CTCAAACAAAAAGTCC 3-10-3 MOE 581

338535

397 410 GGTGACATTGGTCA 3-8-3 MOE 584

338464

397 412 GTGGTGACATTGGTCA 3-10-3 MOE 583

338466

470 485 CAGGCCAGCAGGAGTA 3-10-3 MOE 579

338537

470 483 GGCCAGCAGGAGTA 3-8-3 MOE 580

385048

497 510 TTGGCAGTGGTGTT 3-8-3 MOE 587

385049

500 513 ATGTTGGCAGTGGT 3-8-3 MOE 588

338467

503 518 AGGAAATGTTGGCAGT 3-10-3 MOE 589

338538

503 516 GAAATGTTGGCAGT 3-8-3 MOE 590

385050

506 519 CAGGAAATGTTGGC 3-8-3 MOE 591

385051

509 522 GGGCAGGAAATGTT 3-8-3 MOE 592

385052

523 536 AAGGTAGGTACCAG 3-8-3 MOE 593

385053

526 539 ACCAAGGTAGGTAC 3-8-3 MOE 594

385056

535 548 CTTTGTGGCACCAA  3-8-3 MOE 595

385057

538 551 GCACTTTGTGGCAC  3-8-3 MOE 596

338539

539 552 TGCACTTTGTGGCA  3-8-3 MOE 597

385058

541 554 GCTGCACTTTGTGG  3-8-3 MOE 598

385059

544 557 GGTGCTGCACTTTG  3-8-3 MOE 599

385060

547 560 GGCGGTGCTGCACT 3-8-3 MOE 600

385063

556 569 TGAACACTAGGCGG 3-8-3 MOE 601

385064

559 572 TCTTGAACACTAGG 3-8-3 MOE 602

338469

561 576 CACCTCTTGAACACTA 3-10-3 MOE 603

338540

561 574 CCTCTTGAACACTA 3-8-3 MOE 604

385065

562 575 ACCTCTTGAACACT 3-8-3 MOE 605

385066

565 578 CACACCTCTTGAAC 3-8-3 MOE 606

338541

590 603 CCTCGAACCCACTG 3-8-3 MOE 607

338473

658 673 CTTCTGGACCTCGATC 3-10-3 MOE 608

338544

658 671 TCTGGACCTCGATC 3-8-3 MOE 609

338474

681 696 CTGCTATACATCTTGG 3-10-3 MOE 610

338545

681 694 GCTATACATCTTGG 3-8-3 MOE 611

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338475

703 718 CACGGTGTACATCACC 3-10-3 MOE 612

338546

703 716 CGGTGTACATCACC 3-8-3 MOE 613

338547

718 731 ACAGACTGTAGCCC 3-8-3 MOE 615

338476

718 733 GGACAGACTGTAGCCC 3-10-3 MOE 614

338550

889 902 CATCGCCAATCTTC 3-8-3 MOE 617

338479

889 904 GTCATCGCCAATCTTC 3-10-3 MOE 616

338551

899 912 ACACTGAGGTCATC 3-8-3 MOE 619

338480

899 914 TCACACTGAGGTCATC 3-10-3 MOE 618

338552

924 937 CGCCCCGTCACTGA 3-8-3 MOE 620

338555

992 1005 AGCAACCAGCAATA 3-8-3 MOE 622

338484

992 1007 CCAGCAACCAGCAATA 3-10-3 MOE 621

338485

1018 1033 CAGGCTGTACAGGTAC 3-10-3 MOE 623

338556

1018 1031 GGCTGTACAGGTAC 3-8-3 MOE 624

338558

1051 1064 AGCTCCTCTCAGAG 3-8-3 MOE 626

338487

1051 1066 GAAGCTCCTCTCAGAG 3-10-3 MOE 625

338559

1079 1092 CAGCCAATGCCCAG 3-8-3 MOE 628

338488

1079 1094 CCCAGCCAATGCCCAG 3-10-3 MOE 627

338560

1131 1144 AAACAGACACTTGA 3-8-3 MOE 630

338489

1131 1146 TCAAACAGACACTTGA 3-10-3 MOE 629

338490

1145 1160 AGCACTGAACATTCTC 3-10-3 MOE 631

338561

1145 1158 CACTGAACATTCTC 3-8-3 MOE 632

338563

1181 1194 ATCCACCAGAATCC 3-8-3 MOE 634

338492

1181 1196 GGATCCACCAGAATCC 3-10-3 MOE 633

338564

1216 1229 TGATCAGTAAGGCC 3-8-3 MOE 635

338565

1232 1245 ACAAAGATGAAAAA 3-8-3 MOE 637

338494

1232 1247 GGACAAAGATGAAAAA 3-10-3 MOE 636

338566

1267 1280 CACGCAGCTTGGCC 3-8-3 MOE 639

338495

1267 1282 GGCACGCAGCTTGGCC 3-10-3 MOE 638

338571

1344 1357 GACCCCCAGCAGAG 3-8-3 MOE 641

338500

1344 1359 TGGACCCCCAGCAGAG 3-10-3 MOE 640

385068

1366 1379 CAAAGGCAAAGACC 3-8-3 MOE 642

385069

1369 1382 TCACAAAGGCAAAG 3-8-3 MOE 643

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

385070

1372 1385 CAGTCACAAAGGCA 3-8-3 MOE 644

385071

1375 1388 CGTCAGTCACAAAG 3-8-3 MOE 645

385072

1378 1391 GCTCGTCAGTCACA 3-8-3 MOE 646

385073

1381 1394 CATGCTCGTCAGTC 3-8-3 MOE 647

386608

1384 1397 GGGCATGCTCGTCA 1-12-1 MOE 648

386593

1384 1397 GGGCATGCTCGTCA 2-10-2 MOE 648

396146

1384 1397 GGGCATGCTCGTCA 2-10-2 MOE 648

338572

1384 1397 GGGCATGCTCGTCA 3-8-3 MOE 648

396149

1384 1397 GGGCATGCTCGTCA 1-1-10-2 2 ’- (butylacetamide) - palmitamide / OMe / OMe 648

386627

1384 1397 GGGCATGCTCGTCA 2-10-2 Methylene BNA 648

386610

1387 1400 CTTGGGCATGCTCG 1-12-1 MOE 654

386595

1387 1400 CTTGGGCATGCTCG 2-10-2 MOE 654

385074

1387 1400 CTTGGGCATGCTCG 3-8-3 MOE 654

385075

1390 1403 TGCGTTGGGCATGC 3-8-3 MOE 657

385076

1393 1406 GGGTGCCTTGGGCA 3-8-3 MOE 648

385077

1396 1409 GCAGGGTGCCTTGG 3-8-3 MOE 659

385078

1399 1412 AGCGCAGGGTGCCT 3-8-3 MOE 660

338502

1401 1416 GTGGAGCGCAGGGTG C 3-10-3 MOE 661

385079

1402 1415 TGGAGCGCAGGGTG 3-8-3 MOE 662

385080

1405 1418 TGGTGGAGCGCAGG 3-8-3 MOE 663

385081

1408 1421 GCTTGGTGGAGCGC 3-8-3 MOE 664

385082

1411 1424 AGAGCTTGGTGGAG 3-8-3 MOE 665

338503

1412 1427 AAAAGAGCTTGGTGGA 3-10-3 MOE 666

338574

1412 1425 AAGAGCTTGGTGGA 3-8-3 MOE 667

385083

1414 1427 AAAAGAGCTTGGTG 3-8-3 MOE 668

385084

1417 1430 CAAAAAAGAGCTTG 3-8-3 MOE 669

338504

1434 1449 AAGGAGCTGAGGAACA 3-10-3 MOE 670

338575

1434 1447 GGAGCTGAGGAACA 3-8-3 MOE 671

327167

1441 1454 CCTGGAAGCTGCTG 3-8-3 MOE 526

338576

1445 1458 AGACCCTGGAAGGA 3-8-3 MOE 673

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

338505

1445 1460 GCAGACCCTGGAAGGA 3-10-3 MOE 672

338506

1449 1464 ACCAGCAGACCCTGGA 3-10-3 MOE 674

338577

1449 1462 CAGCAGACCCTGGA 3-8-3 MOE 576

338507

1464 1479 CAGTAGAGAACAGCCA 3-10-3 MOE 676

338578

1464 1477 GTAGAGAACAGCCA 3-8-3 MOE 677

338508

1475 1490 TGTTGAGGAAACAGTA 3-10-3 MOE 678

338579

1475 1488 TTGAGGAAACAGTA 3-8-3 MOE 679

338509

1487 1502 CCTGCACCTCCTTGTT 3-10-3 MOE 680

338580

1610 1623 TGCACCTCCTTGTT 3-8-3 MOE 575

In certain embodiments, a target region is nucleotides 378-391 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 378-391 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 378-391 comprises a nucleotide sequence selected from SEQ ID

No. 486 or 487. In certain such embodiments, a short antisense compound directed to nucleotides 378-391 of SEQ ID NO: 9 is selected from Isis No. 338463 or 338534.

In certain embodiments, a target region is nucleotides 499-521 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 499-521 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 499-521 comprises a nucleotide sequence selected from SEQ ID

No. 488, 489, 490, 491, 492, 493, 494, 495, 496 or 497. In certain such embodiments, a short antisense compound directed to nucleotides 499-521 of SEQ ID NO: 9 is selected from No. Isis 327130, 327131, 327132, 327133, 327134, 327135, 327136, 327137, 327138 or 327139.

In certain embodiments, a target region is nucleotides 531-553 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 531-553 of SEQ ID No. 9. In certain embodiments, a compound

Short antisense directed to nucleotides 531-553 comprises a nucleotide sequence selected from SEQ ID NO: 498, 499, 500, 501, 502, 503, 504, 505, 506 or 507. In certain of said embodiments, an antisense compound Short targeting nucleotides 531-553 of SEQ ID No. 9 is selected from No. Isis 327140, 327141, 327142, 327143, 327144, 327145, 327146, 327147, 327148 or 327149.

In certain embodiments, a target region is nucleotides 545-567 of SEQ ID NO. 9. In certain embodiments, a

20 short antisense compound targeting nucleotides 545-567 of SEQ ID NO. 9. In certain embodiments, a short antisense compound targeting nucleotides 545-567 comprises a nucleotide sequence selected from SEQ ID NO: 508, 509, 510, 511, 512, 513, 514, 515, 516 or 517. In certain such embodiments, a short antisense compound directed to nucleotides 545-567 of SEQ ID No. 9 is selected from Isis No. 327150, 327151, 327152, 327153 , 327154, 327155, 327156, 327157, 327158 or 327159.

In certain embodiments, a target region is nucleotides 531-567 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 531-567 of SEQ ID No. 9. In certain embodiments, an antisense compound. Short nucleotide targeting 531-567 comprises a nucleotide sequence selected from SEQ ID NO: 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513 , 514, 515, 516, or 517. In certain such embodiments, a short antisense compound directed to nucleotides 531-567 of SEQ ID NO: 9 is selected

30 of No. Isis 327140, 327141, 327142, 327143, 327144, 327145, 327146, 327147, 327148, 327149, 327150, 327151, 327152, 327153, 327154, 327155, 327156, 327157, 327157, 327157, 327157, 327157, 327157, 327157, 327157, 327157, 327157, 327157, 329157

In certain embodiments, a target region is nucleotides 684-714 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 684-714 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 684-714 comprises a nucleotide sequence selected from SEQ ID

35 No. 518, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, or 536. In certain of said embodiments, a directed short antisense compound to nucleotides 684-714 of SEQ ID NO: 9 is selected from No. Isis 345897, 327160, 327161, 327162, 327163, 327164, 327165, 327166, 327167, 327168, 327169, 327170, 327171, 327172, 327173, 327173, 327173, 327173, 327173 327175, 327176 or 327177.

In certain embodiments, a target region is nucleotides 869-891 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 869-891 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 869-891 comprises a nucleotide sequence selected from SEQ ID Nos. 537, 538, 539, 540, 541, 542, 543, 544, 545 or 546. In certain such embodiments, a short antisense compound directed to Nucleotides 869-891 of SEQ ID No. 9 is selected from No. Isis 327178, 327179, 327180, 327181, 327182, 327183, 327184, 327185, 327186 or 327187.

In certain embodiments, a target region is nucleotides 955-977 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 955-977 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 955-977 comprises a nucleotide sequence selected from SEQ ID NO: 547, 548, 549, 550, 551, 552, 553, 554, 555 or 556. In certain such embodiments, a short antisense compound directed to Nucleotides 955-977 of SEQ ID No. 9 is selected from No. Isis 327188, 327189, 327190, 327191, 327192, 327193, 327194, 327195, 327196 or 327197.

In certain embodiments, a target region is nucleotides 1019-1041 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 1019-1041 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 1019-1041 comprises a nucleotide sequence selected from SEQ ID NO: 557, 558, 559, 560, 561, 562, 563, 564, 565 or 566. In certain such embodiments, a short antisense compound directed to Nucleotides 1019-1041 of SEQ ID No. 9 is selected from No. Isis 327198, 327199, 327200, 327201, 327202, 327203, 327204, 327205, 327206 or 327207.

In certain embodiments, a target region is nucleotides 1160-1175 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 1160-1175 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 1160-1175 comprises a nucleotide sequence selected from SEQ ID No. 567 or 568. In certain such embodiments, a short antisense compound directed to nucleotides 1160-1175 of SEQ ID No. 9 is selected from No. Isis 338491 or 338562.

In certain embodiments, a target region is nucleotides 1307-1377 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 1307-1377 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 1307-1377 comprises a nucleotide sequence selected from SEQ ID Nos. 569, 570, 571, 572 or 573. In certain such embodiments, a short antisense compound directed to nucleotides 1307-1377 of SEQ ID NO. 9 is selected from No. Isis 338498, 338569, 338499, 338570 or 385067.

In certain embodiments, a target region is nucleotides 1307-1414 of SEQ ID No. 9. In certain embodiments, a short antisense compound directed to nucleotides 1307-1414 of SEQ ID No. 9. In certain embodiments, a short antisense compound. directed to nucleotides 1307-1414 comprises a nucleotide sequence selected from SEQ ID Nos. 569, 570, 571, 572, 573 or 574. In certain such embodiments, a short antisense compound directed to nucleotides 1307-1414 of SEC ID No. 9 is selected from No. Isis 338498, 338569, 338499, 338570, 385067, or 338573.

In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are short captamers. In certain of said embodiments, the short catometers directed to a GCGR nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from α-L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a GCGR nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds directed to a GCGR nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid have a monomer length. In certain embodiments, short antisense compounds targeting a GCGR nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to a GCGR nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating GCGR expression are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a GCGR nucleic acid, wherein the short antisense compound targeting a GCGR nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating GCGR expression using one

or more short antisense compounds directed to a GCGR nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers.

In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 8 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 9 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 10 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 11 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 12 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 13 monomers in length. In certain embodiments, GCGR modulation procedures comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 14 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 15 monomers in length. In certain embodiments, GCGR modulation methods comprise the use of a short antisense compound directed to a GCGR nucleic acid that is 16 monomers in length.

In certain embodiments, methods of modulating GCGR expression comprise the use of a short antisense compound targeting a GCGR nucleic acid comprising 9 to 15 monomers. In certain embodiments, methods of modulating GCGR expression comprise the use of a short antisense compound targeting a GCGR nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating GCGR expression comprise the use of a short antisense compound directed to a GCGR nucleic acid comprising 12 to 14 monomers. In certain embodiments, methods of modulating GCGR expression comprise the use of a short antisense compound directed to a GCGR nucleic acid comprising 12 or 14 nucleotides or nucleosides.

8. DGAT2

Diacylglycerol transferase 2 (also known as DGAT2, diacylglycerol-O-transferase 2, acyl-CoA: diacylglycerol acyltransferase 2). It has been shown that diacylglycerol transferase 2 is involved in the process of absorption of triglycerides (also called triacylglycerols) from food.

The absorption of triglycerides from food is a very efficient process that occurs in a series of stages, in which the triacylglycerols in the diet are hydrolyzed in the intestinal lumen and then re-synthesized inside the Enterocytes The new synthesis of triacylglycerols can occur through the monoacrylic glycerol pathway, which begins when monoacrylic glycerol acyl transferase (MGAT) catalyzes the synthesis of diacylglycerol from fatty monocyclycerol and acyl-CoA. An alternative synthesis of diacylglycerols is provided by the glycerol phosphate pathway, which describes the coupling of two fatty acyl-CoA molecules to glycerol-3-phosphate. In any case, diacylglycerol is then acylated with another fatty acyl-CoA molecule in a reaction catalyzed by one of two diacylglycerol acyltransferase enzymes to form triglyceride (Farese et al., Curr. Opin. Lipidol., 2000, 11, 229 -2. 3. 4).

The reaction catalyzed by diacylglycerol acyltransferase is the last stage and the only one involved in the synthesis of triglycerides. As such, diacylglycerol acyltransferase is involved in the absorption of fats in the intestine, the assembly of lipoproteins, the regulation of plasma triglyceride concentrations and the storage of fat in adipocytes. The first diacylglycerol acyltransferase, diacylglycerol transferase 1, was identified in 1960 and the human and mouse genes encoding this protein were isolated in 1988 (Cases et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 13018 -13023; Oelkers et al., J. Biol. Chem., 1998, 273, 26765-26771). Mice lacking diacylglycerol acyltransferase 1 are viable and can continue to synthesize triglycerides through other biological pathways, suggesting the existence of multiple mechanisms for the synthesis of triglycerides (Smith et al., Nat. Genet., 2000, 25, 87-90).

Subsequently, a second diacylglycerol transferase, diacylglycerol transferase 2 (also known as DGAT2, diacylglycerol-O-transferase 2, acyl-CoA: diacylglycerol acyltransferase 2) was identified in the Mortierella fungus, in humans and mice (Cases et al., J Biol. Chem., 2001, 276, 38870-38876; Lardizabal et al., J. Biol. Chem., 2001, 276, 3886238869). Enzymatic assays indicate that this newly identified protein does possess diacylglycerol transferase activity that uses a wide range of long-chain fatty acyl-CoA substrates (Cases et al., J. Biol. Chem., 2001, 276, 38870-38876) .

Diacylglycerol transferase 2 is a member of a family of genes whose sequences are not related to diacylglycerol transferase 1. In addition to differing in sequence compared to diacylglycerol transferase 1, in vitro assays illustrate that diacylglycerol transferase 2 has greater activity at lower concentrations of magnesium chloride and oleoyl-CoA (Cases et al., J. Biol. Chem., 2001, 276, 38870-38876). The predicted protein sequence of diacylglycerol transferase 2 contains at least one supposed transmembrane domain, three sites of N-linked glycosylation potential, six potential consensus sites of phosphorylation of protein kinase C, in addition to sequences in common with an alleged phosphorylation site of glycerol found in acyltransferase enzymes (Cases et al., J. Biol. Chem., 2001, 276, 3887038876). The International Radiation Hybrid Mapping Consortium Consortium has deciphered the human diacylglycerol transferase 2 map on chromosome 11q13.3.

In human tissues, the highest levels of diacylglycerol transferase 2 are detected in the liver and white adipose tissue, and the lowest levels are found in the mammary gland, testicles and peripheral blood leukocytes (Cases et al., J. Biol. Chem., 2001, 276, 38870-38876). In human tissues, two mRNA species of 2.4 and 1.8 kilobases are detected, while the main species of diacylglycerol transferase 2 mRNA in mouse tissues has 2.4 kilobases. In addition to the liver and white adipose tissue, diacylglycerol transferase 2 is expressed in all segments of the small intestine in mice, its expression being greater in the proximal area of the intestine and lower in the distal area of the intestine (Cases et al. ., J. Biol. Chem., 2001, 276, 38870-38876).

Diacylglycerol transferase activity exhibits different patterns during the postnatal development of rat liver. Since there is no correlation between mRNA expression and activity patterns, posttranslational modifications can participate in the regulation of diacylglycerol transferase 2 activity during rat development (Waterman et al., J. Lipid. Res. , 2002, 43, 1555-1562).

Preferably, the mRNA of diacylglycerol transferase 2 is regulated by increase by insulin treatment, as shown in in vitro assays in which diacylglycerol activity is measured in the membrane fraction of cultured mouse adipocytes (Meegalla et al. ., Biochem. Biophys. Res. Commun., 2002, 298, 317-323). In fasting mice, the expression of diacylglycerol transferase 2 is greatly reduced and dramatically increased once food is reintroduced. The expression patterns of two enzymes involved in the synthesis of fatty acids, acetyl-CoA carboxylase and fatty acid synthase, respond to fasting and feedback situations in a similar way. These results, combined with the observation that diacylglycerol transferase 2 is abundantly expressed in the liver, suggest that diacylglycerol transferase 2 is closely linked to the endogenous fatty acid synthesis pathway (Meegalla et al., Biochem. Biophys. Res. Commun., 2002, 298, 317-323).

Studies of mice harboring an alteration in the diacylglycerol acyltransferase 1 gene provide evidence that diacylglycerol acyltransferase 2 contributes to the synthesis of triglycerides. Diacylglycerol transferase 2 mRNA expression levels are similar in the intestinal segments of wild mice and diacylglycerol transferase 1 deficient (Buhman et al., J. Biol. Chem., 2002, 277, 25474-25479). Using magnesium chloride to distinguish between diacylglycerol transferase 1 and 2 activity, Buhman, et al. They observed that, in mice deficient in diacylglycerol transferase 1, the activity of diacylglycerol transferase is reduced by 50% in the proximal area of the intestine and by 10-15% in the distal area of the intestine (Buhman et al., J. Biol Chem., 2002, 277, 25474-25479).

Additionally, the levels of diacylglycerol transferase 2 mRNA are not regulated by an increase in the liver or adipose tissues of diacylglycerol transferase 1 deficient mice, even after weeks of a high-fat diet (Cases et al., J. Biol. Chem. , 2001,276,38870-38876; Chen et al., J. Clin. Invest., 2002, 109, 1049-1055). However, in ob / ob mice, which have a mutation in the leptin gene that results in obesity, diacylglycerol transferase 2 is expressed much more than in wild-type mice, suggesting that diacylglycerol transferase 2 may be partly responsible for the abundantly accumulated fat mass observed in these mice. In addition, the combined mutations of leptin and diacylglycerol transferase 2 lead to a threefold increase in the expression of diacylglycerol transferase 2 in white adipose tissue, compared to the levels in the same tissue of diacylglycerol transferase 1 deficient mice (Chen et al. ., J. Clin. Invest., 2002, 109, 1049-1055). The mRNA of diacylglycerol transferase 2 is also regulated by increase in the skin of these mice (Chen et al., J. Clin. Invest., 2002, 109, 175-181). These data suggest that leptin normally regulates by decreasing the expression of diacylglycerol transferase 2 and that regulation by increasing diacylglycerol transferase 2 in white adipose tissue in these mice may provide an alternative route for the synthesis of triglycerides that continues to occur in leptin deficient / diacylglycerol transferase 1 deficient mice (Chen et al., J. Clin. Invest., 2002, 109, 1049-1055).

Defective mice in diacylglycerol transferase 1 exhibit interesting phenotypes in that they have low mass, are resistant to diet-induced obesity, have lower levels of tissue triglycerides and greater sensitivity to leptin and insulin ((Chen et al., J. Clin. Invest., 2002, 109, 1049-1055; Smith et al., Nat. Genet., 2000, 25, 87-90) Since diacylglycerol transferase 2 also participates in the synthesis of triglycerides, so that interference With diacylglycerol transferase 2 it can lead similarly to the reduction of fat content in the body.

Definitions

"DGAT2" means the gene product or protein whose expression is to be modulated by the administration of a short antisense compound.

"DGAT2 nucleic acid" means any nucleic acid encoding DGAT2. For example, in certain embodiments, a DGAT2 nucleic acid includes, without limitation, a DNA sequence encoding DGAT2, an RNA sequence transcribed from DNA encoding DGAT2, and an mRNA sequence encoding DGAT2.

"DGAT2 mRNA" means an mRNA encoding DGAT2.

Therapeutic indications

Antisense technology is an effective means to reduce the expression of DGAT2 and has been shown to be unique in its usefulness in a number of therapeutic, diagnostic and research applications. As such, in certain embodiments, compounds directed to a nucleic acid encoding DGAT2 and modulating DGAT2 expression are disclosed herein. Short antisense compounds capable of effectively inhibiting the expression of are also disclosed herein.

In certain embodiments, a subject suspected of having a disease associated with DGAT2 is treated by administering one or more short antisense compounds directed to a nucleic acid encoding DGAT2. For example, in a non-limiting embodiment, said methods comprise the step of administering to a animal a therapeutically effective amount of a short antisense compound. In certain of said embodiments, short antisense compounds effectively inhibit DGAT2 activity or inhibit DGAT2 expression. In one embodiment, the activity or expression of DGAT2 in a subject is inhibited by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in at least 95%, at least 98%, at least 99%, or 100%. In certain embodiments, the activity or expression of DGAT2 in a subject is inhibited by approximately 30%. More preferably, the activity or expression of DGAT2 in a subject is 50% inhibited.

or more.

The reduction of DGAT2 expression can be measured in, for example, blood, plasma, serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. Preferably, the cells contained within said fluids, tissues or organs being analyzed contain a nucleic acid molecule encoding DGAT2 and / or the DGAT2 protein itself.

In certain embodiments, pharmaceutical and other compositions comprising the compounds of the disclosure are also disclosed. In certain embodiments, short antisense compounds directed to a DRAT2 nucleic acid can be used in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier.

Certain short antisense compounds directed to DGAT2 may have any one or more properties or characteristics of short antisense compounds in general described herein. In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1, 1-1-10-2, 2-10-l-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 2-8-2, 1-8-1, 3- 6-3 or 16-1. In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid have a motive.

5 (deoxy-wing hollow-wing) selected from 1-10-1, 2-10-2 and 3-10-3.

Methods of treating an individual by administering one or short antisense compounds directed to a DGAT2 nucleic acid or a pharmaceutical composition comprising said compound are disclosed herein. Methods of treating an individual suffering from a disease or condition associated with the activity of DGAT2 are also disclosed by administering a short antisense compound directed to a DGAT2 nucleic acid.

10 Diseases and conditions associated with DGAT2 include, among others, cardiovascular disorders, obesity, diabetes, cholesterolemia and hepatic steatosis.

Certain short antisense compounds targeting a DGAT2 nucleic acid

In certain embodiments, the short antisense compounds are directed to a DGAT2 nucleic acid having the accession number sequence in GENBANK® NM_032564.2, incorporated herein as SEQ ID No. 15 10. In certain such embodiments, a short antisense compound directed to SEQ ID NO. 10 is at least 90% complementary to SEQ ID NO. 10. In certain such embodiments, a short antisense compound directed to SEQ ID NO. 10 is at least 95% complementary to the SEQ ID NO. 10. In certain such embodiments, a short antisense compound directed to SEQ ID NO. 10 IS 100% complementary to SEQ ID NO. 10. In certain embodiments, a short antisense compound directed to SEQ ID NO. 10 includes a nucleotide sequence selected from the sequences

20 nucleotides indicated in Tables 14 and 15.

The nucleotide sequence indicated in each of Tables 14 and 15 is independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds comprising a nucleotide sequence as indicated in Tables 14 and 15 may independently comprise one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base. The 25 antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base. Tables 14 and 15 illustrate examples of short antisense compounds directed to SEQ ID No. 10. Table 14 illustrates short antisense compounds that are 100% complementary to SEQ ID No. 10. Table 15 illustrates short antisense compounds having one or two. erroneous pairing with respect to SEQ ID NO. 10. The column called 30 "capper motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The links

Internucleosides are phosphorothioate. Short antisense compounds comprise 5-methylcytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 14: Short antisense compounds directed to SEQ ID No. 10

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372556

231 244  ATGAGGGTCTTCAT  2-10-2 MOE 681

372557

249 262  ACCCCGGAGTAGGC 2-10-2 MOE 682

382601

249 260  CCCGGAGTAGGC 1-10-1 MOE 683

372480

251 266  CAGGACCCCGGAGTAG 3-10-3 MOE 684

372481

252 267  GCAGGACCCCGGAGTA 3-10-3 MOE 685

372558

252 265  AGGACCCCGGAGTA 2-10-2 MOE 686

372559

253 266 CAGGACCCCGGAGT  2-10-2 MOE 687

382603

331 342  CAGACCCCTCGC 1-10-1 MOE 688

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

382604

361 372  AGAGGATGCTGG 1-10-1 MOE 689

372485

392 407  GAGCCAGGTGACAGAG 3-10-3 MOE 690

372563

393 406  AGCCAGGTGACAGA 2-10-2 MOE 691

382605

397 408  TGAGCCAGGTGA 1-10-1 MOE 692

372565

414 427 TTTTCCACCTTGGA  2-10-2 MOE 693

382606

482 493  CTGCAGGCCACT  1-10-1 MOE 694

372497

651 666  TCACCAGCTGGATGGG 3-10-3 MOE 695

372498

652 667  TTCACCAGCTGGATGG 3-10-3 MOE 696

372575

652 665  CACCAGCTGGATGG 2-10-2 MOE 697

372576

653 666  TCACCAGCTGGATG  2-10-2 MOE 698

382607

655 666  TCACCAGCTGGA 1-10-1 MOE 699

372499

656 671  TGTCTTCACCAGCTGG 3-10-3 MOE 700

372577

657 670  GTCTTCACCAGCTG  2-10-2 MOE 701

372500

659 674  GTGTGTCTTCACCAGC 3-10-3 MOE 702

372578

660 673  TGTGTCTTCACCAG 2-10-2 MOE 703

372501

661 676  TTGTGTGTCTTCACCA 3-10-3 MOE 704

372579

662 675  TGTGTGTCTTCACC 2-10-2 MOE 705

372502

664 679  AGGTTGTGTGTCTTCA 3-10-3 MOE 706

372580

665 678  GGTTGTGTGTCTTC  2-10-2 MOE 707

372503

666 681  GCAGGTTGTGTGTCTT  3-10-3 MOE 708

372581

667 680  CAGGTTGTGTGTCT  2-10-2 MOE 709

372504

669 684  TCAGCAGGTTGTGTGT  3-10-3 MOE 710

372582

670 683  CAGCAGGTTGTGTG  2-10-2 MOE 711

372505

671 686  GGTCAGCAGGTTGTGT  3-10-3 MOE 712

372506

672 687  TGGTCAGCAGGTTGTG  3-10-3 MOE 713

372583

672 685  GTCAGCAGGTTGTG  2-10-2 MOE 714

372584

673 686  GGTCAGCAGGTTGT  2-10-2 MOE 715

372507

676 691  CTGGTGGTCAGCAGGT  3-10-3 MOE 716

372585

677 690  TGGTGGTCAGCAGG 2-10-2 MOE 717

382608

680 691  CTGGTGGTCAGC 1-10-1 MOE 718

372508

681 696  AGTTCCTGGTGGTCAG 3-10-3 MOE 719

372586

682 695  GTTCCTGGTGGTCA 2-10-2 MOE 720

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372509

684 699  TATAGTTCCTGGTGGT  3-10-3 MOE 721

372587

685 698  ATAGTTCCTGGTGG 2-10-2 MOE 722

372510

686 701  GATATAGTTCCTGGTG 3-10-3 MOE 723

372588

687 700  ATATAGTTCCTGGT  2-10-2 MOE 724

372511

691 706  CCAAAGATATAGTTCC 3-10-3 MOE 725

372512

692 707  TCCAAAGATATAGTTC  3-10-3 MOE 726

372589

692 705  CAAAGATATAGTTC  2-10-2 MOE 727

372590

693 706  CCAAAGATATAGTT  2-10-2 MOE 728

382609

724 735  CCAGGCCCATGA 1-10-1 MOE 729

372514

725 740  GGCACCCAGGCCCATG  3-10-3 MOE 730

372592

726 739 GCACCCAGGCCCAT  2-10-2 MOE 731

372515

730 745 CAGAAGGCACCCAGGC 3-10-3 MOE 732

372593

731 744 AGAAGGCACCCAGG 2-10-2 MOE 733

382610

851 862  CCAGACATCAGG 1-10-1 MOE 734

382611

867 878 GACAGGGCAGAT  1-10-1 MOE 735

382602

868 879  TGACAGGGCAGA 1-10-1 MOE 736

382612

911 922  CCACTCCCATTC  1-10-1 MOE 737

372524

965 980  GCCAGGCATGGAGCTC  3-10-3 MOE 738

372602

966 979  CCAGGCATGGAGCT  2-10-2 MOE 739

382613

968 979  CCAGGCATGGAG 1-10-1 MOE 740

382614

987 998  CAGGGTGACTGC 1-10-1 MOE 741

372525

989 1004  GTTCCGCAGGGTGACT  3-10-3 MOE 742

372603

990 1003  TTCCGCAGGGTGAC 2-10-2 MOE 743

372526

992 1007  GCGGTTCCGCAGGGTG 3-10-3 MOE 744

372604

993 1006  CGGTTCCGCAGGGT  2-10-2 MOE 745

372530

1106 1121  TCGGCCCCAGGAGCCC 3-10-3 MOE 746

372608

1107 1120 CGGCCCCAGGAGCC 2-10-2 MOE 747

372531

1109 1124  CCATCGGCCCCAGGAG 3-10-3 MOE 748

372609

1110 1123  CATCGGCCCCAGGA 2-10-2 MOE 749

372532

1112 1127  GACCCATCGGCCCCAG 3-10-3 MOE 750

372610

1113 1126  ACCCATCGGCCCCA 2-10-2 MOE 751

372533

1117 1132  TTCTGGACCCATCGGC 3-10-3 MOE 752

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

382615

1117 1128  GGACCCATCGGC 1-10-1 MOE 753

372611

1118 1131  TCTGGACCCATCGG 2-10-2 MOE 754

372536

1199 1214  CACCAGCCCCCAGGTG 3-10-3 MOE 755

372614

1200 1213 ACCAGCCCCCAGGT  2-10-2 MOE 756

372537

1204 1219  TAGGGCACCAGCCCCC 3-10-3 MOE 757

372615

1205 1218 AGGGCACCAGCCCC 2-10-2 MOE 758

372538

1209 1224  TGGAGTAGGGCACCAG 3-10-3 MOE 759

372616

1210 1223  GGAGTAGGGCACCA 2-10-2 MOE 760

382616

1215 1226  CTTGGAGTAGGG 1-10-1 MOE 761

372539

1218 1233  TGATGGGCTTGGAGTA 3-10-3 MOE 762

372617

1219 1232  GATGGGCTTGGAGT  2-10-2 MOE 763

372540

1293 1308  TGTGGTACAGGTCGAT  3-10-3 MOE 764

372618

1294 1307  GTGGTACAGGTCGA 2-10-2 MOE 765

382617

1294 1305  GGTACAGGTCGA 1-10-1 MOE 766

372541

1295 1310  GGTGTGGTACAGGTCG 3-10-3 MOE 767

372619

1296 1309  GTGTGGTACAGGTC 2-10-2 MOE 768

372542

1298 1313  CATGGTGTGGTACAGG 3-10-3 MOE 769

372620

1299 1312  ATGGTGTGGTACAG 2-10-2 MOE 770

372543

1300 1315  TACATGGTGTGGTACA 3-10-3 MOE 771

372621

1301 1314  ACATGGTGTGGTAC 2-10-2 MOE 772

372544

1303 1318  ATGTACATGGTGTGGT  3-10-3 MOE 773

372622

1304 1317  TGTACATGGTGTGG 2-10-2 MOE 774

382618

1313 1324  GCCTCCATGTAC 1-10-1 MOE 775

382619

1325 1336  AGCTTCACCAGG 1-10-1 MOE 776

382620

1383 1394  GTTCACCTCCAG 1-10-1 MOE 777

Table 15: Short antisense compounds directed to SEQ ID No. 10 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372608

151 164 CGGCCCCAGGAGCC 2-10-2 MOE 747

372474

156 171 CATGCCCCAGCCGCCG  3-10-3 MOE 778

372552

157 170 ATGCCCCAGCCGCC 2-10-2 MOE 779

382609

167 178  CCAGGCCCATGA 1-10-1 MOE 729

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372478

230 245  GATGAGGGTCTTCATG 3-10-3 MOE 780

372479

248 263  GACCCCGGAGTAGGCA 3-10-3 MOE 781

382611

317 328 GACAGGGCAGAT  1-10-1 MOE 735

372483

352 367  ATGCTGGAGCCAGTGC 3-10-3 MOE 782

372561

353 366  TGCTGGAGCCAGTG 2-10-2 MOE 783

372562

373 386  GTCTTGGAGGGCCG 2-10-2 MOE 784

382602

388 399  TGACAGGGCAGA 1-10-1 MOE 736

372613

392 405  CCCAGGTGTCAGAG 2-10-2 MOE 785

372486

412 427 TTTTCCACCTTGGATC  3-10-3 MOE 786

372564

413 426 TTTCCACCTTGGAT  2-10-2 MOE 787

372487

413 428 TTTTTCCACCTTGGAT  3-10-3 MOE 788

372488

418 433 AGGTGTTTTTCCACCT  3-10-3 MOE 789

372566

419 432 GGTGTTTTTCCACC  2-10-2 MOE 790

372489

459 474  CCAGGAAGGATAGGAC 3-10-3 MOE 791

372567

460 473  CAGGAAGGATAGGA 2-10-2 MOE 792

382612

475 486  CCACTCCCATTC  1-10-1 MOE 737

372490

483 498  TGACACTGCAGGCCAC 3-10-3 MOE 793

372568

484 497  GACACTGCAGGCCA 2-10-2 MOE 794

372491

492 507  ACATGAGGATGACACT  3-10-3 MOE 795

372569

493 506  CATGAGGATGACAC 2-10-2 MOE 796

372492

503 518  GCAGAAGGTGTACATG 3-10-3 MOE 797

372570

504 517  CAGAAGGTGTACAT  2-10-2 MOE 798

372493

512 527 GCAGTCAGTGCAGAAG 3-10-3 MOE 799

372571

513 526  CAGTCAGTGCAGAA 2-10-2 MOE 800

372496

612 627 ACACGGCCCAGTTTCG  3-10-3 MOE 801

372574

613 626 CACGGCCCAGTTTC  2-10-2 MOE 802

372513

717 732  GGCCCATGATGCCATG  3-10-3 MOE 803

372591

718 731  GCCCATGATGCCAT  2-10-2 MOE 804

372516

732 747  TACAGAAGGCACCCAG 3-10-3 MOE 805

372594

733 746 ACAGAAGGCACCCA 2-10-2 MOE 806

372518

812 827  GAAGTTGCCAGCCAAT  3-10-3 MOE 807

372596

813 826  AAGTTGCCAGCCAA 2-10-2 MOE 808

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

372560

863 876  CAGGGCAGATCCTT  2-10-2 MOE 809

372519

887 902  CAAGTAGTCTATGGTG 3-10-3 MOE 810

372597

888 901  AAGTAGTCTATGGT  2-10-2 MOE 811

372520

894 909  TGGAAAGCAAGTAGTC 3-10-3 MOE 812

372598

895 908  GGAAAGCAAGTAGT  2-10-2 MOE 813

372527

1013 1028 GGCCAGCTTTACAAAG  3-10-3 MOE 814

372605

1014 1027 GCCAGCTTTACAAA  2-10-2 MOE 815

372606

1020 1033  CGCAGGGCCAGCTT  2-10-2 MOE 816

372529

1052 1067  AAAGGAATAGGTGGGA 3-10-3 MOE 817

372607

1053 1066  AAGGAATAGGTGGG 2-10-2 MOE 818

372534

1144 1159  GCGAAACCAATATACT  3-10-3 MOE 819

372612

1145 1158  CGAAACCAATATAC 2-10-2 MOE 820

372535

1192 1207  CCCCAGGTGTCAGAGG 3-10-3 MOE 821

372613

1193 1206  CCCAGGTGTCAGAG 2-10-2 MOE 822

372545

1332 1347  GATTGTCAAAGAGCTT  3-10-3 MOE 823

372623

1333 1346  ATTGTCAAAGAGCT  2-10-2 MOE 824

372546

1342 1357  TTGGTCTTGTGATTGT  3-10-3 MOE 825

372624

1343 1356  TGGTCTTGTGATTG  2-10-2 MOE 826

372547

1352 1367 AAGGCCGAATTTGGTC 3-10-3 MOE 827

372625

1353 1366 AGGCCGAATTTGGT  2-10-2 MOE 828

382601

1617 1628  CCCGGAGTAGGC 1-10-1 MOE 683

382606

1971 1982  CTGCAGGCCACT  1-10-1 MOE 694

382612

1988 1999  CCACTCCCATTC  1-10-1 MOE 737

In certain embodiments, a target region is nucleotides 231-267 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 231-267 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 231-267 comprises a nucleotide sequence selected from SEQ ID 5 No. 681, 682, 683, 684, 685, 686 or 687. In certain such embodiments, a short antisense compound directed to nucleotides 231-267 of SEQ ID No. 10 is selected from No. Isis 372556, 372557, 382601, 372480, 372481, 372558 or 372559.

In certain embodiments, a target region is nucleotides 249-267 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 249-267 of SEQ ID No. 10. In certain embodiments, a compound

Short antisense directed at nucleotides 249-267 comprises a nucleotide sequence selected from SEQ ID Nos. 683, 684, 685, 686 or 687. In certain such embodiments, a short antisense compound directed at nucleotides 249-267 of the SEQ ID NO. 10 is selected from No. Isis 382601, 372480, 372481, 372558 or 372559.

In certain embodiments, a target region is nucleotides 331-493 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 331-493 of SEQ ID No. 10. In certain embodiments, an antisense compound 15 Short nucleotide targeting 331-493 comprises a nucleotide sequence selected from SEQ ID

No. 688, 689, 690, 691, 692, 693 or 694. In certain such embodiments, a short antisense compound directed to nucleotides 331-493 of SEQ ID No. 10 is selected from Isis No. 382603, 382604, 372485, 372563, 382605, 372565 or 382606.

In certain embodiments, a target region is nucleotides 331-427 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 331-427 of SEQ ID No. 10. In certain embodiments, a short antisense compound. addressed to nucleotides 331-427 comprises a nucleotide sequence selected from SEQ ID Nos. 688, 689, 690, 691, 692 or 693. In certain such embodiments, a short antisense compound directed to nucleotides 331-427 of SEC ID No. 10 is selected from No. Isis 382603, 382604, 372485, 372563, 382605, or 372565.

In certain embodiments, a target region is nucleotides 392-408 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 392-408 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 392-408 comprises a nucleotide sequence selected from SEQ ID NO: 690, 691 or 692. In certain such embodiments, a short antisense compound directed to nucleotides 392-408 of SEQ ID NO: 10 is selected from No. Isis 372485, 372563 or 382605.

In certain embodiments, a target region is nucleotides 651-707 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 651-707 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 651-707 comprises a nucleotide sequence selected from SEQ ID NO: 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727 or 728. In certain such embodiments, a short antisense compound directed to the nucleotides 651-707 of SEQ ID No. 10 is selected from No. Isis 372497, 372498, 372575, 372576, 382607, 372499, 372577, 372500, 372578, 372501, 372579, 372502, 372580, 372503, 372581, 372504, 372582, 372505 , 372506, 372583, 372584, 372507, 372585, 382608, 372508, 372586, 372509, 372587, 372510, 372588, 372511, 372512, 372589 or 372590.

In certain embodiments, a target region is nucleotides 724-745 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 724-745 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 724-745 comprises a nucleotide sequence selected from SEQ ID Nos. 729, 730, 731, 732 or 733. In certain such embodiments, a short antisense compound directed to nucleotides 724-745 of SEQ ID NO. 10 is selected from No. Isis 382609, 372514, 372592, 372515 or 372593.

In certain embodiments, a target region is nucleotides 651-745 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 651-745 of SEQ ID No. 10. In certain embodiments, a short antisense compound. Nucleotide targeting 651-745 comprises a nucleotide sequence selected from SEQ ID Nos. 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732 or 733. In certain of those embodiments, a short antisense compound targeting nucleotides 651-745 of SEQ ID NO: 10 is selected from No. Isis 372497, 372498, 372575, 372576, 382607, 372499, 372577, 372500, 372578, 372501, 372579, 372502, 372580 , 372503, 372581, 372504, 372582, 372505, 372506, 372583, 372584, 372507, 372585, 382608, 372508, 372586, 372509, 372587, 372510, 372588, 372511, 372512, 372589, 372590, 382609 372514, 372592, 372515 or 372593.

In certain embodiments, a target region is nucleotides 851-922 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 851-922 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 851-922 comprises a nucleotide sequence selected from SEQ ID NO: 734, 735, 736 or 737. In certain such embodiments, a short antisense compound directed to nucleotides 851922 of SEQ ID NO: 10 is selected from No. Isis 382610, 382611, 382602 or 382612.

In certain embodiments, a target region is nucleotides 851-879 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 851-879 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 851-879 comprises a nucleotide sequence selected from SEQ ID NO: 734, 735 or 736. In certain such embodiments, a short antisense compound directed to nucleotides 851-879 of SEQ ID NO: 10 is selected from No. Isis 382610, 382611 or 382602.

In certain embodiments, a target region is nucleotides 965-1007 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 965-1007 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 965-1007 comprises a nucleotide sequence selected from SEQ ID Nos. 738, 739, 740, 741, 742, 743, 744 or 745. In certain such embodiments, a short antisense compound directed to nucleotides 965- 1007 of SEQ ID No. 10 is selected from No. Isis 372524, 372602, 382613, 382614, 372525, 372603, 372526 or 372604.

In certain embodiments, a target region is nucleotides 965-979 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 965-979 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 965-979 comprises a nucleotide sequence selected from SEQ ID NO: 738, 739 or 740. In certain such embodiments, a short antisense compound directed to nucleotides 965-979 of SEQ ID NO: 10 is selected from No. Isis 372524, 372602 or 382613.

In certain embodiments, a target region is nucleotides 987-1007 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 987-1007 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 987-1007 comprises a nucleotide sequence selected from SEQ ID Nos. 741, 742, 743, 744 or 745. In certain such embodiments, a short antisense compound directed to nucleotides 987-1007 of SEQ ID NO. 10 is selected from No. Isis 382614, 372525, 372603, 372526 or 372604.

In certain embodiments, a target region is nucleotides 1106-1132 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 1106-1132 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 1106-1132 comprises a nucleotide sequence selected from SEQ ID Nos. 746, 747, 748, 749, 750, 751, 752, 753 or 754. In certain such embodiments, a short antisense compound directed to nucleotides 1106-1132 of SEQ ID NO: 10 is selected from No. Isis 372530, 372608, 372531, 372609, 372532, 372610, 372533, 382615 or 372611.

In certain embodiments, a target region is nucleotides 1199-1233 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 1199-1233 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 1199-1233 comprises a nucleotide sequence selected from SEQ ID Nos. 755, 756, 757, 758, 759, 760, 761, 762 or 763. In certain such embodiments, a short antisense compound directed to nucleotides 1199-1233 of SEQ ID No. 10 is selected from No. Isis 372536, 372614, 372537, 372615, 372538, 372616, 382616, 372539 or 372617.

In certain embodiments, a target region is nucleotides 1293-1394 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 1293-1394 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 1293-1394 comprises a nucleotide sequence selected from SEQ ID Nos. 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774 or 775. In certain of said embodiments, a compound Short antisense targeting nucleotides 1293-1394 of SEQ ID NO: 10 is selected from No. Isis 372540, 372618, 382617, 372541, 372619, 372542, 372620, 372543, 372621, 372544, 372622, 382618, 382619 or 382620.

In certain embodiments, a target region is nucleotides 1293-1336 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 1293-1336 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 1293-1336 comprises a nucleotide sequence selected from SEQ ID Nos. 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775 or 776. In certain such embodiments, A short antisense compound targeting nucleotides 1293-1336 of SEQ ID NO: 10 is selected from No. Isis 372540, 372618, 382617, 372541, 372619, 372542, 372620, 372543, 372621, 372544, 372622, 382618 or 382619.

In certain embodiments, a target region is nucleotides 1293-1324 of SEQ ID No. 10. In certain embodiments, a short antisense compound directed to nucleotides 1293-1324 of SEQ ID No. 10. In certain embodiments, a short antisense compound. directed to nucleotides 1293-1324 comprises a nucleotide sequence selected from SEQ ID Nos. 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774 or 775. In certain of said embodiments, a compound Short antisense targeting nucleotides 1293-1324 of SEQ ID NO: 10 is selected from No. Isis 372540, 372618, 382617, 372541, 372619, 372542, 372620, 372543, 372621, 372544, 372622 or 382618.

In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid are short captamers. In certain of said embodiments, short captamers directed to a DGAT2 nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from α-L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in a short antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a DGAT2 nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid have a monomer length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to a DGAT2 nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of DGAT2 are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a DGAT2 nucleic acid, wherein the short antisense compound targeting a DGAT2 nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating DGAT2 expression using one or more short antisense compounds targeting a DGAT2 nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers

In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 8 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 9 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 10 monomers in length. In certain embodiments, the DGAT2 modulation procedures comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 11 monomers in length. In certain embodiments, the DGAT2 modulation procedures comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 12 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 13 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 14 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 15 monomers in length. In certain embodiments, the DGAT2 modulation methods comprise the use of a short antisense compound directed to a DGAT2 nucleic acid that is 16 monomers in length.

In certain embodiments, the methods of modulating the expression of DGAT2 comprise the use of a short antisense compound directed to a DGAT2 nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating DGAT2 expression comprise the use of a short antisense compound targeting a DGAT2 nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of DGAT2 comprise the use of a short antisense compound directed to a DGAT2 nucleic acid comprising from 12 to 14 monomers. In certain embodiments, the methods of modulating DGAT2 expression comprise the use of a short antisense compound targeting a DGAT2 nucleic acid comprising 12 or 14 nucleotides or nucleosides.

9. PTP1B

PTP1B (also known as protein phosphatase 1B and PTPN1) is an enzyme associated with the endoplasmic reticulum (ER) initially isolated as the main tyrosine phosphatase protein of the human placenta (Tonks et al., J. Biol. Chem., 1988, 263, 6731-6737; Tonks et al., J. Biol. Chem., 1988, 263, 6722-6730).

An essential regulatory role in signaling mediated by the insulin receptor for PTP1B has been established. In certain cases, PTP1B interacts and dephosphorylates the activated insulin receptor both in vitro and in intact cells, which results in regulation by decreased signaling pathway (Goldstein et al., Mol. Cell. Biochem., 1998 , 182, 91-99; Seely et al., Diabetes. 1996, 45, 1379-1385). In addition, PTP1B modulates the mitogenic actions of insulin (Goldstein et al., Mol. Cell. Biochem., 1998, 182, 91-99). In rat fat cells that overexpress PTP1B, translocation of the GLUT4 glucose transporter was inhibited, which implies that PTP1B is a negative regulator of glucose transport as well (Chen et al., J. Biol. Chem., 1997, 272 , 8026-8031).

Defective mouse models that lack the PTP1B gene also point to a negative regulation of insulin signaling by PTP1B. Mice harboring an altered PTP1B gene showed an increase in insulin sensitivity and an increase in phosphorylation of the insulin receptor. When fed with a high-fat diet, PTP1B - / - mice were resistant to weight gain and remained sensitive to insulin (Elchebly et al., Science, 1999, 283, 1544-1548). These studies clearly state that PTP1B is a therapeutic target in the treatment of diabetes and obesity.

Diabetes and obesity (sometimes referred to collectively as "diabesity") are interrelated. Most human obesity is associated with insulin resistance and leptin resistance. In fact, obesity can have an impact on the action of insulin even greater than diabetes itself (Sindelka et al., Physiol Res., 2002, 51, 85-91). Syndrome X or metabolic syndrome is a new term coined for a group of conditions that, when they occur together, may indicate a predisposition to diabetes and cardiovascular disease. These symptoms, including hypertension, high triglyceride levels, low HDL levels and obesity, tend to appear together in some individuals. Given its role in diabetes and obesity, PTP1B is believed to be a therapeutic target for a number of metabolic conditions, including diabetes, obesity and metabolic syndrome. By improving blood glucose control, PTP1B inhibitors may also be useful in slowing down, preventing delaying or improving the sequelae of diabetes, including retinopathy, neuropathy, cardiovascular complications and kidney disease.

PTP1B, which is regulated differently during the cell cycle (Schievella et al., Cell. Growth Differ., 1993, 4, 239246), is expressed in insulin-sensitive tissues as two different isoforms that arise from the alternative splicing of the pre-mRNA (Shifrin and Neel, J. Biol. Chem., 1993, 268, 25376-25384). The proportion of alternative splicing products is affected by growth factors, such as insulin, and differs in several tissues analyzed (Sell and Reese, Mol. Genet. Metab., 1999, 66, 189-192). In these studies, variant levels were correlated with plasma insulin concentration and body fat percentage. Therefore, these variants can be used as a biomarker for patients with chronic hyperinsulinemia or type 2 diabetes.

Definitions

"Tyrosine phosphatase 1B protein" is the gene product or protein whose expression is to be modulated by the administration of a short antisense compound. In general, tyrosine phosphatase 1B protein is referred to as PTP1B, but it can also be referred to as tyrosine phosphatase protein; PTPN1; RKPTP; Type 1 non-receptor tyrosine phosphatase protein.

"PTP1B nucleic acid" means any nucleic acid encoding PTP1B. For example, in certain embodiments, a PTP1B nucleic acid includes, without limitation, a DNA sequence encoding PTP1B, an RNA sequence transcribed from DNA encoding PTP1B, and an mRNA sequence encoding PTP1B.

"PTP1B mRNA" means an mRNA that encodes a PTP1B protein.

Therapeutic indications

Antisense technology is an effective means to reduce the expression of PTP1B and has been shown to be unique in its usefulness in a number of therapeutic, diagnostic and research applications. As such, in certain embodiments, compounds directed to a nucleic acid encoding PTP1B and modulating the expression of PTP1B are disclosed herein. Short antisense compounds capable of effectively inhibiting the expression of are also disclosed herein.

For certain therapeutics, a subject suspected of having a disease or disorder, which can be treated by modulating the expression of PTP1B is treated by administering one or more short antisense compounds directed to a nucleic acid encoding PTP1B. For example, in a non-limiting embodiment, the methods comprise the step of administering to a animal a therapeutically effective amount of a short antisense compound. The short antisense compounds of the present invention effectively inhibit the activity of PTP1B or inhibit the expression of PTP1B. In one embodiment, the activity or expression of PTP1B in a subject is inhibited by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, in at least 95%, at least 98%, at least 99%, or 100%. In certain embodiments, the activity or expression of PTP1B in a subject is inhibited by approximately 30%. In certain embodiments, the activity or expression of PTP1B in a subject is inhibited by 50% or more.

The reduction in PTP1B expression can be measured in, for example, blood, plasma, serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. Preferably, the cells contained within said fluids, tissues or organs being analyzed contain a nucleic acid molecule encoding PTP1B and / or the PTP1B protein itself.

Certain pharmaceutical and other compositions comprising the compounds of the disclosure are also disclosed. In certain embodiments, short antisense compounds directed to a PTPQB nucleic acid are used in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier.

Short antisense compounds targeting PTP1B may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid have a motif (deoxyl-wing-hollow) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1, 1-10-2, 3-8-3, 2-8-2, 1-8-1, 3- 6-3 or 1-6-1, more preferably 1-10-1, 2-10-2, 3-10-3 and 1-9-2.

In certain embodiments, methods of treating an individual by administering one are disclosed herein.

or short antisense compounds directed to a PTP1B nucleic acid or a pharmaceutical composition comprising said compound. Methods of treating an individual suffering from a disease or condition associated with the activity of PTP1B by administering a short antisense compound directed to a PTP1B nucleic acid are also disclosed. Diseases and conditions associated with PTP1B include, among others, elevated blood glucose levels or hyperglycemia, prediabetes, diabetes, type 2 diabetes, metabolic syndrome, obesity and insulin resistance. Therefore, methods of treating elevated blood glucose levels or hyperglycemia, prediabetes, diabetes, type 2 diabetes, metabolic syndrome, obesity and insulin resistance, by administering a compound, are disclosed herein. short antisense directed to a PTP1B nucleic acid.

In certain embodiments herein, compositions and methods for lowering blood glucose levels in a subject or to prevent or delay the onset of an increase in blood glucose levels in a subject are disclosed, administering to the subject an antisense inhibitor. short of the expression of PTP1B.

In certain embodiments herein, compositions and methods for improving insulin sensitivity in a subject or to prevent or delay the onset of insulin resistance in a subject are disclosed, administering to the subject a short antisense inhibitor of the expression of PTP1B.

In certain embodiments herein, compositions and methods for treating a metabolic condition in a subject or to prevent or delay the onset of a metabolic condition in a subject are disclosed, administering to the subject a short antisense compound directed to a PTP1B nucleic acid. Said metabolic condition can be any metabolic condition associated with the expression of PTP1B, including, but not limited to, diabetes and obesity. Procedures for reducing adiposity are also disclosed. A procedure to treat obesity in which the metabolic rate is increased is also disclosed.

In certain embodiments, the subject has type 2 diabetes. In certain of said embodiments, the subject exhibits elevated HbAlc levels. In certain of said embodiments, HbAlc levels are at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%

or at least about 11%. In preferred embodiments, HbAlc levels are reduced by approximately 7% or less than 7%. In certain of said embodiments, the subject exhibits a high body mass index. In certain of these embodiments, the high body mass index is greater than 25 kg / m2. In certain embodiments, the subject exhibits hyperglycemia or elevated blood glucose levels. In a specific embodiment, blood glucose levels are fasting blood glucose levels. In certain embodiments, fasting blood glucose levels are at least 130 mg / dl. In certain embodiments, the subject exhibits hyperglycemia before the start of treatment or exhibits fasting blood glucose levels greater than about 130 mg / dl, baseline HbAlc levels of at least about 7%, or a body mass index greater than 25 kg. / m2 or any combination thereof.

In certain embodiments, a method of reducing one or more of said levels is disclosed by administering a short antisense compound directed to a PTP1B nucleic acid. For example, a method of reducing fasting glucose levels, HbAlc levels or body mass index levels or any combination thereof in a subject is disclosed, administering to a subject a short antisense compound directed to PTP1B. Fasting glucose levels can be fasting blood glucose levels, fasting serum glucose levels or fasting plasma glucose levels. In some embodiments, fasting plasma glucose levels are reduced by at least about 25 mg / d or at least about 10 mg / dl. In certain embodiments, said subject does not reach

5 normal glucose levels in a therapeutic regimen of a hypoglycemic agent, such as insulin, sulfonylurea or metformin.

In certain embodiments, methods of altering lipid levels are disclosed herein. Certain of these procedures reduce the levels of cholesterol, LDL and / or VLDL, or any combination thereof, in a subject by administering to the subject a short antisense compound directed to a PTP1B nucleic acid. In certain embodiments, HDL levels in a subject are increased by administering to the subject a short antisense compound directed to a PTP1B nucleic acid. In certain embodiments, the LDL: HDL ratio and the total cholesterol: HDL ratio in a subject are reduced by administering to the subject a short antisense compound directed to a PTP1B nucleic acid. In certain embodiments, the HDL: LDL ratio and / or the HDL: total cholesterol ratio in a subject is increased by administering to the subject a short antisense compound directed to a PTP1B nucleic acid. In certain embodiments, it

15 improves the lipid profile in a subject by increasing HDL levels, decreasing LDL levels, decreasing VLDL levels, decreasing triglyceride levels, decreasing apolipoprotein B levels or decreasing total cholesterol levels, or a combination thereof, administering to the subject a short antisense compound directed to a PTP1B nucleic acid. In such embodiments, the subject is an animal, including a human being.

Combination therapy

In certain embodiments, one or more pharmaceutical compositions comprising a short antisense compound directed to a PTP1B nucleic acid are co-administered with one more different pharmaceutical agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat an undesired effect of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present

The disclosure and one or more other pharmaceutical agents are prepared separately.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to a PTP1B nucleic acid include hypoglycemic agents and therapies. In some embodiments, the hypoglycemic agent is a PPAR agonist (gamma, double

or pan), a dipeptidyl peptidase (IV) inhibitor, a GLP-1 analogue, insulin or an insulin analogue, an insulin secretagogue, an SGLT2 inhibitor, a human amylin analogue, a biguanide, a alphaglucosidase inhibitor, a meglitinide, a thiazolidinedione or a sulfonylurea.

In some embodiments, hypoglycemic therapy is an analog of GLP-1. In some embodiments, the GLP-1 analog is exendin-4 or liraglutide.

In some embodiments, the hypoglycemic therapy is a sulfonylurea. In some embodiments, the sulfonylurea is acetohexamide, chlorpropamide, tolbutamide, tolazamide, glimepiride, a glipizide, a glyburide or a gliclazide.

In some embodiments, the hypoglycemic drug is a biguanide. In some embodiments, biguanide is metformin and in some embodiments glucose levels are decreased without an increase in lactic acidosis compared to lactic acidosis observed after treatment with metformin alone.

In some embodiments, the hypoglycemic drug is a meglitinide. In some embodiments, meglitinide is nateglinide or repaglinide.

In some embodiments, the hypoglycemic drug is thiazolidinedione. In some embodiments, the thiazolidinedione is pioglitazone, rosiglitazone or troglitazone. In some embodiments, blood glucose levels are decreased without greater weight gain than that seen with rosiglitazone alone treatment.

In some embodiments, the hypoglycemic drug is an alpha-glucosidase inhibitor. In some embodiments, the alpha-glucosidase inhibitor is acarbose or miglitol.

In a certain embodiment, a co-administered hypoglycemic agent is ISIS 113715.

In a certain embodiment, hypoglycemic therapy is a therapeutic lifestyle change.

In certain of said embodiments, the hypoglycemic agent is administered prior to the administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the hypoglycemic agent is administered after administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the hypoglycemic agent is administered at the same time as the pharmaceutical composition of the present disclosure. In certain of said embodiments, the dose of a co-administered hypoglycemic agent is the same as the dose that would be administered if the hypoglycemic agent was administered alone. In certain of said embodiments, the dose of a co-administered hypoglycemic agent is less than the dose that would be administered if the hypoglycemic agent was administered alone. In certain of said embodiments, the dose of a co-administered hypoglycemic agent is greater than the dose that would be administered if the hypoglycemic agent was administered alone.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to a PTP1B nucleic acid include lipid lowering agents. Such lipid lowering agents are discussed at another point in the application and are now included with respect to PTP1B. Such lipid lowering agents can be administered as described above for hypoglycemic agents.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition comprising a short antisense compound directed to a PTP1B nucleic acid include therapeutics with anti-obesity agents. Such therapies with anti-obesity agents can be administered as described above for hypoglycemic agents.

Additionally, a method of administering a short antisense compound directed to a PTPB1 nucleic acid by injection is disclosed and also includes administering a topical steroid at the injection site.

Medicines

Uses of a short antisense compound that is directed to a PTP1B nucleic acid for the preparation of a medicament for reducing blood glucose levels, including fasting glucose levels, and HbAIc levels are also disclosed herein. , body mass index levels or any combination thereof. The medicine can be administered during a loading period and a maintenance period. In some embodiments, the medicament is administered subcutaneously or intravenously. In other embodiments, administration of said medicament occurs at least once a day, at least once or at least once a month. In a specific embodiment, the short antisense compound present in the medicament is administered at a dose lower than that of a short antisense compound with a longer sequence and, particularly, a sequence of 20 or more nucleotide bases. The medication can be administered to a subject that exhibits elevated blood glucose levels or hyperglycemia, prediabetes, diabetes, type 2 diabetes, metabolic syndrome, obesity and insulin resistance.

Other aspects and advantages of short antisense compounds are disclosed herein. All aspects and advantages disclosed herein, and specifically with respect to other targets, apply with respect to compositions that include short antisense compounds directed to a PTP1B nucleic acid and methods of its use.

Certain short antisense compounds targeting a PTP1B nucleic acid

In certain embodiments, short antisense compounds are directed to a PTP1B nucleic acid having the registration number sequence in GENBANK® NM_002827.2, incorporated herein as SEQ ID No. 11 or nucleotides 14178000 to 1425600 of the sequence of GENBANK® with registration number NT_011362.9, incorporated herein as SEQ ID NO. 12. In certain such embodiments, a short antisense compound directed to SEQ ID NO. 11 is at least 90% complementary to SEQ ID. No. 11. In certain such embodiments, a short antisense compound directed to SEQ ID No. 11 is at least 95% complementary to SEQ ID No. 11. In certain such embodiments, a short antisense compound directed to SEQ ID NO. 12 EN 100% complementary to SEQ ID No. 12. In certain such embodiments, a short antisense compound directed to SEQ ID No. 12 is at least 90% complementary to SEQ ID No. 12. In certain cases In such embodiments, a short antisense compound directed to SEQ ID No. 12 is at least 95% complementary to SEQ ID No. 12. In certain such embodiments, a short antisense compound directed to SEQ ID No. 12 EN is 100% complementary to SEQ ID No. 12.

In certain embodiments, a short antisense compound directed to SEQ ID No. 11 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Tables 16 and 17. In certain embodiments, a short antisense compound directed to SEQ ID No. 12 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Tables 18 and 19.

Each nucleotide sequence indicated in each of Tables 16, 17 and 18 is independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds comprising a nucleotide sequence as indicated in Tables 16, 17, 18 and 19 may comprise, of

5 independently, one or more modifications to a sugar moiety, an internucleoside bond or a nucleotide base.

The antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

Tables 16 and 17 illustrate examples of short antisense compounds directed to SEQ ID No. 11. Table 16 illustrates short antisense compounds that are 100% complementary to SEQ ID No. 11. Table 17 illustrates short antisense compounds 10 having one or more two mismatches with respect to SEQ ID No. 11. Table 18 illustrates short antisense compounds that are 100% complementary to SEQ ID No. 12. Table 19 illustrates short antisense compounds that have 1 or 2 mismatches with respect to SEC. ID No. 12. The column called "gápmero motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. Sugar 15 modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, '2-10-2 MOE' means a 2-10-2 catheter motif, in which a gap segment of ten 2'-deoxynucleotides is flanked by two nucleotide wing segments, in which the nucleotides of the wing segments are 2'-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methylcytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the gimer motif, in which case the

20 cytosines indicated are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

Table 16: Short antisense compounds directed to SEQ ID NO: 11

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147022

177 188 TTGTCGATCTCC 1-10-1 MOE 886

147023

178 189 CTTGTCGATCTC 1-10-1 MOE 859

147024

179 190 CCTTGTCGATCT 1-10-1 MOE 853

147019

195 206 TCGATCTCCTCG 1-10-1 MOE 877

147020

196 207 GTCGATCTCCTC 1-10-1 MOE 868

147021

197 208 TGTCGATCTCCT 1-10-1 MOE 882

147022

198 209 TTGTCGATCTCC 1-10-1 MOE 886

147023

199 210 CTTGTCGATCTC 1-10-1 MOE 859

147024

200 211 CCTTGTCGATCT 1-10-1 MOE 853

147025

201 212 GCCTTGTCGATC 1-10-1 MOE 865

147026

202 213 AGCCTTGTCGAT 1-10-1 MOE 835

147027

203 214 CAGCCTTGTCGA 1-10-1 MOE 843

147028

204 215 CCAGCCTTGTCG 1-10-1 MOE 846

147073

204 215 CACTGATCCTGC 1-10-1 MOE 842

147029

205 216 CCCAGCCTTGTC 1-10-1 MOE 848

147030

206 217 TCCCAGCCTTGT 1-10-1 MOE 874

147036

212 223 CCCAGTTCCCAG 1-10-1 MOE 849

147037

213 224 GCCCAGTTCCCA 1-10-1 MOE 863

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147038

214 225 CGCCCAGTTCCC 1-10-1 MOE 855

147039

215 226 CCGCCCAGTTCC 1-10-1 MOE 850

147040

216 227 GCCGCCCAGTTC  1-10-1 MOE 864

147041

217 228 AGCCGCCCAGTT  1-10-1 MOE 834

147073

311 322 CACTGATCCTGC 1-10-1 MOE 842

147042

323 334 GGTCAAAAGGGC 1-10-1 MOE 866

147043

324 335 TGGTCAAAAGGG 1-10-1 MOE 881

147044

325 336 GTGGTCAAAAGG 1-10-1 MOE 869

147045

326 337 TGTGGTCAAAAG 1-10-1 MOE 883

147046

327 338 CTGTGGTCAAAA 1-10-1 MOE 858

147047

328 339 ACTGTGGTCAAA 1-10-1 MOE 833

147051

332 343 TCCGACTGTGGT 1-10-1 MOE 875

147052

333 344 ATCCGACTGTGG 1-10-1 MOE 837

147053

334 3. 4. 5 AATCCGACTGTG 1-10-1 MOE 829

147054

335 346 TAATCCGACTGT 1-10-1 MOE 871

147055

336 347 TTAATCCGACTG 1-10-1 MOE 884

147056

337 348 TTTAATCCGACT  1-10-1 MOE 887

147057

338 349 ATTTAATCCGAC 1-10-1 MOE 839

147058

339 350 AATTTAATCCGA 1-10-1 MOE 830

147059

340 351 CAATTTAATCCG 1-10-1 MOE 840

147060

341 352 GCAATTTAATCC 1-10-1 MOE 861

147061

342 353 TGCAATTTAATC 1-10-1 MOE 879

147045

679 690 TGTGGTCAAAAG 1-10-1 MOE 883

147046

680 691 CTGTGGTCAAAA 1-10-1 MOE 858

147045

787 798 TGTGGTCAAAAG 1-10-1 MOE 883

147046

788 799 CTGTGGTCAAAA 1-10-1 MOE 858

147066

816 827 CCTGCACTGACG 1-10-1 MOE 851

404131

992 1005 ACCTTCGATCACAG 2-10-2 MOE 831

147062

1024 1035 CACTGACGAGTC 1-10-1 MOE 841

147063

1025 1036 GCACTGACGAGT 1-10-1 MOE 862

147064

1026 1037 TGCACTGACGAG 1-10-1 MOE 880

147065

1027 1038 CTGCACTGACGA 1-10-1 MOE 857

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147066

1028 1039 CCTGCACTGACG 1-10-1 MOE 851

147067

1029 1040 TCCTGCACTGAC 1-10-1 MOE 876

147068

1030 1041 ATCCTGCACTGA 1-10-1 MOE 838

147069

1031 1042 GATCCTGCACTG 1-10-1 MOE 860

147070

1032 1043 TGATCCTGCACT 1-10-1 MOE 878

147071

1033 1044 CTGATCCTGCAC 1-10-1 MOE 856

147072

1034 1045 ACTGATCCTGCA 1-10-1 MOE 832

147073

1035 1046 CACTGATCCTGC 1-10-1 MOE 842

147067

1199 1210 TCCTGCACTGAC 1-10-1 MOE 876

147040

1288 1299 GCCGCCCAGTTC  1-10-1 MOE 864

147040

1396 1407 GCCGCCCAGTTC  1-10-1 MOE 864

147022

1868 1879 TTGTCGATCTCC 1-10-1 MOE 886

147023

1869 1880 CTTGTCGATCTC 1-10-1 MOE 859

147024

1870 1881 CCTTGTCGATCT 1-10-1 MOE 853

147019

1886 1897 TCGATCTCCTCG 1-10-1 MOE 877

147020

1887 1898 GTCGATCTCCTC 1-10-1 MOE 868

147021

1888 1899 TGTCGATCTCCT 1-10-1 MOE 882

147022

1889 1900 TTGTCGATCTCC 1-10-1 MOE 886

147023

1890 1901 CTTGTCGATCTC 1-10-1 MOE 859

147025

1892 1903 GCCTTGTCGATC 1-10-1 MOE 865

147027

1894 1905 CAGCCTTGTCGA 1-10-1 MOE 843

147028

1895 1906 CCAGCCTTGTCG 1-10-1 MOE 846

147030

1897 1908 TCCCAGCCTTGT 1-10-1 MOE 874

147037

1904 1915 GCCCAGTTCCCA 1-10-1 MOE 863

147038

1905 1916 CGCCCAGTTCCC 1-10-1 MOE 855

147040

1907 1918 GCCGCCCAGTTC  1-10-1 MOE 864

147041

1908 1919 AGCCGCCCAGTT  1-10-1 MOE 834

147022

1976 1987 TTGTCGATCTCC 1-10-1 MOE 886

147023

1977 1988 CTTGTCGATCTC 1-10-1 MOE 859

147024

1978 1989 CCTTGTCGATCT 1-10-1 MOE 853

147020

nineteen ninety five 2006 GTCGATCTCCTC 1-10-1 MOE 868

147021

nineteen ninety six 2007 TGTCGATCTCCT 1-10-1 MOE 882

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147022

1997 2008 TTGTCGATCTCC 1-10-1 MOE 886

147023

1998 2009 CTTGTCGATCTC 1-10-1 MOE 859

147024

1999 2010 CCTTGTCGATCT 1-10-1 MOE 853

147025

2000 2011 GCCTTGTCGATC 1-10-1 MOE 865

147026

2001 2012 AGCCTTGTCGAT 1-10-1 MOE 835

147027

2002 2013 CAGCCTTGTCGA 1-10-1 MOE 843

147028

2003 2014 CCAGCCTTGTCG 1-10-1 MOE 846

147029

2004 2015 CCCAGCCTTGTC 1-10-1 MOE 848

147030

2005 2016 TCCCAGCCTTGT 1-10-1 MOE 874

147036

2011 2022 CCCAGTTCCCAG 1-10-1 MOE 849

147037

2012 2023 GCCCAGTTCCCA 1-10-1 MOE 863

147038

2013 2024 CGCCCAGTTCCC 1-10-1 MOE 855

147039

2014 2025 CCGCCCAGTTCC 1-10-1 MOE 850

147040

2015 2026 GCCGCCCAGTTC  1-10-1 MOE 864

147041

2016 2027 AGCCGCCCAGTT  1-10-1 MOE 834

404199

2366 2379 GGTCATGCACAGGC 2-10-2 MOE 867

404134

2369 2382 TCAGGTCATGCACA 2-10-2 MOE 873

404132

2548 2561 CCTTGGAATGTCTG 2-10-2 MOE 852

147020

2613 2624 GTCGATCTCCTC 1-10-1 MOE 868

147020

2721 2732 GTCGATCTCCTC 1-10-1 MOE 868

404133

3289 3302 TATTCCATGGCCAT 2-10-2 MOE 872

147032

6220 6231 GTTCCCAGCCTT 1-10-1 MOE 870

147033

6221 6232 AGTTCCCAGCCT 1-10-1 MOE 836

147034

6222 6233 CAGTTCCCAGCC 1-10-1 MOE 844

147044

6288 6299 GTGGTCAAAAGG 1-10-1 MOE 869

147045

6289 6300 TGTGGTCAAAAG 1-10-1 MOE 883

147032

6329 6340 GTTCCCAGCCTT 1-10-1 MOE 870

147033

6330 6341 AGTTCCCAGCCT 1-10-1 MOE 836

147034

6331 6342 CAGTTCCCAGCC 1-10-1 MOE 844

147044

6397 6408 GTGGTCAAAAGG 1-10-1 MOE 869

147045

6398 6409 TGTGGTCAAAAG 1-10-1 MOE 883

147058

7057 7068 AATTTAATCCGA 1-10-1 MOE 830

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147059

7058 7069 CAATTTAATCCG 1-10-1 MOE 840

147060

7059 7070 GCAATTTAATCC 1-10-1 MOE 861

147058

7166 7177 AATTTAATCCGA 1-10-1 MOE 830

147059

7167 7178 CAATTTAATCCG 1-10-1 MOE 840

147041

8084 8095 AGCCGCCCAGTT  1-10-1 MOE 834

147041

8192 8203 AGCCGCCCAGTT  1-10-1 MOE 834

147027

8630 8641 CAGCCTTGTCGA 1-10-1 MOE 843

147028

8631 8642 CCAGCCTTGTCG 1-10-1 MOE 846

147027

8738 8749 CAGCCTTGTCGA 1-10-1 MOE 843

147028

8739 8750 CCAGCCTTGTCG 1-10-1 MOE 846

147043

10957 10968 TGGTCAAAAGGG 1-10-1 MOE 881

147044

10958 10969 GTGGTCAAAAGG 1-10-1 MOE 869

147043

11065 11076 TGGTCAAAAGGG 1-10-1 MOE 881

147044

11066 11077 GTGGTCAAAAGG 1-10-1 MOE 869

147071

11605 11616 CTGATCCTGCAC 1-10-1 MOE 856

147070

11611 11622 TGATCCTGCACT 1-10-1 MOE 878

147071

11612 11623 CTGATCCTGCAC 1-10-1 MOE 856

147072

12294 12305 ACTGATCCTGCA 1-10-1 MOE 832

147072

12299 12310 ACTGATCCTGCA 1-10-1 MOE 832

147030

12805 12816 TCCCAGCCTTGT 1-10-1 MOE 874

147031

12806 12817 TTCCCAGCCTTG 1-10-1 MOE 885

147053

12939 12950 AATCCGACTGTG 1-10-1 MOE 829

147030

12986 12997 TCCCAGCCTTGT 1-10-1 MOE 874

147031

12987 12998 TTCCCAGCCTTG 1-10-1 MOE 885

147053

13120 13131 AATCCGACTGTG 1-10-1 MOE 829

147051

13162 13173 TCCGACTGTGGT 1-10-1 MOE 875

147061

13316 13327 TGCAATTTAATC 1-10-1 MOE 879

147047

13339 13350 ACTGTGGTCAAA 1-10-1 MOE 833

147029

14058 14069 CCCAGCCTTGTC 1-10-1 MOE 848

147029

14239 14250 CCCAGCCTTGTC 1-10-1 MOE 848

147067

15560 15571 TCCTGCACTGAC 1-10-1 MOE 876

147068

15561 15572 ATCCTGCACTGA 1-10-1 MOE 838

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147067

15742 15753 TCCTGCACTGAC 1-10-1 MOE 876

147069

15744 15755 GATCCTGCACTG 1-10-1 MOE 860

147042

16561 16572 GGTCAAAAGGGC 1-10-1 MOE 866

147042

16727 16738 GGTCAAAAGGGC 1-10-1 MOE 866

147030

17619 17630 TCCCAGCCTTGT 1-10-1 MOE 874

147064

17762 17773 TGCACTGACGAG 1-10-1 MOE 880

147030

17787 17798 TCCCAGCCTTGT 1-10-1 MOE 874

147064

17930 17941 TGCACTGACGAG 1-10-1 MOE 880

147042

19201 19212 GGTCAAAAGGGC 1-10-1 MOE 866

147042

19369 19380 GGTCAAAAGGGC 1-10-1 MOE 866

147027

21190 21201 CAGCCTTGTCGA 1-10-1 MOE 843

147028

21191 21202 CCAGCCTTGTCG 1-10-1 MOE 846

147027

21358 21369 CAGCCTTGTCGA 1-10-1 MOE 843

147028

21359 21370 CCAGCCTTGTCG 1-10-1 MOE 846

147070

22021 22032 TGATCCTGCACT 1-10-1 MOE 878

147070

22189 22200 TGATCCTGCACT 1-10-1 MOE 878

147047

22606 22617 ACTGTGGTCAAA 1-10-1 MOE 833

147043

24318 24329 TGGTCAAAAGGG 1-10-1 MOE 881

147044

24319 24330 GTGGTCAAAAGG 1-10-1 MOE 869

147045

24320 24331 TGTGGTCAAAAG 1-10-1 MOE 883

147046

24321 24332 CTGTGGTCAAAA 1-10-1 MOE 858

147043

24486 24497 TGGTCAAAAGGG 1-10-1 MOE 881

147044

24487 24498 GTGGTCAAAAGG 1-10-1 MOE 869

147046

24489 24500 CTGTGGTCAAAA 1-10-1 MOE 858

147047

24490 24501 ACTGTGGTCAAA 1-10-1 MOE 833

147040

25065 25076 GCCGCCCAGTTC  1-10-1 MOE 864

147041

25066 25077 AGCCGCCCAGTT  1-10-1 MOE 834

147046

25160 25171 CTGTGGTCAAAA 1-10-1 MOE 858

147039

25232 25243 CCGCCCAGTTCC 1-10-1 MOE 850

147040

25233 25244 GCCGCCCAGTTC  1-10-1 MOE 864

147041

25234 25245 AGCCGCCCAGTT  1-10-1 MOE 834

147046

25328 25339 CTGTGGTCAAAA 1-10-1 MOE 858

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147057

25508 25519 ATTTAATCCGAC 1-10-1 MOE 839

147061

25512 25523 TGCAATTTAATC 1-10-1 MOE 879

147057

25676 25687 ATTTAATCCGAC 1-10-1 MOE 839

147069

28878 28889 GATCCTGCACTG 1-10-1 MOE 860

147070

28879 28890 TGATCCTGCACT 1-10-1 MOE 878

147053

30133 30144 AATCCGACTGTG 1-10-1 MOE 829

147053

30278 30289 AATCCGACTGTG 1-10-1 MOE 829

147054

30864 30875 TAATCCGACTGT 1-10-1 MOE 871

147043

30985 30996 TGGTCAAAAGGG 1-10-1 MOE 881

147054

31011 31022 TAATCCGACTGT 1-10-1 MOE 871

147043

31133 31144 TGGTCAAAAGGG 1-10-1 MOE 881

147036

32233 32244 CCCAGTTCCCAG 1-10-1 MOE 849

147072

32372 32383 ACTGATCCTGCA 1-10-1 MOE 832

147072

32520 32531 ACTGATCCTGCA 1-10-1 MOE 832

147069

33056 33067 GATCCTGCACTG 1-10-1 MOE 860

147070

33057 33068 TGATCCTGCACT 1-10-1 MOE 878

147071

33058 33069 CTGATCCTGCAC 1-10-1 MOE 856

147051

33126 33137 TCCGACTGTGGT 1-10-1 MOE 875

147070

33205 33216 TGATCCTGCACT 1-10-1 MOE 878

147071

33206 33217 CTGATCCTGCAC 1-10-1 MOE 856

147051

33274 33285 TCCGACTGTGGT 1-10-1 MOE 875

147046

33318 33329 CTGTGGTCAAAA 1-10-1 MOE 858

147049

33321 33332 CGACTGTGGTCA 1-10-1 MOE 854

147051

33323 33334 TCCGACTGTGGT 1-10-1 MOE 875

147046

33466 33477 CTGTGGTCAAAA 1-10-1 MOE 858

147047

33467 33478 ACTGTGGTCAAA 1-10-1 MOE 833

147051

33471 33482 TCCGACTGTGGT 1-10-1 MOE 875

147046

33640 33651 CTGTGGTCAAAA 1-10-1 MOE 858

147051

33645 33656 TCCGACTGTGGT 1-10-1 MOE 875

147046

33788 33799 CTGTGGTCAAAA 1-10-1 MOE 858

147051

33793 33804 TCCGACTGTGGT 1-10-1 MOE 875

147059

35437 35448 CAATTTAATCCG 1-10-1 MOE 840

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147060

35438 35449 GCAATTTAATCC 1-10-1 MOE 861

147060

35586 35597 GCAATTTAATCC 1-10-1 MOE 861

147021

36093 36104 TGTCGATCTCCT 1-10-1 MOE 882

147061

36250 36261 TGCAATTTAATC 1-10-1 MOE 879

147061

36398 36409 TGCAATTTAATC 1-10-1 MOE 879

147073

37485 37496 CACTGATCCTGC 1-10-1 MOE 842

147073

37633 37644 CACTGATCCTGC 1-10-1 MOE 842

147043

40214 40225 TGGTCAAAAGGG 1-10-1 MOE 881

147061

40353 40364 TGCAATTTAATC 1-10-1 MOE 879

147043

40362 40373 TGGTCAAAAGGG 1-10-1 MOE 881

147061

40501 40512 TGCAATTTAATC 1-10-1 MOE 879

147031

42527 42538 TTCCCAGCCTTG 1-10-1 MOE 885

147032

42528 42539 GTTCCCAGCCTT 1-10-1 MOE 870

147034

42530 42541 CAGTTCCCAGCC 1-10-1 MOE 844

147031

42675 42686 TTCCCAGCCTTG 1-10-1 MOE 885

147032

42676 42687 GTTCCCAGCCTT 1-10-1 MOE 870

147033

42677 42688 AGTTCCCAGCCT 1-10-1 MOE 836

147034

42678 42689 CAGTTCCCAGCC 1-10-1 MOE 844

147074

43848 43859 CCACTGATCCTG 1-10-1 MOE 845

147074

43996 44007 CCACTGATCCTG 1-10-1 MOE 845

147051

45402 45413 TCCGACTGTGGT 1-10-1 MOE 875

147051

45550 45561 TCCGACTGTGGT 1-10-1 MOE 875

147074

46125 46136 CCACTGATCCTG 1-10-1 MOE 845

147057

46313 46324 ATTTAATCCGAC 1-10-1 MOE 839

147058

46314 46325 AATTTAATCCGA 1-10-1 MOE 830

147059

46315 46326 CAATTTAATCCG 1-10-1 MOE 840

147061

46317 46328 TGCAATTTAATC 1-10-1 MOE 879

147057

46461 46472 ATTTAATCCGAC 1-10-1 MOE 839

147059

46463 46474 CAATTTAATCCG 1-10-1 MOE 840

147061

46465 46476 TGCAATTTAATC 1-10-1 MOE 879

147058

47413 47424 AATTTAATCCGA 1-10-1 MOE 830

147073

48221 48232 CACTGATCCTGC 1-10-1 MOE 842

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147073

48369 48380 CACTGATCCTGC 1-10-1 MOE 842

147074

48370 48381 CCACTGATCCTG 1-10-1 MOE 845

147027

48566 48577 CAGCCTTGTCGA 1-10-1 MOE 843

147027

48714 48725 CAGCCTTGTCGA 1-10-1 MOE 843

147028

48715 48726 CCAGCCTTGTCG 1-10-1 MOE 846

147067

49050 49061 TCCTGCACTGAC 1-10-1 MOE 876

147068

49051 49062 ATCCTGCACTGA 1-10-1 MOE 838

147067

49198 49209 TCCTGCACTGAC 1-10-1 MOE 876

147073

49524 49535 CACTGATCCTGC 1-10-1 MOE 842

147073

49672 49683 CACTGATCCTGC 1-10-1 MOE 842

147074

49673 49684 CCACTGATCCTG 1-10-1 MOE 845

147036

50421 50432 CCCAGTTCCCAG 1-10-1 MOE 849

147036

52292 52303 CCCAGTTCCCAG 1-10-1 MOE 849

147037

52293 52304 GCCCAGTTCCCA 1-10-1 MOE 863

147036

52438 52449 CCCAGTTCCCAG 1-10-1 MOE 849

147037

52439 52450 GCCCAGTTCCCA 1-10-1 MOE 863

147034

53148 53159 CAGTTCCCAGCC 1-10-1 MOE 844

147034

53294 53305 CAGTTCCCAGCC 1-10-1 MOE 844

147042

53445 53456 GGTCAAAAGGGC 1-10-1 MOE 866

147043

53446 53457 TGGTCAAAAGGG 1-10-1 MOE 881

147044

53447 53458 GTGGTCAAAAGG 1-10-1 MOE 869

147042

53591 53602 GGTCAAAAGGGC 1-10-1 MOE 866

147030

53592 53603 TCCCAGCCTTGT 1-10-1 MOE 874

147043

53592 53603 TGGTCAAAAGGG 1-10-1 MOE 881

147031

53593 53604 TTCCCAGCCTTG 1-10-1 MOE 885

147044

53593 53604 GTGGTCAAAAGG 1-10-1 MOE 869

147030

53738 53749 TCCCAGCCTTGT 1-10-1 MOE 874

147031

53739 53750 TTCCCAGCCTTG 1-10-1 MOE 885

147040

53783 53794 GCCGCCCAGTTC  1-10-1 MOE 864

147041

53784 53795 AGCCGCCCAGTT  1-10-1 MOE 834

147041

53930 53941 AGCCGCCCAGTT  1-10-1 MOE 834

147042

55008 55019 GGTCAAAAGGGC 1-10-1 MOE 866

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147043

55009 55020 TGGTCAAAAGGG 1-10-1 MOE 881

147042

55154 55165 GGTCAAAAGGGC 1-10-1 MOE 866

147043

55155 55166 TGGTCAAAAGGG 1-10-1 MOE 881

147058

55281 55292 AATTTAATCCGA 1-10-1 MOE 830

147058

55427 55438 AATTTAATCCGA 1-10-1 MOE 830

147019

55682 55693 TCGATCTCCTCG 1-10-1 MOE 877

147021

55684 55695 TGTCGATCTCCT 1-10-1 MOE 882

147021

55830 55841 TGTCGATCTCCT 1-10-1 MOE 882

147054

56275 56286 TAATCCGACTGT 1-10-1 MOE 871

147055

56276 56287 TTAATCCGACTG 1-10-1 MOE 884

147056

56277 56288 TTTAATCCGACT  1-10-1 MOE 887

147058

56279 56290 AATTTAATCCGA 1-10-1 MOE 830

147059

56280 56291 CAATTTAATCCG 1-10-1 MOE 840

147060

56281 56292 GCAATTTAATCC 1-10-1 MOE 861

147061

56282 56293 TGCAATTTAATC 1-10-1 MOE 879

147051

56418 56429 TCCGACTGTGGT 1-10-1 MOE 875

147053

56420 56431 AATCCGACTGTG 1-10-1 MOE 829

147054

56421 56432 TAATCCGACTGT 1-10-1 MOE 871

147055

56422 56433 TTAATCCGACTG 1-10-1 MOE 884

147056

56423 56434 TTTAATCCGACT  1-10-1 MOE 887

147057

56424 56435 ATTTAATCCGAC 1-10-1 MOE 839

147058

56425 56436 AATTTAATCCGA 1-10-1 MOE 830

147061

56428 56439 TGCAATTTAATC 1-10-1 MOE 879

147045

57118 57129 TGTGGTCAAAAG 1-10-1 MOE 883

147045

57264 57275 TGTGGTCAAAAG 1-10-1 MOE 883

147046

57265 57276 CTGTGGTCAAAA 1-10-1 MOE 858

147071

58028 58039 CTGATCCTGCAC 1-10-1 MOE 856

147071

58174 58185 CTGATCCTGCAC 1-10-1 MOE 856

147043

61111 61122 TGGTCAAAAGGG 1-10-1 MOE 881

147071

61130 61141 CTGATCCTGCAC 1-10-1 MOE 856

147020

61226 61237 GTCGATCTCCTC 1-10-1 MOE 868

147043

61257 61268 TGGTCAAAAGGG 1-10-1 MOE 881

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147071

61276 61287 CTGATCCTGCAC 1-10-1 MOE 856

147035

61277 61288 CCAGTTCCCAGC 1-10-1 MOE 847

147036

61278 61289 CCCAGTTCCCAG 1-10-1 MOE 849

147037

61279 61290 GCCCAGTTCCCA 1-10-1 MOE 863

147038

61280 61291 CGCCCAGTTCCC 1-10-1 MOE 855

147039

61281 61292 CCGCCCAGTTCC 1-10-1 MOE 850

147040

61282 61293 GCCGCCCAGTTC  1-10-1 MOE 864

147071

61309 61320 CTGATCCTGCAC 1-10-1 MOE 856

147020

61372 61383 GTCGATCTCCTC 1-10-1 MOE 868

147034

61422 61433 CAGTTCCCAGCC 1-10-1 MOE 844

147035

61423 61434 CCAGTTCCCAGC 1-10-1 MOE 847

147036

61424 61435 CCCAGTTCCCAG 1-10-1 MOE 849

147037

61425 61436 GCCCAGTTCCCA 1-10-1 MOE 863

147038

61426 61437 CGCCCAGTTCCC 1-10-1 MOE 855

147040

61428 61439 GCCGCCCAGTTC  1-10-1 MOE 864

147071

61455 61466 CTGATCCTGCAC 1-10-1 MOE 856

147073

62003 62014 CACTGATCCTGC 1-10-1 MOE 842

147073

62149 62160 CACTGATCCTGC 1-10-1 MOE 842

147066

63065 63076 CCTGCACTGACG 1-10-1 MOE 851

147068

63067 63078 ATCCTGCACTGA 1-10-1 MOE 838

147069

63146 63157 GATCCTGCACTG 1-10-1 MOE 860

147062

63207 63218 CACTGACGAGTC 1-10-1 MOE 841

147066

63211 63222 CCTGCACTGACG 1-10-1 MOE 851

147057

64054 64065 ATTTAATCCGAC 1-10-1 MOE 839

147036

64538 64549 CCCAGTTCCCAG 1-10-1 MOE 849

147037

64539 64550 GCCCAGTTCCCA 1-10-1 MOE 863

147037

64685 64696 GCCCAGTTCCCA 1-10-1 MOE 863

147066

64864 64875 CCTGCACTGACG 1-10-1 MOE 851

147067

64865 64876 TCCTGCACTGAC 1-10-1 MOE 876

147066

65010 65021 CCTGCACTGACG 1-10-1 MOE 851

147067

65011 65022 TCCTGCACTGAC 1-10-1 MOE 876

147045

65017 65028 TGTGGTCAAAAG 1-10-1 MOE 883

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147045

65163 65174 TGTGGTCAAAAG 1-10-1 MOE 883

147046

65164 65175 CTGTGGTCAAAA 1-10-1 MOE 858

147068

65408 65419 ATCCTGCACTGA 1-10-1 MOE 838

147071

65411 65422 CTGATCCTGCAC 1-10-1 MOE 856

147069

65549 65560 GATCCTGCACTG 1-10-1 MOE 860

147068

65554 65565 ATCCTGCACTGA 1-10-1 MOE 838

147071

65557 65568 CTGATCCTGCAC 1-10-1 MOE 856

147029

67741 67752 CCCAGCCTTGTC 1-10-1 MOE 848

147030

67742 67753 TCCCAGCCTTGT 1-10-1 MOE 874

147031

67743 67754 TTCCCAGCCTTG 1-10-1 MOE 885

147028

67886 67897 CCAGCCTTGTCG 1-10-1 MOE 846

147029

67887 67898 CCCAGCCTTGTC 1-10-1 MOE 848

147030

67888 67899 TCCCAGCCTTGT 1-10-1 MOE 874

147031

67889 67900 TTCCCAGCCTTG 1-10-1 MOE 885

147043

68867 68878 TGGTCAAAAGGG 1-10-1 MOE 881

147044

68868 68879 GTGGTCAAAAGG 1-10-1 MOE 869

147045

68869 68880 TGTGGTCAAAAG 1-10-1 MOE 883

147043

69013 69024 TGGTCAAAAGGG 1-10-1 MOE 881

147044

69014 69025 GTGGTCAAAAGG 1-10-1 MOE 869

147045

69015 69026 TGTGGTCAAAAG 1-10-1 MOE 883

147046

69016 69027 CTGTGGTCAAAA 1-10-1 MOE 858

147071

69519 69530 CTGATCCTGCAC 1-10-1 MOE 856

147072

69520 69531 ACTGATCCTGCA 1-10-1 MOE 832

147073

69521 69532 CACTGATCCTGC 1-10-1 MOE 842

147071

69665 69676 CTGATCCTGCAC 1-10-1 MOE 856

147072

69666 69677 ACTGATCCTGCA 1-10-1 MOE 832

147073

69667 69678 CACTGATCCTGC 1-10-1 MOE 842

147074

69668 69679 CCACTGATCCTG 1-10-1 MOE 845

147066

69869 69880 CCTGCACTGACG 1-10-1 MOE 851

147066

70015 70026 CCTGCACTGACG 1-10-1 MOE 851

147023

70465 70476 CTTGTCGATCTC 1-10-1 MOE 859

147023

70611 70622 CTTGTCGATCTC 1-10-1 MOE 859

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147062

70615 70626 CACTGACGAGTC 1-10-1 MOE 841

147063

70616 70627 GCACTGACGAGT 1-10-1 MOE 862

147064

70617 70628 TGCACTGACGAG 1-10-1 MOE 880

147065

70618 70629 CTGCACTGACGA 1-10-1 MOE 857

147066

70619 70630 CCTGCACTGACG 1-10-1 MOE 851

147063

70762 70773 GCACTGACGAGT 1-10-1 MOE 862

147064

70763 70774 TGCACTGACGAG 1-10-1 MOE 880

147065

70764 70775 CTGCACTGACGA 1-10-1 MOE 857

147066

70765 70776 CCTGCACTGACG 1-10-1 MOE 851

147072

70998 71009 ACTGATCCTGCA 1-10-1 MOE 832

147073

70999 71010 CACTGATCCTGC 1-10-1 MOE 842

147072

71144 71155 ACTGATCCTGCA 1-10-1 MOE 832

147073

71145 71156 CACTGATCCTGC 1-10-1 MOE 842

147074

71146 71157 CCACTGATCCTG 1-10-1 MOE 845

147037

71351 71362 GCCCAGTTCCCA 1-10-1 MOE 863

147038

71352 71363 CGCCCAGTTCCC 1-10-1 MOE 855

147039

71353 71364 CCGCCCAGTTCC 1-10-1 MOE 850

147037

71497 71508 GCCCAGTTCCCA 1-10-1 MOE 863

147038

71498 71509 CGCCCAGTTCCC 1-10-1 MOE. 855

147039

71499 71510 CCGCCCAGTTCC 1-10-1 MOE 850

147061

71641 71652 TGCAATTTAATC 1-10-1 MOE 879

147061

71787 71798 TGCAATTTAATC 1-10-1 MOE 879

Table 17: Short antisense compounds directed to SEQ ID No. 11 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147022

177 188 TTGTCGATCTCC 1-10-1 MOE 886

147023

178 189 CTTGTCGATCTC 1-10-1 MOE 859

147020

196 207 GTCGATCTCCTC 1-10-1 MOE 868

147022

198 209 TTGTCGATCTCC 1-10-1 MOE 886

147024

200 211 CCTTGTCGATCT 1-10-1 MOE 853

147026

202 213 AGCCTTGTCGAT 1-10-1 MOE 835

147028

204 215 CCAGCCTTGTCG 1-10-1 MOE 846

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147029

205 216 CCCAGCCTTGTC 1-10-1 MOE 848

147030

206 217 TCCCAGCCTTGT 1-10-1 MOE 874

147036

212 223 CCCAGTTCCCAG 1-10-1 MOE 849

147073

311 322 CACTGATCCTGC 1-10-1 MOE 842

147046

327 338 CTGTGGTCAAAA 1-10-1 MOE 858

147047

328 339 ACTGTGGTCAAA 1-10-1 MOE 833

147048

329 340 GACTGTGGTCAA 1-10-1 MOE 888

147049

330 341 CGACTGTGGTCA 1-10-1 MOE 854

147050

331 342 CCGACTGTGGTC 1-10-1 MOE 889

147051

332 343 TCCGACTGTGGT 1-10-1 MOE 875

147052

333 344 ATCCGACTGTGG 1-10-1 MOE 837

147053

334 3. 4. 5 AATCCGACTGTG 1-10-1 MOE 829

147054

335 346 TAATCCGACTGT 1-10-1 MOE 871

147055

336 347 TTAATCCGACTG 1-10-1 MOE 884

147056

337 348 TTTAATCCGACT  1-10-1 MOE 887

147057

338 349 ATTTAATCCGAC 1-10-1 MOE 839

147058

339 350 AATTTAATCCGA 1-10-1 MOE 830

147060

341 352 GCAATTTAATCC 1-10-1 MOE 861

147061

342 353 TGCAATTTAATC 1-10-1 MOE 879

147062

1024 1035 CACTGACGAGTC 1-10-1 MOE 841

147063

1025 1036 GCACTGACGAGT 1-10-1 MOE 862

147068

1030 1041 ATCCTGCACTGA 1-10-1 MOE 838

147071

1033 1044 CTGATCCTGCAC 1-10-1 MOE 856

147073

1035 1046 CACTGATCCTGC 1-10-1 MOE 842

147074

1036 1047 CCACTGATCCTG 1-10-1 MOE 845

147067

1091 1102 TCCTGCACTGAC 1-10-1 MOE 876

147024

1891 1902 CCTTGTCGATCT 1-10-1 MOE 853

147026

1893 1904 AGCCTTGTCGAT 1-10-1 MOE 835

147029

1896 1907 CCCAGCCTTGTC 1-10-1 MOE 848

147036

1903 1914 CCCAGTTCCCAG 1-10-1 MOE 849

147039

1906 1917 CCGCCCAGTTCC 1-10-1 MOE 850

147019

1994 2005 TCGATCTCCTCG 1-10-1 MOE 877

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

401385

2815 2828 CCCAGTGGGTTTGA  2-10-2 MOE 890

147033

5265 5276 AGTTCCCAGCCT 1-10-1 MOE 836

147033

5373 5384 AGTTCCCAGCCT 1-10-1 MOE 836

147060

7168 7179 GCAATTTAATCC 1-10-1 MOE 861

147053

10527 10538 AATCCGACTGTG 1-10-1 MOE 829

147053

10635 10646 AATCCGACTGTG 1-10-1 MOE 829

147070

11604 11615 TGATCCTGCACT 1-10-1 MOE 878

147071

11612 11623 CTGATCCTGCAC 1-10-1 MOE 856

147072

12294 12305 ACTGATCCTGCA 1-10-1 MOE 832

147072

12299 12310 ACTGATCCTGCA 1-10-1 MOE 832

147052

12938 12949 ATCCGACTGTGG 1-10-1 MOE 837

147052

13119 13130 ATCCGACTGTGG 1-10-1 MOE 837

147047

13158 13169 ACTGTGGTCAAA 1-10-1 MOE 833

147048

13159 13170 GACTGTGGTCAA 1-10-1 MOE 888

147049

13160 13171 CGACTGTGGTCA 1-10-1 MOE 854

147048

13340 13351 GACTGTGGTCAA 1-10-1 MOE 888

147049

13341 13352 CGACTGTGGTCA 1-10-1 MOE 854

147051

13343 13354 TCCGACTGTGGT 1-10-1 MOE 875

147061

13497 13508 TGCAATTTAATC 1-10-1 MOE 879

147069

15562 15573 GATCCTGCACTG 1-10-1 MOE 860

147068

15743 15754 ATCCTGCACTGA 1-10-1 MOE 838

147049

17181 17192 CGACTGTGGTCA 1-10-1 MOE 854

147049

17349 17360 CGACTGTGGTCA 1-10-1 MOE 854

147047

22438 22449 ACTGTGGTCAAA 1-10-1 MOE 833

147047

24322 24333 ACTGTGGTCAAA 1-10-1 MOE 833

147045

24488 24499 TGTGGTCAAAAG 1-10-1 MOE 883

147039

25064 25075 CCGCCCAGTTCC 1-10-1 MOE 850

147057

25508 25519 ATTTAATCCGAC 1-10-1 MOE 839

147057

25676 25687 ATTTAATCCGAC 1-10-1 MOE 839

147061

25680 25691 TGCAATTTAATC 1-10-1 MOE 879

147069

28731 28742 GATCCTGCACTG 1-10-1 MOE 860

147052

30132 30143 ATCCGACTGTGG 1-10-1 MOE 837

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147052

30277 30288 ATCCGACTGTGG 1-10-1 MOE 837

147036

32085 32096 CCCAGTTCCCAG 1-10-1 MOE 849

147072

32520 32531 ACTGATCCTGCA 1-10-1 MOE 832

147071

33058 33069 CTGATCCTGCAC 1-10-1 MOE 856

147050

33125 33136 CCGACTGTGGTC 1-10-1 MOE 889

147069

33204 33215 GATCCTGCACTG 1-10-1 MOE 860

147050

33273 33284 CCGACTGTGGTC 1-10-1 MOE 889

147047

33319 33330 ACTGTGGTCAAA 1-10-1 MOE 833

147050

33322 33333 CCGACTGTGGTC 1-10-1 MOE 889

147052

33324 33335 ATCCGACTGTGG 1-10-1 MOE 837

147049

33469 33480 CGACTGTGGTCA 1-10-1 MOE 854

147050

33470 33481 CCGACTGTGGTC 1-10-1 MOE 889

147052

33472 33483 ATCCGACTGTGG 1-10-1 MOE 837

147047

33641 33652 ACTGTGGTCAAA 1-10-1 MOE 833

147047

33789 33800 ACTGTGGTCAAA 1-10-1 MOE 833

147059

35585 35596 CAATTTAATCCG 1-10-1 MOE 840

147021

36241 36252 TGTCGATCTCCT 1-10-1 MOE 882

147073

37633 37644 CACTGATCCTGC 1-10-1 MOE 842

147033

42529 42540 AGTTCCCAGCCT 1-10-1 MOE 836

147050

45401 45412 CCGACTGTGGTC 1-10-1 MOE 889

147050

45549 45560 CCGACTGTGGTC 1-10-1 MOE 889

147074

46125 46136 CCACTGATCCTG 1-10-1 MOE 845

147057

46313 46324 ATTTAATCCGAC 1-10-1 MOE 839

147058

46462 46473 AATTTAATCCGA 1-10-1 MOE 830

147058

47413 47424 AATTTAATCCGA 1-10-1 MOE 830

147058

47561 47572 AATTTAATCCGA 1-10-1 MOE 830

147073

48221 48232 CACTGATCCTGC 1-10-1 MOE 842

147073

48369 48380 CACTGATCCTGC 1-10-1 MOE 842

147028

48567 48578 CCAGCCTTGTCG 1-10-1 MOE 846

147068

49199 49210 ATCCTGCACTGA 1-10-1 MOE 838

147036

50273 50284 CCCAGTTCCCAG 1-10-1 MOE 849

147040

53929 53940 GCCGCCCAGTTC  1-10-1 MOE 864

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147047

54769 54780 ACTGTGGTCAAA 1-10-1 MOE 833

147048

54770 54781 GACTGTGGTCAA 1-10-1 MOE 888

147047

54915 54926 ACTGTGGTCAAA 1-10-1 MOE 833

147048

54916 54927 GACTGTGGTCAA 1-10-1 MOE 888

147019

55828 55839 TCGATCTCCTCG 1-10-1 MOE 877

147047

56268 56279 ACTGTGGTCAAA 1-10-1 MOE 833

147048

56269 56280 GACTGTGGTCAA 1-10-1 MOE 888

147049

56270 56281 CGACTGTGGTCA 1-10-1 MOE 854

147050

56271 56282 CCGACTGTGGTC 1-10-1 MOE 889

147051

56272 56283 TCCGACTGTGGT 1-10-1 MOE 875

147052

56273 56284 ATCCGACTGTGG 1-10-1 MOE 837

147053

56274 56285 AATCCGACTGTG 1-10-1 MOE 829

147056

56277 56288 TTTAATCCGACT  1-10-1 MOE 887

147057

56278 56289 ATTTAATCCGAC 1-10-1 MOE 839

147047

56414 56425 ACTGTGGTCAAA 1-10-1 MOE 833

147048

56415 56426 GACTGTGGTCAA 1-10-1 MOE 888

147049

56416 56427 CGACTGTGGTCA 1-10-1 MOE 854

147050

56417 56428 CCGACTGTGGTC 1-10-1 MOE 889

147052

56419 56430 ATCCGACTGTGG 1-10-1 MOE 837

147057

56424 56435 ATTTAATCCGAC 1-10-1 MOE 839

147058

56425 56436 AATTTAATCCGA 1-10-1 MOE 830

147059

56426 56437 CAATTTAATCCG 1-10-1 MOE 840

147060

56427 56438 GCAATTTAATCC 1-10-1 MOE 861

147046

57119 57130 CTGTGGTCAAAA 1-10-1 MOE 858

147071

58174 58185 CTGATCCTGCAC 1-10-1 MOE 856

147071

61130 61141 CTGATCCTGCAC 1-10-1 MOE 856

147034

61276 61287 CAGTTCCCAGCC 1-10-1 MOE 844

147071

61309 61320 CTGATCCTGCAC 1-10-1 MOE 856

147039

61427 61438 CCGCCCAGTTCC 1-10-1 MOE 850

147071

61455 61466 CTGATCCTGCAC 1-10-1 MOE 856

147073

62003 62014 CACTGATCCTGC 1-10-1 MOE 842

147062

63061 63072 CACTGACGAGTC 1-10-1 MOE 841

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147068

63213 63224 ATCCTGCACTGA 1-10-1 MOE 838

147069

63292 63303 GATCCTGCACTG 1-10-1 MOE 860

147057

64054 64065 ATTTAATCCGAC 1-10-1 MOE 839

147057

64200 64211 ATTTAATCCGAC 1-10-1 MOE 839

147070

64427 64438 TGATCCTGCACT 1-10-1 MOE 878

147070

64573 64584 TGATCCTGCACT 1-10-1 MOE 878

147036

64684 64695 CCCAGTTCCCAG 1-10-1 MOE 849

147046

65018 65029 CTGTGGTCAAAA 1-10-1 MOE 858

147071

65557 65568 CTGATCCTGCAC 1-10-1 MOE 856

147069

65695 65706 GATCCTGCACTG 1-10-1 MOE 860

147047

66163 66174 ACTGTGGTCAAA 1-10-1 MOE 833

147047

66309 66320 ACTGTGGTCAAA 1-10-1 MOE 833

147028

67740 67751 CCAGCCTTGTCG 1-10-1 MOE 846

147046

68870 68881 CTGTGGTCAAAA 1-10-1 MOE 858

147047

68871 68882 ACTGTGGTCAAA 1-10-1 MOE 833

147048

68872 68883 GACTGTGGTCAA 1-10-1 MOE 888

147049

68873 68884 CGACTGTGGTCA 1-10-1 MOE 854

147047

69017 69028 ACTGTGGTCAAA 1-10-1 MOE 833

147048

69018 69029 GACTGTGGTCAA 1-10-1 MOE 888

147049

69019 69030 CGACTGTGGTCA 1-10-1 MOE 854

147071

69519 69530 CTGATCCTGCAC 1-10-1 MOE 856

147073

69521 69532 CACTGATCCTGC 1-10-1 MOE 842

147071

69665 69676 CTGATCCTGCAC 1-10-1 MOE 856

147072

69666 69677 ACTGATCCTGCA 1-10-1 MOE 832

147024

70466 70477 CCTTGTCGATCT 1-10-1 MOE 853

147024

70612 70623 CCTTGTCGATCT 1-10-1 MOE 853

147062

70761 70772 CACTGACGAGTC 1-10-1 MOE 841

147072

70998 71009 ACTGATCCTGCA 1-10-1 MOE 832

147073

70999 71010 CACTGATCCTGC 1-10-1 MOE 842

147072

71144 71155 ACTGATCCTGCA 1-10-1 MOE 832

147073

71145 71156 CACTGATCCTGC 1-10-1 MOE 842

147048

71366 71377 GACTGTGGTCAA 1-10-1 MOE 888

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147048

71512 71523 GACTGTGGTCAA 1-10-1 MOE 888

Table 18: Short antisense compounds directed to SEQ ID No. 12

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398163

twenty 31 ATGTCAACCGGC 1-10-1 MOE 908

384545

2. 3 3. 4 CAAGTAGGATGT 1-10-1 MOE 951

147705

159 170 CGGTTTTTGTTC  1-10-1 MOE 1002

147703

245 256 TGGCTTCATGTC 1-10-1 MOE 971

398090

283 296 TTGTTCTTAGGAAG 2-10-2 MOE 972

147704

285 296 TTGTTCTTAGGA 1-10-1 MOE 1012

147705

291 302 CGGTTTTTGTTC  1-10-1 MOE 1002

147709

311 322 CCATTTTTATCA  1-10-1 MOE 978

147733

349 360 TTCTTGATGTCC 1-10-1 MOE 891

147707

360 371 TAGTCATTATCT 1-10-1 MOE 977

147708

366 377 TTGATATAGTCA 1-10-1 MOE 997

390030

381 392 TTTATAAAACTG 1-10-1 MOE 1074

147709

386 397 CCATTTTTATCA  1-10-1 MOE 978

147081

393 404 GCTCCTTCCACT 1-10-1 MOE 1006

398091

393 406 GGGCTTCTTCCATT 2-10-2 MOE 979

398166

395 406 GGGCTTCTTCCA 1-10-1 MOE 1070

147709

418 429 CCATTTTTATCA  1-10-1 MOE 978

147711

425 436 AAGGGCCCTGGG 1-10-1 MOE 1040

147712

461 472 ACACCATCTCCC 1-10-1 MOE 1005

147713

466 477 CTCCCACACCAT 1-10-1 MOE 985

147714

471 482 TTCTGCTCCCAC 1-10-1 MOE 986

147715

496 507 GTTGAGCATGAC 1-10-1 MOE 1077

147716

521 532 TTAACGAGCCTT 1-10-1 MOE 949

147717

574 585 ATCTTCAGAGAT 1-10-1 MOE 996

147717

607 618 ATCTTCAGAGAT 1-10-1 MOE 996

147708

612 623 TTGATATAGTCA 1-10-1 MOE 997

147718

621 632 TAATATGACTTG 1-10-1 MOE 998

147746

625 636 TAAAAACAACAA 1-10-1 MOE 1073

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398167

704 715 CAGGCCATGTGG 1-10-1 MOE 1059

398092

705 718 AGTCAGGCCATGTG 2-10-2 MOE 1060

147723

715 726 GACTCCAAAGTC 1-10-1 MOE 892

398093

758 771 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

760 771 TCGGACTTTGAA  1-10-1 MOE 1008

147738

780 791 TGGGTGGCCGGG 1-10-1 MOE 1069

398094

848 861 ATCAGCCAGACAGA 2-10-2 MOE 1010

398169

849 860 TCAGCCAGACAG 1-10-1 MOE 909

398164

873 884 TTGTCGATCTGC 1-10-1 MOE 1014

147735

973 984 GGAGAAGCGCAG 1-10-1 MOE 1016

147737

984 995 ACAGCCAGGTAG 1-10-1 MOE 1067

368369

1025 1040 TCCTGCACTGACGAGT 3-10-3 MOE 893

368372

1031 1046 CACTGATCCTGCACTG 3-10-3 MOE 894

368353

1033 1046 CACTGATCCTGCAC 2-10-2 MOE 1007

368354

1035 1048 TCCACTGATCCTGC 2-10-2 MOE 1024

368388

1035 1050 CTTCCACTGATCCTTA 3-10-3 MOE 895

368355

1036 1049 TTCCACTGATCCTG 2-10-2 MOE 1025

368356

1037 1050 CTTCCACTGATCCT 2-10-2 MOE 1027

368376

1037 1052 TCCTTCCACTGATCCT 3-10-3 MOE 1028

147076

1038 1049 TTCCACTGATCC 1-10-1 MOE 1029

368357

1038 1051 CCTTCCACTGATCC 2-10-2 MOE 1046

147077

1039 1050 CTTCCACTGATC 1-10-1 MOE 1047

368358

1039 1052 TCCTTCCACTGATC 2-10-2 MOE 1031

368378

1039 1054 GCTCCTTCCACTGATC 3-10-3 MOE 1032

368359

1041 1054 GCTCCTTCCACTGA 2-10-2 MOE 1033

147080

1042 1053 CTCCTTCCACTG 1-10-1 MOE 1021

147081

1043 1054 GCTCCTTCCACT 1-10-1 MOE 1006

368360

1043 1056 AAGCTCCTTCCACT 2-10-2 MOE 1035

368380

1043 1058 GAAAGCTCCTTCCACT 3-10-3 MOE 896

147082

1044 1055 AGCTCCTTCCAC 1-10-1 MOE 1036

368381

1045 1060 GGGAAAGCTCCTTCCA 3-10-3 MOE 1037

147739

1107 1118 CGTTTGGGTGGC 1-10-1 MOE 1023

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147741

1165 1176 CACCCACTGGTG 1-10-1 MOE 1055

398097

1194 1207 GGCAGTCTTTATCC  2-10-2 MOE 897

147742

1273 1284 AACTTCAGTGTC 1-10-1 MOE 1041

147743

1388 1399 AGGGCTTCCAGT 1-10-1 MOE 1042

147744

1392 1403 AGGAAGGGCTTC 1-10-1 MOE 1043

147745

1398 1409 TTGACCAGGAAG 1-10-1 MOE 1058

398157

1455 1468 GGAAACATACCCTG 2-10-2 MOE 1045

398167

1475 1486 CAGGCCATGTGG 1-10-1 MOE 1059

398092

1476 1489 AGTCAGGCCATGTG 2-10-2 MOE 1060

368357

1596 1609 CCTTCCACTGATCC 2-10-2 MOE 1046

398160

1691 1704 GAATAGGTTAAGGC 2-10-2 MOE 1048

398163

1711 1722 ATGTCAACCGGC 1-10-1 MOE 908

147746

1750 1761 TAAAAACAACAA 1-10-1 MOE 1073

389949

1777 1788 GCGCGAGCCCGA 1-10-1 MOE 1061

398161

1790 1803 AACAATGTGTTGTA 2-10-2 MOE 1049

147746

1799 1810 TAAAAACAACAA 1-10-1 MOE 1073

398163

1819 1830 ATGTCAACCGGC 1-10-1 MOE 908

389950

1848 1859 CCCTGAAGGTTC 1-10-1 MOE 1063

398164

1889 1900 TTGTCGATCTGC 1-10-1 MOE 1014

147702

1917 1928 CTGGTAAATAGC 1-10-1 MOE 898

147088

1971 1982 CCCTCTACACCA 1-10-1 MOE 1050

398102

2003 2016 CTACCTGAGGATTT 2-10-2 MOE 899

398103

2010 2023 CCCAGTACTACCTG 2-10-2 MOE 900

147737

2386 2397 ACAGCCAGGTAG 1-10-1 MOE 1067

398095

2407 2420 CATCAGCAAGAGGC 2-10-2 MOE 1011

398106

2441 2454 TGGAAAACTGCACC 2-10-2 MOE 1068

147745

2497 2508 TTGACCAGGAAG 1-10-1 MOE 1058

147712

2499 2510 ACACCATCTCCC 1-10-1 MOE 1005

147712

2607 2618 ACACCATCTCCC 1-10-1 MOE 1005

147745

2689 2700 TTGACCAGGAAG 1-10-1 MOE 1058

398167

2706 2717 CAGGCCATGTGG 1-10-1 MOE 1059

398092

2707 2720 AGTCAGGCCATGTG 2-10-2 MOE 1060

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398166

2966 2977 GGGCTTCTTCCA 1-10-1 MOE 1070

147091

2992 3003 GTTCCCTCTACA 1-10-1 MOE 1004

147092

2993 3004 TGTTCCCTCTAC 1-10-1 MOE 901

389949

3008 3019 GCGCGAGCCCGA 1-10-1 MOE 1061

147087

3149 3160 CCTCTACACCAG 1-10-1 MOE 982

147088

3150 3161 CCCTCTACACCA 1-10-1 MOE 1050

398113

3160 3173 AGGAGGTTAAACCA 2-10-2 MOE 905

147087

3257 3268 CCTCTACACCAG 1-10-1 MOE 982

147088

3258 3269 CCCTCTACACCA 1-10-1 MOE 1050

147737

3591 3602 ACAGCCAGGTAG 1-10-1 MOE 1067

147737

3617 3628 ACAGCCAGGTAG 1-10-1 MOE 1067

147079

3637 3648 TCCTTCCACTGA 1-10-1 MOE 1001

147080

3638 3649 CTCCTTCCACTG 1-10-1 MOE 1021

398095

3638 3651 CATCAGCAAGAGGC 2-10-2 MOE 1011

398106

3672 3685 TGGAAAACTGCACC 2-10-2 MOE 1068

398107

3678 3691 TATTCCTGGAAAAC 2-10-2 MOE 902

147691

3806 3817 GAGGTGGGAAAA 1-10-1 MOE 966

147683

3848 3859 GCTTACGATTGT 1-10-1 MOE 922

147738

3853 3864 TGGGTGGCCGGG 1-10-1 MOE 1069

398167

3926 3937 CAGGCCATGTGG 1-10-1 MOE 1059

398109

3945 3958 CAAGAAGTGTGGTT 2-10-2 MOE 903

398167

4034 4045 CAGGCCATGTGG 1-10-1 MOE 1059

398110

4083 4096 GTTCCCTTTGCAGG  2-10-2 MOE 952

398111

4168 4181 GTGAAAATGCTGGC 2-10-2 MOE 904

147706

4238 4249 GCTGACATCTCG 1-10-1 MOE 1071

398112

4282 4295 CAGCCTGGCACCTA 2-10-2 MOE 1072

147746

4315 4326 TAAAAACAACAA 1-10-1 MOE 1073

398113

4391 4404 AGGAGGTTAAACCA 2-10-2 MOE 905

398115

4484 4497 AGTAAATATTGGCT 2-10-2 MOE 1076

390030

4491 4502 TTTATAAAACTG 1-10-1 MOE 1074

390030

4537 4548 TTTATAAAACTG 1-10-1 MOE 1074

147703

5034 5045 TGGCTTCATGTC 1-10-1 MOE 971

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147684

5035 5046 ACCCAGTCAGGG 1-10-1 MOE 964

398125

5075 5088 CAGTAAGGAATTTT 2-10-2 MOE 913

147696

5083 5094 TGGATGATTGGC 1-10-1 MOE 906

147684

5143 5154 ACCCAGTCAGGG 1-10-1 MOE 964

147712

5366 5377 ACACCATCTCCC 1-10-1 MOE 1005

147714

5416 5427 TTCTGCTCCCAC 1-10-1 MOE 986

398128

5443 5456 CTAAATTTAGTTCA  2-10-2 MOE 911

147712

5474 5485 ACACCATCTCCC 1-10-1 MOE 1005

147746

5498 5509 TAAAAACAACAA 1-10-1 MOE 1073

147714

5524 5535 TTCTGCTCCCAC 1-10-1 MOE 986

147736

5600 5611 AGGTAGGAGAAG 1-10-1 MOE 963

147085

5762 5773 TCTACACCAGGT 1-10-1 MOE 961

147679

5825 5836 CAAAAGGATCCC 1-10-1 MOE 907

390030

6803 6814 TTTATAAAACTG 1-10-1 MOE 1074

398142

6885 6898 CCAGCACACTGGAA 2-10-2 MOE 923

398142

6994 7007 CCAGCACACTGGAA 2-10-2 MOE 923

398166

7306 7317 GGGCTTCTTCCA 1-10-1 MOE 1070

147684

7551 7562 ACCCAGTCAGGG 1-10-1 MOE 964

147085

8308 8319 TCTACACCAGGT 1-10-1 MOE 961

147085

8416 8427 TCTACACCAGGT 1-10-1 MOE 961

398163

8473 8484 ATGTCAACCGGC 1-10-1 MOE 908

147718

8523 8534 TAATATGACTTG 1-10-1 MOE 998

147718

8631 8642 TAATATGACTTG 1-10-1 MOE 998

147691

8806 8817 GAGGTGGGAAAA 1-10-1 MOE 966

147728

8835 8846 GCCAGACAGAAG 1-10-1 MOE 1013

147728

8943 8954 GCCAGACAGAAG 1-10-1 MOE 1013

398169

8946 8957 TCAGCCAGACAG 1-10-1 MOE 909

147742

9060 9071 AACTTCAGTGTC 1-10-1 MOE 1041

404136

9162 9175 TAAGTGTCCCTTTG  2-10-2 MOE 910

147746

9963 9974 TAAAAACAACAA 1-10-1 MOE 1073

147746

9966 9977 TAAAAACAACAA 1-10-1 MOE 1073

147746

9969 9980 TAAAAACAACAA 1-10-1 MOE 1073

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147746

9991 10002 TAAAAACAACAA 1-10-1 MOE 1073

147746

10071 10082 TAAAAACAACAA 1-10-1 MOE 1073

147746

10074 10085 TAAAAACAACAA 1-10-1 MOE 1073

147746

10077 10088 TAAAAACAACAA 1-10-1 MOE 1073

390030

10170 10181 TTTATAAAACTG 1-10-1 MOE 1074

147084

10220 10231 CTACACCAGGTC 1-10-1 MOE 993

390030

10278 10289 TTTATAAAACTG 1-10-1 MOE 1074

147085

10329 10340 TCTACACCAGGT 1-10-1 MOE 961

147711

10684 10695 AAGGGCCCTGGG 1-10-1 MOE 1040

147711

10792 10803 AAGGGCCCTGGG 1-10-1 MOE 1040

398128

11333 11346 CTAAATTTAGTTCA  2-10-2 MOE 911

147707

11960 11971 TAGTCATTATCT 1-10-1 MOE 977

147707

11965 11976 TAGTCATTATCT 1-10-1 MOE 977

147090

12013 12024 TTCCCTCTACAC 1-10-1 MOE 955

398096

12146 12159 GGAGAAGCGCAGCT  2-10-2 MOE 1015

398166

12214 12225 GGGCTTCTTCCA 1-10-1 MOE 1070

398135

12308 12321 GACTACATTTTACA  2-10-2 MOE 912

147741

12389 12400 CACCCACTGGTG 1-10-1 MOE 1055

398125

12431 12444 CAGTAAGGAATTTT 2-10-2 MOE 913

147714

12585 12596 TTGTGCTCCCAC 1-10-1 MOE 986

147718

12594 12605 TAATATGACTTG 1-10-1 MOE 998

398125

12612 12625 CAGTAAGGAATTTT 2-10-2 MOE 913

147737

12803 12814 ACAGCCAGGTAG 1-10-1 MOE 1067

147746

12876 12887 TAAAAACAACAA 1-10-1 MOE 1073

147691

12900 12911 GAGGTGGGAAAA 1-10-1 MOE 966

398137

13111 13124 TGTGTCCCTCAGTC 2-10-2 MOE 914

398138

13254 13267 AACATCAAGCTTGA 2-10-2 MOE 931

398137

13292 13305 TGTGTCCCTCAGTC 2-10-2 MOE 914

398138

13435 13448 AACATCAAGCTTGA 2-10-2 MOE 931

389764

14020 14031 CTGCAACATGAT 1-9-2 MOE 1018

389948

14067 14078 CCGTTGGACCCC 1-10-1 MOE 915

389948

14248 14259 CCGTTGGACCCC 1-10-1 MOE 915

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147738

14279 14290 TGGGTGGCCGGG 1-10-1 MOE 1069

147698

14572 14583 CCCGCCACCACC 1-10-1 MOE 928

147717

14750 14761 ATCTTCAGAGAT 1-10-1 MOE 996

147717

14932 14943 ATCTTCAGAGAT 1-10-1 MOE 996

398167

15374 15385 CAGGCCATGTGG 1-10-1 MOE 1059

147736

16444 16455 AGGTAGGAGAAG 1-10-1 MOE 963

147746

16510 16521 TAAAAACAACAA 1-10-1 MOE 1073

147738

16590 16601 TGGGTGGCCGGG 1-10-1 MOE 1069

147746

16676 16687 TAAAAACAACAA 1-10-1 MOE 1073

398167

16797 16808 CAGGCCATGTGG 1-10-1 MOE 1059

398144

16911 16924 GACAGCTTCTATAA 2-10-2 MOE 916

389764

17096 17107 CTGCAACATGAT 1-9-2 MOE 1018

147709

17238 17249 CCATTTTTATCA  1-10-1 MOE 978

147709

17406 17417 CCATTTTTATCA  1-10-1 MOE 978

147695

17466 17477 TCATTCCCCACT 1-10-1 MOE 984

147746

17497 17508 TAAAAACAACAA 1-10-1 MOE 1073

147088

17539 17550 CCCTCTACACCA 1-10-1 MOE 1050

147711

17808 17819 AAGGGCCCTGGG 1-10-1 MOE 1040

147711

17976 17987 AAGGGCCCTGGG 1-10-1 MOE 1040

398139

18049 18062 AGTGACTGACCACA 2-10-2 MOE 917

398139

18217 18230 AGTGACTGACCACA 2-10-2 MOE 917

398140

18596 18609 GTAGCATAGAGCCT 2-10-2 MOE 918

398140

18764 18777 GTAGCATAGAGCCT 2-10-2 MOE 918

398167

18927 18938 CAGGCCATGTGG 1-14-1 MOE 1059

398141

18947 18960 CAGATCTTGTCAAG 2-10-2 MOE 919

398167

19095 19106 CAGGCCATGTGG 1-10-1 MOE 1059

398141

19115 19128 CAGATCTTGTCAAG 2-10-2 MOE 919

147746

19207 19218 TAAAAACAACAA 1-10-1 MOE 1073

147711

19508 19519 AAGGGCCCTGGG 1-10-1 MOE 1040

147729

19554 19565 GTAAGAGGCAGG 1-10-1 MOE 920

147718

19617 19628 TAATATGACTTG 1-10-1 MOE 998

390030

19618 19629 TTTATAAAACTG 1-10-1 MOE 1074

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147701

19671 19682 CCATGGCGGGAC 1-10-1 MOE 921

147711

19676 19687 AAGGGCCCTGGG 1-10-1 MOE 1040

147718

19785 19796 TAATATGACTTG 1-10-1 MOE 998

147079

20515 20526 TCCTTCCACTGA 1-10-1 MOE 1001

389764

20620 20631 CTGCAACATGAT 1-9-2 MOE 1018

398142

20653 20666 CCAGCACACTGGAA 2-10-2 MOE 923

147078

20682 20693 CCTTCCACTGAT 1-10-1 MOE 1044

147079

20683 20694 TCCTTCCACTGA 1-10-1 MOE 1001

147080

20704 20715 CTCCTTCCACTG 1-10-1 MOE 1021

147081

20705 20716 GCTCCTTCCACT 1-10-1 MOE 1006

389965

20788 20799 CTGCAACATGAT 1-10-1 MOE 1018

147746

20870 20881 TAAAAACAACAA 1-10-1 MOE 1073

147746

21038 21049 TAAAAACAACAA 1-10-1 MOE 1073

147717

21080 21091 ATCTTCAGAGAT 1-10-1 MOE 996

147076

21222 21233 TTCCACTGATCC 1-10-1 MOE 1029

398094

21441 21454 ATCAGCCAGACAGA 2-10-2 MOE 1010

147746

21633 21644 TAAAAACAACAA 1-10-1 MOE 1073

147738

21884 21895 TGGGTGGCCGGG 1-10-1 MOE 1069

147683

21939 21950 GCTTACGATTGT 1-10-1 MOE 922

147743

22213 22224 AGGGCTTCCAGT 1-10-1 MOE 1042

147736

22759 22770 AGGTAGGAGAAG 1-10-1 MOE 963

147736

22927 22938 AGGTAGGAGAAG 1-10-1 MOE 963

398142

23008 23021 CCAGCACACTGGAA 2-10-2 MOE 923

398147

23784 23797 CTACAGGACAATAC 2-10-2 MOE 957

398147

23952 23965 CTACAGGACAATAC 2-10-2 MOE 957

147713

24434 24445 CTCCCACACCAT 1-10-1 MOE 985

389965

24543 24554 CTGCAACATGAT 1-10-1 MOE 1018

147713

24602 24613 CTCCCACACCAT 1-10-1 MOE 985

389965

24711 24722 CTGCAACATGAT 1-10-1 MOE 1018

147746

25384 25395 TAAAAACAACAA 1-10-1 MOE 1073

398143

25505 25518 GTCAGTCCCAGCTA 2-10-2 MOE 924

147691

25610 25621 GAGGTGGGAAAA 1-10-1 MOE 966

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398130

25672 25685 TTAGTATGACAGCT 2-10-2 MOE 925

147746

25810 25821 TAAAAACAACAA 1-10-1 MOE 1073

147746

25978 25989 TAAAAACAACAA 1-10-1 MOE 1073

147746

26172 26183 TAAAAACAACAA 1-10-1 MOE 1073

398151

26718 26731 TCAGTGTAGGAAGA 2-10-2 MOE 926

147728

26917 26928 GCCAGACAGAAG 1-10-1 MOE 1013

398152

27708 27721 TGAATATACAGATG 2-10-2 MOE 927

147698

28629 28640 CCCGCCACCACC 1-10-1 MOE 928

389965

28714 28725 CTGCAACATGAT 1-10-1 MOE 1018

389764

28714 28725 CTGCAACATGAT 1-9-2 MOE 1018

389764

28861 28872 CTGCAACATGAT 1-9-2 MOE 1018

390030

29945 29956 TTTATAAAACTG 1-10-1 MOE 1074

147744

30654 30665 AGGAAGGGCTTC 1-10-1 MOE 1043

147093

30836 30847 TTGTTCCCTCTA 1-10-1 MOE 929

147746

30957 30968 TAAAAACAACAA 1-10-1 MOE 1073

147746

31105 31116 TAAAAACAACAA 1-10-1 MOE 1073

390030

31477 31488 TTTATAAAACTG 1-10-1 MOE 1074

384545

31829 31840 CAAGTAGGATGT 1-10-1 MOE 951

384545

31977 31988 CAAGTAGGATGT 1-10-1 MOE 951

401382

32094 32107 TCTACCTGAGTCCA 2-10-2 MOE 930

147089

32387 32398 TCCCTCTACACC 1-10-1 MOE 956

389950

32949 32960 CCCTGAAGGTTC 1-10-1 MOE 1063

398165

33002 33013 GTTCTTAGGAAG 1-10-1 MOE 968

147081

33073 33084 GCTCCTTCCACT 1-10-1 MOE 1006

147082

33074 33085 AGCTCCTTCCAC 1-10-1 MOE 1036

389950

33097 33108 CCCTGAAGGTTC 1-10-1 MOE 1063

147736

33160 33171 AGGTAGGAGAAG 1-10-1 MOE 963

147081

33221 33232 GCTCCTTCCACT 1-10-1 MOE 1006

368360

33221 33234 AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

33222 33233 AGCTCCTTCCAC 1-10-1 MOE 1036

398138

33244 33257 AACATCAAGCTTGA 2-10-2 MOE 931

147746

33250 33261 TAAAAACAACAA 1-10-1 MOE 1073

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398138

33392 33405 AACATCAAGCTTGA 2-10-2 MOE 931

401383

33588 33601 GATCACCTTCAGAG 2-10-2 MOE 932

147746

33886 33897 TAAAAACAACAA 1-10-1 MOE 1073

147746

34606 34617 TAAAAACAACAA 1-10-1 MOE 1073

398165

34704 34715 GTTCTTAGGAAG 1-10-1 MOE 968

147717

34745 34756 ATCTTCAGAGAT 1-10-1 MOE 996

147746

34754 34765 TAAAAACAACAA 1-10-1 MOE 1073

398165

34852 34863 GTTCTTAGGAAG 1-10-1 MOE 968

147717

34893 34904 ATCTTCAGAGAT 1-10-1 MOE 996

401384

34905 34918 TGAACACATCACTA 2-10-2 MOE 933

147738

35391 35402 TGGGTGGCCGGG 1-10-1 MOE 1069

147736

35396 35407 AGGTAGGAGAAG 1-10-1 MOE 963

147738

35539 35550 TGGGTGGCCGGG 1-10-1 MOE 1069

147691

35554 35565 GAGGTGGGAAAA 1-10-1 MOE 966

147691

35702 35713 GAGGTGGGAAAA 1-10-1 MOE 966

147746

35814 35825 TAAAAACAACAA 1-10-1 MOE 1073

401385

36109 36122 CCCAGTGGGTTTGA  2-10-2 MOE 890

147691

36360 36371 GAGGTGGGAAAA 1-10-1 MOE 966

147746

36416 36427 TAAAAACAACAA 1-10-1 MOE 1073

147731

36620 36631 TTTCCTCTTGTC  1-10-1 MOE 934

147714

37881 37892 TTCTGCTCCCAC 1-10-1 MOE 986

147714

38029 38040 TTCTGCTCCCAC 1-10-1 MOE 986

147681

38512 38523 ATGTCATTAAAC 1-10-1 MOE 965

401386

38516 38529 TAATTGATGTCAAT 2-10-2 MOE 935

401387

38518 38531 AGTAATTGATGTCA 2-10-2 MOE 936

401388

38520 38533 ACAGTAATTGATGT 2-10-2 MOE 937

401389

38522 38535 TTACAGTAATTGAT 2-10-2 MOE 938

401390

38524 38537 ACTTACAGTAATTG 2-10-2 MOE 939

401391

38526 38539 AGACTTACAGTAAT 2-10-2 MOE 940

401392

38528 38541 TCAGACTTACAGTA 2-10-2 MOE 941

401393

38530 38543 AATCAGACTTACAG 2-10-2 MOE 942

401394

38532 38545 TGAATCAGACTTAC 2-10-2 MOE 943

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

401395

38534 38547 AATGAATCAGACTT 2-10-2 MOE 944

147738

38909 38920 TGGGTGGCCGGG 1-10-1 MOE 1069

147738

39057 39068 TGGGTGGCCGGG 1-10-1 MOE 1069

390030

39249 39260 TTTATAAAACTG 1-10-1 MOE 1074

390030

39397 39408 TTTATAAAACTG 1-10-1 MOE 1074

401396

39488 39501 TGCAGGATGTTGAG 2-10-2 MOE 945

147717

39545 39556 ATCTTCAGAGAT 1-10-1 MOE 996

147746

39641 39652 TAAAAACAACAA 1-10-1 MOE 1073

147717

39693 39704 ATCTTCAGAGAT 1-10-1 MOE 996

147746

39729 39740 TAAAAACAACAA 1-10-1 MOE 1073

147746

39877 39888 TAAAAACAACAA 1-10-1 MOE 1073

147746

40185 40196 TAAAAACAACAA 1-10-1 MOE 1073

147746

40478 40489 TAAAAACAACAA 1-10-1 MOE 1073

398166

40589 40600 GGGCTTCTTCCA 1-10-1 MOE 1070

147735

40662 40673 GGAGAAGCGCAG 1-10-1 MOE 1016

147746

40706 40717 TAAAAACAACAA 1-10-1 MOE 1073

398166

40737 40748 GGGCTTCTTCCA 1-10-1 MOE 1070

147746

40854 40865 TAAAAACAACAA 1-10-1 MOE 1073

401397

41012 41025 CTGGTCAGCATTGA 2-10-2 MOE 946

147718

41070 41081 TAATATGACTTG 1-10-1 MOE 998

147718

41218 41229 TAATATGACTTG 1-10-1 MOE 998

147717

41221 41232 ATCTTCAGAGAT 1-10-1 MOE 996

147717

41369 41380 ATCTTCAGAGAT 1-10-1 MOE 996

147717

41599 41610 ATCTTCAGAGAT 1-10-1 MOE 996

147717

41747 41758 ATCTTCAGAGAT 1-10-1 MOE 996

401398

41768 41781 CAAAGTCCCTTAGC 2-10-2 MOE 947

390030

42056 42067 TTTATAAAACTG 1-10-1 MOE 1074

398153

42157 42170 ATTTCTCTTACAGG  2-10-2 MOE 948

398153

42305 42318 ATTTCTCTTACAGG  2-10-2 MOE 948

147710

42691 42702 TATAGCTCCTCT 1-10-1 MOE 994

147079

43322 43333 TCCTTCCACTGA 1-10-1 MOE 1001

147080

43323 43334 CTCCTTCCACTG 1-10-1 MOE 1021

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147716

43477 43488 TTAACGAGCCTT 1-10-1 MOE 949

147746

43992 44003 TAAAAACAACAA 1-10-1 MOE 1073

147736

44137 44148 AGGTAGGAGAAG 1-10-1 MOE 963

384545

44242 44253 CAAGTAGGATGT 1-10-1 MOE 951

147687

44354 44365 CGACACGGGAAC 1-10-1 MOE 950

384545

44390 44401 CAAGTAGGATGT 1-10-1 MOE 951

398110

44713 44726 GTTCCCTTTGCAGG  2-10-2 MOE 952

147705

45092 45103 CGGTTTTTGTTC  1-10-1 MOE 1002

147705

45240 45251 CGGTTTTTGTTC  1-10-1 MOE 1002

147074

45977 45988 CCACTGATCCTG 1-10-1 MOE 845

147075

45978 45989 TCCACTGATCCT 1-10-1 MOE 1026

147076

45979 45990 TTCCACTGATCC 1-10-1 MOE 1029

147076

46127 46138 TTCCACTGATCC 1-10-1 MOE 1029

401399

46247 46260 ATTAGCCATATCTC 2-10-2 MOE 953

147705

46555 46566 CGGTTTTTGTTC  1-10-1 MOE 1002

147714

46685 46696 TTCTGCTCCCAC 1-10-1 MOE 986

147705

46703 46714 CGGTTTTTGTTC  1-10-1 MOE 1002

390030

46859 46870 TTTATAAAACTG 1-10-1 MOE 1074

390030

46933 46944 TTTATAAAACTG 1-10-1 MOE 1074

147681

46984 46995 ATGTCATTAAAC 1-10-1 MOE 965

390030

47007 47018 TTTATAAAACTG 1-10-1 MOE 1074

147746

47023 47034 TAAAAACAACAA 1-10-1 MOE 1073

390030

47081 47092 TTTATAAAACTG 1-10-1 MOE 1074

147681

47132 47143 ATGTCATTAAAC 1-10-1 MOE 965

147746

47171 47182 TAAAAACAACAA 1-10-1 MOE 1073

401400

47411 47424 AGCATTCAGCAGTG 2-10-2 MOE 954

147746

47461 47472 TAAAAACAACAA 1-10-1 MOE 1073

147086

47608 47619 CTCTACACCAGG 1-10-1 MOE 969

147087

47609 47620 CCTCTACACCAG 1-10-1 MOE 982

147088

47610 47621 CCCTCTACACCA 1-10-1 MOE 1050

147090

47612 47623 TTCCCTCTACAC 1-10-1 MOE 955

147691

47729 47740 GAGGTGGGAAAA 1-10-1 MOE 966

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147086

47756 47767 CTCTACACCAGG 1-10-1 MOE 969

147088

47758 47769 CCCTCTACACCA 1-10-1 MOE 1050

147089

47759 47770 TCCCTCTACACC 1-10-1 MOE 956

390030

47847 47858 TTTATAAAACTG 1-10-1 MOE 1074

390030

47995 48006 TTTATAAAACTG 1-10-1 MOE 1074

147691

48393 48404 GAGGTGGGAAAA 1-10-1 MOE 966

398147

48887 48900 CTACAGGACAATAC 2-10-2 MOE 957

147706

49133 49144 GCTGACATCTCG 1-10-1 MOE 1071

147706

49281 49292 GCTGACATCTCG 1-10-1 MOE 1071

398168

49742 49753 TCGGACTTTGAA  1-10-1 MOE 1008

401401

49791 49804 AACTGGGTTAAGTA 2-10-2 MOE 958

147689

49936 49947 CAGAGAAGGTCT 1-10-1 MOE 987

401402

50192 50205 TGAACACGCTATCC 2-10-2 MOE 959

398117

50241 50254 TTTCCACTTGGGTG 2-10-2 MOE 960

147736

50582 50593 AGGTAGGAGAAG 1-10-1 MOE 963

398168

50703 50714 TCGGACTTTGAA  1-10-1 MOE 1008

398168

50849 50860 TCGGACTTTGAA  1-10-1 MOE 1008

147746

51019 51030 TAAAAACAACAA 1-10-1 MOE 1073

147708

51101 51112 TTGATATAGTCA 1-10-1 MOE 997

147746

51178 51189 TAAAAACAACAA 1-10-1 MOE 1073

147708

51247 51258 TTGATATAGTCA 1-10-1 MOE 997

147083

51281 51292 TACACCAGGTCA 1-10-1 MOE 973

147081

51287 51298 GCTCCTTCCACT 1-10-1 MOE 1006

147082

51288 51299 AGCTCCTTCCAC 1-10-1 MOE 1036

147746

51331 51342 TAAAAACAACAA 1-10-1 MOE 1073

147085

51416 51427 TCTACACCAGGT 1-10-1 MOE 961

147083

51427 51438 TACACCAGGTCA 1-10-1 MOE 973

147081

51433 51444 GCTCCTTCCACT 1-10-1 MOE 1006

147082

51434 51445 AGCTCCTTCCAC 1-10-1 MOE 1036

147728

51522 51533 GCCAGACAGAAG 1-10-1 MOE 1013

147085

51562 51573 TCTACACCAGGT 1-10-1 MOE 961

147081

51633 51644 GCTCCTTCCACT 1-10-1 MOE 1006

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

368360

51633 51646 AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

51634 51645 AGCTCCTTCCAC 1-10-1 MOE 1036

368361

51635 51648 GAAAGCTCCTTCCA 2-10-2 MOE 962

368360

51779 51792 AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

51780 51791 AGCTCCTTCCAC 1-10-1 MOE 1036

147736

51859 51870 AGGTAGGAGAAG 1-10-1 MOE 963

147684

51867 51878 ACCCAGTCAGGG 1-10-1 MOE 964

147746

51918 51929 TAAAAACAACAA 1-10-1 MOE 1073

147077

51988 51999 CTTCCACTGATC 1-10-1 MOE 1047

147746

52064 52075 TAAAAACAACAA 1-10-1 MOE 1073

147084

52125 52136 CTACACCAGGTC 1-10-1 MOE 993

147079

52136 52147 TCCTTCCACTGA 1-10-1 MOE 1001

147681

52231 52242 ATGTCATTAAAC 1-10-1 MOE 965

147084

52271 52282 CTACACCAGGTC 1-10-1 MOE 993

147691

52312 52323 GAGGTGGGAAAA 1-10-1 MOE 966

401403

52318 52331 TTTCCTAGGAGGTG 2-10-2 MOE 967

398167

52527 52538 CAGGCCATGTGG 1-10-1 MOE 1059

147703

52670 52681 TGGCTTCATGTC 1-10-1 MOE 971

398167

52673 52684 CAGGCCATGTGG 1-10-1 MOE 1059

398165

52708 52719 GTTCTTAGGAAG 1-10-1 MOE 968

398090

52708 52721 TTGTTCTTAGGAAG 2-10-2 MOE 972

147705

52716 52727 CGGTTTTTGTTC  1-10-1 MOE 1002

147682

52717 52728 CGGGTACTATGG 1-10-1 MOE 992

398167

52762 52773 CAGGCCATGTGG 1-10-1 MOE 1059

147703

52816 52827 TGGCTTCATGTC 1-10-1 MOE 971

398090

52854 52867 TTGTTCTTAGGAAG 2-10-2 MOE 972

147704

52856 52867 TTGTTCTTAGGA 1-10-1 MOE 1012

147705

52862 52873 CGGTTTTTGTTC  1-10-1 MOE 1002

398167

52908 52919 CAGGCCATGTGG 1-10-1 MOE 1059

147084

53704 53715 CTACACCAGGTC 1-10-1 MOE 993

147088

53708 53719 CCCTCTACACCA 1-10-1 MOE 1050

147083

53849 53860 TACACCAGGTCA 1-10-1 MOE 973

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147084

53850 53861 CTACACCAGGTC 1-10-1 MOE 993

147086

53852 53863 CTCTACACCAGG 1-10-1 MOE 969

147088

53854 53865 CCCTCTACACCA 1-10-1 MOE 1050

398167

53870 53881 CAGGCCATGTGG 1-10-1 MOE 1059

147703

54137 54148 TGGCTTCATGTC 1-10-1 MOE 971

398155

54172 54185 TGTTTTTACACAGA  2-10-2 MOE 970

390030

54263 54274 TTTATAAAACTG 1-10-1 MOE 1074

147705

54275 54286 CGGTTTTTGTTC  1-10-1 MOE 1002

147703

54283 54294 TGGCTTCATGTC 1-10-1 MOE 971

390030

54409 54420 TTTATAAAACTG 1-10-1 MOE 1074

147704

54965 54976 TTGTTCTTAGGA 1-10-1 MOE 1012

147705

54971 54982 CGGTTTTTGTTC  1-10-1 MOE 1002

398090

55109 55122 TTGTTCTTAGGAAG 2-10-2 MOE 972

147705

55117 55128 CGGTTTTTGTTC  1-10-1 MOE 1002

147083

55206 55217 TACACCAGGTCA 1-10-1 MOE 973

147084

55207 55218 CTACACCAGGTC 1-10-1 MOE 993

147084

55353 55364 CTACACCAGGTC 1-10-1 MOE 993

147705

55524 55535 CGGTTMGTTC 1-10-1 MOE 1002

147685

55602 55613 GGCTGACATTCA 1-10-1 MOE 975

401404

55638 55651 TGAGCTACAGTAGG 2-10-2 MOE 974

147685

55748 55759 GGCTGACATTCA 1-10-1 MOE 975

147712

55819 55830 ACACCATCTCCC 1-10-1 MOE 1005

147712

55965 55976 ACACCATCTCCC 1-10-1 MOE 1005

147707

56300 56311 TAGTCATTATCT 1-10-1 MOE 977

147708

56306 56317 TTGATATAGTCA 1-10-1 MOE 997

390030

56321 56332 TTTATAAAACTG 1-10-1 MOE 1074

147709

56326 56337 CCATTTTTATCA  1-10-1 MOE 978

398091

56333 56346 GGGCTTCTTCCATT 2-10-2 MOE 979

401405

56408 56421 TGGTCAACTGAAAG 2-10-2 MOE 976

147707

56446 56457 TAGTCATTATCT 1-10-1 MOE 977

147708

56452 56463 TTGATATAGTCA 1-10-1 MOE 997

147709

56472 56483 CCATTTTTATCA  1-10-1 MOE 978

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398091

56479 56492 GGGCTTCTTCCATT 2-10-2 MOE 979

401406

56570 56583 GGTGTGGATAACAG 2-10-2 MOE 980

368366

56664 56677 CTGATCCTTAGAAG 2-10-2 MOE 1019

398148

57157 57170 TCATAACTATTAAG 2-10-2 MOE 981

147082

57220 57231 AGCTCCTTCCAC 1-10-1 MOE 1036

398148

57303 57316 TCATAACTATTAAG 2-10-2 MOE 981

147082

57366 57377 AGCTCCTTCCAC 1-10-1 MOE 1036

147743

57758 57769 AGGGCTTCCAGT 1-10-1 MOE 1042

398093

57963 57976 TCGGACTTTGAAAA 2-10-2 MOE 1009

398093

58109 58122 TCGGACTTTGAAAA 2-10-2 MOE 1009

147735

58279 58290 GGAGAAGCGCAG 1-10-1 MOE 1016

147087

58821 58832 CCTCTACACCAG 1-10-1 MOE 982

147087

58967 58978 CCTCTACACCAG 1-10-1 MOE 982

390030

59180 59191 TTTATAAAACTG 1-10-1 MOE 1074

390030

59326 59337 TTTATAAAACTG 1-10-1 MOE 1074

147711

59357 59368 AAGGGCCCTGGG 1-10-1 MOE 1040

147743

59382 59393 AGGGCTTCCAGT 1-10-1 MOE 1042

147711

59503 59514 AAGGGCCCTGGG 1-10-1 MOE 1040

147711

59675 59686 AAGGGCCCTGGG 1-10-1 MOE 1040

401407

59710 59723 CAGCTTAGGCAGAG 2-10-2 MOE 983

147712

59711 59722 ACACCATCTCCC 1-10-1 MOE 1005

147713

59716 59727 CTCCCACACCAT 1-10-1 MOE 985

147714

59721 59732 TTCTGCTCCCAC 1-10-1 MOE 986

147695

59722 59733 TCATTCCCCACT 1-10-1 MOE 984

147715

59746 59757 GTTGAGCATGAC 1-10-1 MOE 1077

147711

59821 59832 AAGGGCCCTGGG 1-10-1 MOE 1040

390030

59847 59858 TTTATAAAACTG 1-10-1 MOE 1074

147712

59857 59868 ACACCATCTCCC 1-10-1 MOE 1005

147713

59862 59873 CTCCCACACCAT 1-10-1 MOE 985

147714

59867 59878 TTCTGCTCCCAC 1-10-1 MOE 986

390030

59993 60004 TTTATAAAACTG 1-10-1 MOE 1074

389949

60471 60482 GCGCGAGCCCGA 1-10-1 MOE 1061

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147746

60619 60630 TAAAAACAACAA 1-10-1 MOE 1073

147689

61113 61124 CAGAGAAGGTCT 1-10-1 MOE 987

398105

61267 61280 TGCACAGGCAGGTT 2-10-2 MOE 1066

147680

61473 61484 GTATGCACTGCT 1-10-1 MOE 988

147080

61757 61768 CTCCTTCCACTG 1-10-1 MOE 1021

147078

61901 61912 CCTTCCACTGAT 1-10-1 MOE 1044

147079

61902 61913 TCCTTCCACTGA 1-10-1 MOE 1001

147088

62215 62226 CCCTCTACACCA 1-10-1 MOE 1050

401408

62600 62613 CAATGAAGCACAGG 2-10-2 MOE 989

147688

62843 62854 TCCCAAACAAAT 1-10-1 MOE 990

147746

63102 63113 TAAAAACAACAA 1-10-1 MOE 1073

147746

63248 63259 TAAAAACAACAA 1-10-1 MOE 1073

401409

63430 63443 ATTCTTAACACAGA 2-10-2 MOE 991

147682

63483 63494 CGGGTACTATGG 1-10-1 MOE 992

147084

63677 63688 CTACACCAGGTC 1-10-1 MOE 993

147710

64847 64858 TATAGCTCCTCT 1-10-1 MOE 994

147710

64993 65004 TATAGCTCCTCT 1-10-1 MOE 994

147746

65151 65162 TAAAAACAACAA 1-10-1 MOE 1073

401410

65263 65276 CATTTAGGGTCTAA  2-10-2 MOE 995

147717

65862 65873 ATCTTCAGAGAT 1-10-1 MOE 996

147717

65895 65906 ATCTTCAGAGAT 1-10-1 MOE 996

147708

65900 65911 TTGATATAGTCA 1-10-1 MOE 997

147718

65909 65920 TAATATGACTTG 1-10-1 MOE 998

147717

66008 66019 ATCTTCAGAGAT 1-10-1 MOE 996

147717

66041 66052 ATCTTCAGAGAT 1-10-1 MOE 996

147708

66046 66057 TTGATATAGTCA 1-10-1 MOE 997

147718

66055 66066 TAATATGACTTG 1-10-1 MOE 998

401411

66123 66136 AGCCGCCTGAAGTG  2-10-2 MOE 999

147697

66497 66508 CCCCAGCAGCGG 1-10-1 MOE 1000

368377

66562 66577 CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

66563 66574 CTTCCACTGATC 1-10-1 MOE 1047

368358

66563 66576 TCCTTCCACTGATC 2-10-2 MOE 1031

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147078

66564 66575 CCTTCCACTGAT 1-10-1 MOE 1044

147079

66565 66576 TCCTTCCACTGA 1-10-1 MOE 1001

147080

66566 66577 CTCCTTCCACTG 1-10-1 MOE 1021

147697

66643 66654 CCCCAGCAGCGG 1-10-1 MOE 1000

368358

66709 66722 TCCTTCCACTGATC 2-10-2 MOE 1031

147078

66710 66721 CCTTCCACTGAT 1-10-1 MOE 1044

147079

66711 66722 TCCTTCCACTGA 1-10-1 MOE 1001

147075

66999 67010 TCCACTGATCCT 1-10-1 MOE 1026

147705

67067 67078 CGGTTTTTGTTC  1-10-1 MOE 1002

147088

67409 67420 CCCTCTACACCA 1-10-1 MOE 1050

147080

67430 67441 CTCCTTCCACTG 1-10-1 MOE 1021

147082

67432 67443 AGCTCCTTCCAC 1-10-1 MOE 1036

147737

67455 67466 ACAGCCAGGTAG 1-10-1 MOE 1067

147088

67555 67566 CCCTCTACACCA 1-10-1 MOE 1050

147082

67578 67589 AGCTCCTTCCAC 1-10-1 MOE 1036

401412

67637 67650 TAAATCCTCTAGCA 2-10-2 MOE 1003

147091

67729 67740 GTTCCCTCTACA 1-10-1 MOE 1004

147742

67737 67748 AACTTCAGTGTC 1-10-1 MOE 1041

147712

68527 68538 ACACCATCTCCC 1-10-1 MOE 1005

147712

68673 68684 ACACCATCTCCC 1-10-1 MOE 1005

147711

68760 68771 AAGGGCCCTGGG 1-10-1 MOE 1040

147711

68906 68917 AAGGGCCCTGGG 1-10-1 MOE 1040

389965

69271 69282 CTGCAACATGAT 1-10-1 MOE 1018

389965

69417 69428 CTGCAACATGAT 1-10-1 MOE 1018

368353

69519 69532 CACTGATCCTGCAC 2-10-2 MOE 1007

147080

69630 69641 CTCCTTCCACTG 1-10-1 MOE 1021

147081

69631 69642 GCTCCTTCCACT 1-10-1 MOE 1006

368353

69665 69678 CACTGATCCTGCAC 2-10-2 MOE 1007

398167

69757 69768 CAGGCCATGTGG 1-10-1 MOE 1059

398092

69758 69771 AGTCAGGCCATGTG 2-10-2 MOE 1060

398093

69811 69824 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

69813 69824 TCGGACTTTGAA  1-10-1 MOE 1008

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398167

69903 69914 CAGGCCATGTGG 1-10-1 MOE 1059

398093

69957 69970 TCGGACTTTGAAAA 2-10-2 MOE 1009

398094

70047 70060 ATCAGCCAGACAGA 2-10-2 MOE 1010

398095

70065 70078 CATCAGCAAGAGGC 2-10-2 MOE 1011

147704

70137 70148 TTGTTCTTAGGA 1-10-1 MOE 1012

147728

70450 70461 GCCAGACAGAAG 1-10-1 MOE 1013

398164

70464 70475 TTGTCGATCTGC 1-10-1 MOE 1014

398096

70562 70575 GGAGAAGCGCAGCT  2-10-2 MOE 1015

147735

70564 70575 GGAGAAGCGCAG 1-10-1 MOE 1016

147737

70575 70586 ACAGCCAGGTAG 1-10-1 MOE 1067

147735

70710 70721 GGAGAAGCGCAG 1-10-1 MOE 1016

147737

70721 70732 ACAGCCAGGTAG 1-10-1 MOE 1067

404131

70729 70742 ACCTTCGATCACAG 2-10-2 MOE 831

368349

70762 70775 CTGCACTGACGAGT 2-10-2 MOE 1017

389965

70930 70941 CTGCAACATGAT 1-10-1 MOE 1018

368366

70995 71008 CTGATCCTTAGAAG 2-10-2 MOE 1019

368354

70999 71012 TCCACTGATCCTGC 2-10-2 MOE 1024

368375

71000 71015 CCTTCCACTGATCCTG 3-10-3 MOE 1020

368356

71001 71014 CTTCCACTGATCCT 2-10-2 MOE 1027

368376

71001 71016 TCCTTCCACTGATCCT 3-10-3 MOE 1028

368357

71002 71015 CCTTCCACTGATCC 2-10-2 MOE 1046

368377

71002 71017 CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

71003 71014 CTTCCACTGATC 1-10-1 MOE 1047

368358

71003 71016 TCCTTCCACTGATC 2-10-2 MOE 1031

368378

71003 71018 GCTCCTTCCACTGATC 3-10-3 MOE 1032

147078

71004 71015 CCTTCCACTGAT 1-10-1 MOE 1044

368359

71005 71018 GCTCCTTCCACTGA 2-10-2 MOE 1033

368379

71005 71020 AAGCTCCTTCCACTGA 3-10-3 MOE 1034

147080

71006 71017 CTCCTTCCACTG 1-10-1 MOE 1021

147082

71008 71019 AGCTCCTTCCAC 1-10-1 MOE 1036

401413

71019 71032 TGCAGCCATGTACT 2-10-2 MOE 1022

147738

71067 71078 TGGGTGGCCGGG 1-10-1 MOE 1069

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147739

71071 71082 CGTTTGGGTGGC 1-10-1 MOE 1023

147741

71129 71140 CACCCACTGGTG 1-10-1 MOE 1055

368354

71145 71158 TCCACTGATCCTGC 2-10-2 MOE 1024

368355

71146 71159 TTCCACTGATCCTG 2-10-2 MOE 1025

147075

71147 71158 TCCACTGATCCT 1-10-1 MOE 1026

368356

71147 71160 CTTCCACTGATCCT 2-10-2 MOE 1027

368376

71147 71162 TCCTTCCACTGATCCT 3-10-3 MOE 1028

147076

71148 71159 TTCCACTGATCC 1-10-1 MOE 1029

368357

71148 71161 CCTTCCACTGATCC 2-10-2 MOE 1046

368377

71148 71163 CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

71149 71160 CTTCCACTGATC 1-10-1 MOE 1047

368358

71149 71162 TCCTTCCACTGATC 2-10-2 MOE 1031

368378

71149 71164 GCTCCTTCCACTGATC 3-10-3 MOE 1032

147078

71150 71161 CCTTCCACTGAT 1-10-1 MOE 1044

368359

71151 71164 GCTCCTTCCACTGA 2-10-2 MOE 1033

368379

71151 71166 AAGCTCCTTCCACTGA 3-10-3 MOE 1034

368360

71153 71166 AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

71154 71165 AGCTCCTTCCAC 1-10-1 MOE 1036

368381

71155 71170 GGGAAAGCTCCTTCCA 3-10-3 MOE 1037

390030

71986 71997 TTTATAAAACTG 1-10-1 MOE 1074

390030

72132 72143 TTTATAAAACTG 1-10-1 MOE 1074

147711

72300 72311 AAGGGCCCTGGG 1-10-1 MOE 1040

401414

72347 72360 TTGCAATGTCTGGC 2-10-2 MOE 1038

147741

72400 72411 CACCCACTGGTG 1-10-1 MOE 1055

401415

72415 72428 GATTTATCTGGCTG  2-10-2 MOE 1039

147711

72446 72457 AAGGGCCCTGGG 1-10-1 MOE 1040

147742

72575 72586 AACTTCAGTGTC 1-10-1 MOE 1041

147743

72690 72701 AGGGCTTCCAGT 1-10-1 MOE 1042

147744

72694 72705 AGGAAGGGCTTC 1-10-1 MOE 1043

147745

72700 72711 TTGACCAGGAAG 1-10-1 MOE 1058

147742

72721 72732 AACTTCAGTGTC 1-10-1 MOE 1041

147743

72836 72847 AGGGCTTCCAGT 1-10-1 MOE 1042

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147744

72840 72851 AGGAAGGGCTTC 1-10-1 MOE 1043

368357

72898 72911 CCTTCCACTGATCC 2-10-2 MOE 1046

147078

72900 72911 CCTTCCACTGAT 1-10-1 MOE 1044

398157

72903 72916 GGAAACATACCCTG 2-10-2 MOE 1045

368357

73044 73057 CCTTCCACTGATCC 2-10-2 MOE 1046

147077

73045 73056 CTTCCACTGATC 1-10-1 MOE 1047

147746

73052 73063 TAAAAACAACAA 1-10-1 MOE 1073

147746

73101 73112 TAAAAACAACAA 1-10-1 MOE 1073

398160

73139 73152 GAATAGGTTAAGGC 2-10-2 MOE 1048

147746

73198 73209 TAAAAACAACAA 1-10-1 MOE 1073

398161

73238 73251 AACAATGTGTTGTA 2-10-2 MOE 1049

147088

73419 73430 CCCTCTACACCA 1-10-1 MOE 1050

404140

73457 73470 GCACACAGCTGAGG 2-10-2 MOE 1051

404139

73459 73472 GTGCACACAGCTGA 2-10-2 MOE 1052

399301

73461 73474 GTGTGCACACAGCT 2-10-2 MOE 1542

404137

73463 73476 CAGTGTGCACACAG 2-10-2 MOE 1053

404138

73465 73478 CTCAGTGTGCACAC 2-10-2 MOE 1054

147741

73705 73716 CACCCACTGGTG 1-10-1 MOE 1055

404135

73858 73871 CATTTCCATGGCCA 2-10-2 MOE 1056

398167

74008 74019 CAGGCCATGTGG 1-10-1 MOE 1059

398092

74009 74022 AGTCAGGCCATGTG 2-10-2 MOE 1060

398162

74114 74127 ACCAAACAGTTCAG 2-10-2 MOE 1057

147745

74137 74148 TTGACCAGGAAG 1-10-1 MOE 1058

398167

74154 74165 CAGGCCATGTGG 1-10-1 MOE 1059

398092

74155 74168 AGTCAGGCCATGTG 2-10-2 MOE 1060

389949

74310 74321 GCGCGAGCCCGA 1-10-1 MOE 1061

147740

74485 74496 TGTGAGGCTCCA 1-10-1 MOE 1062

389950

74527 74538 CCCTGAAGGTTC 1-10-1 MOE 1063

398101

74656 74669 TTTGATAAAGCCCT  2-10-2 MOE 1064

398104

74805 74818 CAAGAAGACCTTAC 2-10-2 MOE 1065

147737

74893 74904 ACAGCCAGGTAG 1-10-1 MOE 1067

398105

74894 74907 TGCACAGGCAGGTT 2-10-2 MOE 1066

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147737

74919 74930 ACAGCCAGGTAG 1-10-1 MOE 1067

398106

74974 74987 TGGAAAACTGCACC 2-10-2 MOE 1068

404199

75045 75058 GGTCATGCACAGGC 2-10-2 MOE 867

404134

75048 75061 TCAGGTCATGCACA 2-10-2 MOE 873

398106

75120 75133 TGGAAAACTGCACC 2-10-2 MOE 1068

147738

75155 75166 TGGGTGGCCGGG 1-10-1 MOE 1069

404132

75227 75240 CCTTGGAATGTCTG 2-10-2 MOE 852

147738

75301 75312 TGGGTGGCCGGG 1-10-1 MOE 1069

398166

75499 75510 GGGCTTCTTCCA 1-10-1 MOE 1070

147746

75617 75628 TAAAAACAACAA 1-10-1 MOE 1073

147706

75686 75697 GCTGACATCTCG 1-10-1 MOE 1071

398112

75730 75743 CAGCCTGGCACCTA 2-10-2 MOE 1072

147746

75763 75774 TAAAAACAACAA 1-10-1 MOE 1073

398115

75786 75799 AGTAAATATTGGCT 2-10-2 MOE 1076

390030

75839 75850 TTTATAAAACTG 1-10-1 MOE 1074

398114

75916 75929 AGGCATATAGCAGA 2-10-2 MOE 1075

398115

75932 75945 AGTAAATATTGGCT 2-10-2 MOE 1076

404133

75968 75981 TATTCCATGGCCAT 2-10-2 MOE 872

147715

77045 77056 GTTGAGCATGAC 1-10-1 MOE 1077

147715

77190 77201 GTTGAGCATGAC 1-10-1 MOE 1077

147693

77385 77396 GTGCGCTCCCAT 1-10-1 MOE 1078

398173

40201 40212 CAGCCTGGGCAC 1-10-1 MOE 1543

398173

72764 72775 CAGCCTGGGCAC 1-10-1 MOE 1543

399096

1986 1999 TGCTCGAACTCCTT 2-10-2 MOE 1544

399102

52822 52835 GAAGTCACTGGCTT 2-10-2 MOE 1545

399103

52824 52837 GGGAAGTCACTGGC 2-10-2 MOE 1546

399113

59827 59840 GTTAGGCAAAGGGC 2-10-2 MOE 1547

399132

69977 69990 GGGCTGAGTGACCC 2-10-2 MOE 1548

399173

74592 74605 ATGCTAGTGCACTA 2-10-2 MOE 1549

399208

75900 75913 AGCTCGCTACCTCT 2-10-2 MOE 1550

399276

27559 27572 GAGGTATCCCATCT 2-10-2 MOE 1551

399315

74039 74052 GGCAACTTCAACCT 2-10-2 MOE 1552

Table 19: Short antisense compounds directed to SEQ ID No. 12 and having 1 or 2 mismatches

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398163

twenty 31  ATGTCAACCGGC 1-10-1 MOE 908

384545

2. 3 3. 4  CAAGTAGGATGT 1-10-1 MOE 951

147733

26 37  TTCTTGATGTCC 1-10-1 MOE 891

147721

59 70  AATGCAGGATCT 1-10-1 MOE 1118

147700

110 121  GCGCTAGGCCGC 1-10-1 MOE 1110

384545

130 141  CAAGTAGGATGT 1-10-1 MOE 951

147705

159 170 CGGTTTTTGTTC 1-10-1 MOE 1002

147701

167 178  CCATGGCGGGAC 1-10-1 MOE 921

398164

198 209  TTGTCGATCTGC 1-10-1 MOE 1014

147730

199 210  CTTGTCCATCAG 1-10-1 MOE 1121

147702

226 237  CTGGTAAATAGC 1-10-1 MOE 898

147703

245 256  TGGCTTCATGTC 1-10-1 MOE 971

147705

266 277 CGGTTTTTGTTC 1-10-1 MOE 1002

398165

283 294  GTTCTTAGGAAG 1-10-1 MOE 968

147704

285 296  TTGTTCTTAGGA 1-10-1 MOE 1012

147705

291 302 CGGTTTTTGTTC 1-10-1 MOE 1002

147709

311 322 CCATTTTTATCA 1-10-1 MOE 978

147733

349 360  TTCTTGATGTCC 1-10-1 MOE 891

147707

360 371  TAGTCATTATCT 1-10-1 MOE 977

147708

366 377  TTGATATAGTCA 1-10-1 MOE 997

390030

381 392 TTTATAAAACTG 1-10-1 MOE 1074

147709

386 397 CCATTTTTATCA 1-10-1 MOE 978

147081

393 404  GCTCCTTCCACT 1-10-1 MOE 1006

398091

393 406  GGGCTTCTTCCATT 2-10-2 MOE 979

398166

395 406  GGGCTTCTTCCA 1-10-1 MOE 1070

147712

461 472  ACACCATCTCCC 1-10-1 MOE 1005

147713

466 477  CTCCCACACCAT 1-10-1 MOE 985

147714

471 482  TTCTGCTCCCAC 1-10-1 MOE 986

147710

502 513  TATAGCTCCTCT 1-10-1 MOE 994

147736

551 562  AGGTAGGAGAAG 1-10-1 MOE 963

147717

574 585  ATCTTCAGAGAT 1-10-1 MOE 996

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147717

607 618  ATCTTCAGAGAT 1-10-1 MOE 996

147710

609 620  TATAGCTCCTCT 1-10-1 MOE 994

147708

612 623  TTGATATAGTCA 1-10-1 MOE 997

147718

621 632  TAATATGACTTG 1-10-1 MOE 998

147746

625 636  TAAAAACAACAA 1-10-1 MOE 1073

147736

658 669  AGGTAGGAGAAG 1-10-1 MOE 963

147720

676 687  GATCTCTCGAGT 1-10-1 MOE 1117

147721

683 694  AATGCAGGATCT 1-10-1 MOE 1118

398167

704 715  CAGGCCATGTGG 1-10-1 MOE 1059

398092

705 718  AGTCAGGCCATGTG 2-10-2 MOE 1060

147722

709 720  AAAGTCAGGCCA 1-10-1 MOE 1130

147723

715 726  GACTCCAAAGTC 1-10-1 MOE 892

147746

733 744  TAAAAACAACAA 1-10-1 MOE 1073

398093

758 771 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

760 771 TCGGACTTTGAA 1-10-1 MOE 1008

147725

761 772 CTCGGACTTTGA 1-10-1 MOE 1119

147726

766 777  TGACTCTCGGAC 1-10-1 MOE 1120

147738

780 791  TGGGTGGCCGGG 1-10-1 MOE 1069

147727

807 818  CAGTGGACCACA 1-10-1 MOE 1128

147728

846 857 GCCAGACAGAAG 1-10-1 MOE 1013

398094

848 861  ATCAGCCAGACAGA 2-10-2 MOE 1010

398169

849 860  TCAGCCAGACAG 1-10-1 MOE 909

147729

863 874  GTAAGAGGCAGG 1-10-1 MOE 920

398095

866 879  CATCAGCAAGAGGC 2-10-2 MOE 1011

398164

873 884  TTGTCGATCTGC 1-10-1 MOE 1014

147730

874 885  CTTGTCCATCAG 1-10-1 MOE 1121

147731

880 891 TTTCCTCTTGTC 1-10-1 MOE 934

147732

885 896 GGGTCTTTCCTC 1-10-1 MOE 1122

147738

888 899  TGGGTGGCCGGG 1-10-1 MOE 1069

147733

906 917  TTCTTGATGTCC 1-10-1 MOE 891

398096

971 984 GGAGAAGCGCAGCT 2-10-2 MOE 1015

147735

973 984 GGAGAAGCGCAG 1-10-1 MOE 1016

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147736

978 989  AGGTAGGAGAAG 1-10-1 MOE 963

147729

979 990  GTAAGAGGCAGG 1-10-1 MOE 920

147737

984 995  ACAGCCAGGTAG 1-10-1 MOE 1067

368349

1025 1038  CTGCACTGACGAGT 2-10-2 MOE 1017

368369

1025 1040  TCCTGCACTGACGAGT 3-10-3 MOE 893

368350

1027 1040  TCCTGCACTGACGA 2-10-2 MOE 1079

368370

1027 1042  GATCCTGCACTGACGA 3-10-3 MOE 1080

368351

1029 1042  GATCCTGCACTGAC 2-10-2 MOE 1081

368371

1029 1044  CTGATCCTGCACTGAC 3-10-3 MOE 1082

368352

1031 1044  CTGATCCTGCACTG 2-10-2 MOE 1105

368372

1031 1046  CACTGATCCTGCACTG 3-10-3 MOE 894

368353

1033 1046  CACTGATCCTGCAC 2-10-2 MOE 1007

368373

1033 1048  TCCACTGATCCTGCAC 3-10-3 MOE 1083

368354

1035 1048  TCCACTGATCCTGC 2-10-2 MOE 1024

368368

1035 1048  TCCACTGATCCTTA 2-10-2 MOE 1127

368374

1035 1050  CTTCCACTGATCCTGC 3-10-3 MOE 1126

368388

1035 1050  CTTCCACTGATCCTTA 3-10-3 MOE 895

147074

1036 1047  CCACTGATCCTG 1-10-1 MOE 845

368355

1036 1049  TTCCACTGATCCTG 2-10-2 MOE 1025

368375

1036 1051  CCTTCCACTGATCCTG 3-10-3 MOE 1020

147075

1037 1048  TCCACTGATCCT 1-10-1 MOE 1026

368356

1037 1050  CTTCCACTGATCCT 2-10-2 MOE 1027

368376

1037 1052  TCCTTCCACTGATCCT 3-10-3 MOE 1028

147076

1038 1049  TTCCACTGATCC 1-10-1 MOE 1029

368357

1038 1051  CCTTCCACTGATCC 2-10-2 MOE 1046

368377

1038 1053  CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

1039 1050  CTTCCACTGATC 1-10-1 MOE 1047

368358

1039 1052  TCCTTCCACTGATC 2-10-2 MOE 1031

368378

1039 1054  GCTCCTTCCACTGATC 3-10-3 MOE 1032

147078

1040 1051  CCTTCCACTGAT 1-10-1 MOE 1044

147079

1041 1052  TCCTTCCACTGA 1-10-1 MOE 1001

368359

1041 1054  GCTCCTTCCACTGA 2-10-2 MOE 1033

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

368379

1041 1056  AAGCTCCTTCCACTGA 3-10-3 MOE 1034

147080

1042 1053  CTCCTTCCACTG 1-10-1 MOE 1021

147081

1043 1054  GCTCCTTCCACT 1-10-1 MOE 1006

368360

1043 1056  AAGCTCCTTCCACT 2-10-2 MOE 1035

368380

1043 1058  GAAAGCTCCTTCCACT 3-10-3 MOE 896

147082

1044 1055  AGCTCCTTCCAC 1-10-1 MOE 1036

368361

1045 1058  GAAAGCTCCTTCCA 2-10-2 MOE 962

368381

1045 1060  GGGAAAGCTCCTTCCA 3-10-3 MOE 1037

147729

1087 1098  GTAAGAGGCAGG 1-10-1 MOE 920

147738

1103 1114  TGGGTGGCCGGG 1-10-1 MOE 1069

147739

1107 1118 CGTTTGGGTGGC 1-10-1 MOE 1023

147740

1124 1135  TGTGAGGCTCCA 1-10-1 MOE 1062

398117

1164 1177 TTTCCACTTGGGTG 2-10-2 MOE 960

147741

1165 1176  CACCCACTGGTG 1-10-1 MOE 1055

398097

1194 1207 GGCAGTCTTTATCC 2-10-2 MOE 897

398098

1272 1285  TAACTTCAGTGTCT 2-10-2 MOE 1131

398117

1272 1285 TTTCCACTTGGGTG 2-10-2 MOE 960

147742

1273 1284  AACTTCAGTGTC 1-10-1 MOE 1041

147698

1293 1304 CCCGCCACCACC 1-10-1 MOE 928

147743

1388 1399  AGGGCTTCCAGT 1-10-1 MOE 1042

398099

1388 1401  GAAGGGCTTCCAGT 2-10-2 MOE 1132

147744

1392 1403  AGGAAGGGCTTC 1-10-1 MOE 1043

398100

1395 1408  TGACCAGGAAGGGC 2-10-2 MOE 1133

147745

1398 1409  TTGACCAGGAAG 1-10-1 MOE 1058

398157

1455 1468  GGAAACATACCCTG 2-10-2 MOE 1045

147745

1458 1469  TTGACCAGGAAG 1-10-1 MOE 1058

398167

1475 1486  CAGGCCATGTGG 1-10-1 MOE 1059

398118

1564 1577  CGCGAGATATCTAA 2-10-2 MOE 1084

147697

1575 1586 CCCCAGCAGCGG 1-10-1 MOE 1000

147076

1596 1607  TTCCACTGATCC 1-10-1 MOE 1029

368357

1596 1609  CCTTCCACTGATCC 2-10-2 MOE 1046

147077

1597 1608  CTTCCACTGATC 1-10-1 MOE 1047

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147078

1598 1609  CCTTCCACTGAT 1-10-1 MOE 1044

398118

1672 1685  CGCGAGATATCTAA 2-10-2 MOE 1084

398158

1681 1694  AGGCCCTGAGATTA 2-10-2 MOE 1134

147697

1683 1694 CCCCAGCAGCGG 1-10-1 MOE 1000

398159

1686 1699  GGTTAAGGCCCTGA 2-10-2 MOE 1135

398160

1691 1704  GAATAGGTTAAGGC 2-10-2 MOE 1048

398163

1711 1722  ATGTCAACCGGC 1-10-1 MOE 908

147733

1717 1728  TTCTTGATGTCC 1-10-1 MOE 891

147089

1747 1758  TCCCTCTACACC 1-10-1 MOE 956

147090

1748 1759  TTCCCTCTACAC 1-10-1 MOE 955

147746

1750 1761  TAAAAACAACAA 1-10-1 MOE 1073

389949

1777 1788 GCGCGAGCCCGA 1-10-1 MOE 1061

398161

1790 1803  AACAATGTGTTGTA 2-10-2 MOE 1049

147746

1799 1810  TAAAAACAACAA 1-10-1 MOE 1073

147700

1801 1812  GCGCTAGGCCGC 1-10-1 MOE 1110

147740

1806 1817  TGTGAGGCTCCA 1-10-1 MOE 1062

398163

1819 1830  ATGTCAACCGGC 1-10-1 MOE 908

147733

1825 1836  TTCTTGATGTCC 1-10-1 MOE 891

389950

1848 1859  CCCTGAAGGTTC 1-10-1 MOE 1063

147701

1858 1869  CCATGGCGGGAC 1-10-1 MOE 921

398164

1889 1900  TTGTCGATCTGC 1-10-1 MOE 1014

147730

1890 1901  CTTGTCCATCAG 1-10-1 MOE 1121

147700

1909 1920  GCGCTAGGCCGC 1-10-1 MOE 1110

398119

1920 1933  CGCACCTGGTAAAT 2-10-2 MOE 1085

147685

1957 1968  GGCTGACATTCA 1-10-1 MOE 975

147701

1966 1977  CCATGGCGGGAC 1-10-1 MOE 921

398120

1966 1979  GTTCAAGCGGCCTA 2-10-2 MOE 1086

398101

1977 1990 TTTGATAAAGCCCT 2-10-2 MOE 1064

398164

1997 2008  TTGTCGATCTGC 1-10-1 MOE 1014

147730

1998 2009  CTTGTCCATCAG 1-10-1 MOE 1121

147702

2025 2036  CTGGTAAATAGC 1-10-1 MOE 898

398119

2028 2041  CGCACCTGGTAAAT 2-10-2 MOE 1085

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398120

2074 2087  GTTCAAGCGGCCTA 2-10-2 MOE 1086

398105

2099 2112  TGCACAGGCAGGTT 2-10-2 MOE 1066

147736

2204 2215  AGGTAGGAGAAG 1-10-1 MOE 963

147741

2257 2268  CACCCACTGGTG 1-10-1 MOE 1055

398104

2272 2285  CAAGAAGACCTTAC 2-10-2 MOE 1065

147737

2360 2371  ACAGCCAGGTAG 1-10-1 MOE 1067

398105

2361 2374  TGCACAGGCAGGTT 2-10-2 MOE 1066

147737

2386 2397  ACAGCCAGGTAG 1-10-1 MOE 1067

398095

2407 2420  CATCAGCAAGAGGC 2-10-2 MOE 1011

398106

2441 2454  TGGAAAACTGCACC 2-10-2 MOE 1068

398107

2447 2460  TATTCCTGGAAAAC 2-10-2 MOE 902

398121

2474 2487  GTGCCTAGCACAGA 2-10-2 MOE 1097

147745

2497 2508  TTGACCAGGAAG 1-10-1 MOE 1058

147712

2499 2510  ACACCATCTCCC 1-10-1 MOE 1005

398108

2544 2557  GGAATGTCTGAGTT 2-10-2 MOE 1136

147691

2575 2586  GAGGTGGGAAAA 1-10-1 MOE 966

398121

2582 2595  GTGCCTAGCACAGA 2-10-2 MOE 1097

147738

2622 2633  TGGGTGGCCGGG 1-10-1 MOE 1069

398162

2666 2679  ACCAAACAGTTCAG 2-10-2 MOE 1057

147745

2689 2700  TTGACCAGGAAG 1-10-1 MOE 1058

398167

2706 2717  CAGGCCATGTGG 1-10-1 MOE 1059

398092

2707 2720  AGTCAGGCCATGTG 2-10-2 MOE 1060

398109

2714 2727  CAAGAAGTGTGGTT 2-10-2 MOE 903

398110

2852 2865 GTTCCCTTTGCAGG 2-10-2 MOE 952

147091

2854 2865  GTTCCCTCTACA 1-10-1 MOE 1004

147723

2924 2935  GACTCCAAAGTC 1-10-1 MOE 892

398111

2937 2950  GTGAAAATGCTGGC 2-10-2 MOE 904

398166

2966 2977  GGGCTTCTTCCA 1-10-1 MOE 1070

147089

2978 2989  TCCCTCTACACC 1-10-1 MOE 956

147090

2979 2990  TTCCCTCTACAC 1-10-1 MOE 955

147706

3007 3018  GCTGACATCTCG 1-10-1 MOE 1071

389949

3008 3019 GCGCGAGCCCGA 1-10-1 MOE 1061

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147723

3032 3043  GACTCCAAAGTC 1-10-1 MOE 892

147740

3037 3048  TGTGAGGCTCCA 1-10-1 MOE 1062

398112

3051 3064  CAGCCTGGCACCTA 2-10-2 MOE 1072

389950

3079 3090  CCCTGAAGGTTC 1-10-1 MOE 1063

147746

3084 3095  TAAAAACAACAA 1-10-1 MOE 1073

398122

3148 3161 CCCTTTACACAAGT 2-10-2 MOE 1087

147089

3151 3162  TCCCTCTACACC 1-10-1 MOE 956

147090

3152 3163  TTCCCTCTACAC 1-10-1 MOE 955

398113

3160 3173  AGGAGGTTAAACCA 2-10-2 MOE 905

147685

3188 3199  GGCTGACATTCA 1-10-1 MOE 975

398101

3208 3221 TTTGATAAAGCCCT 2-10-2 MOE 1064

398102

3234 3247 CTACCTGAGGATTT 2-10-2 MOE 899

398123

3235 3248 CTCAAAATAGATTT 2-10-2 MOE 1088

398114

3237 3250  AGGCATATAGCAGA 2-10-2 MOE 1075

398103

3241 3254  CCCAGTACTACCTG 2-10-2 MOE 900

398115

3253 3266  AGTAAATATTGGCT 2-10-2 MOE 1076

398122

3256 3269 CCCTTTACACAAGT 2-10-2 MOE 1087

147089

3259 3270  TCCCTCTACACC 1-10-1 MOE 956

147090

3260 3271  TTCCCTCTACAC 1-10-1 MOE 955

398116

3266 3279  TAATGACCTGATGA 2-10-2 MOE 1137

390030

3306 3317 TTTATAAAACTG 1-10-1 MOE 1074

398123

3343 3356 CTCAAAATAGATTT 2-10-2 MOE 1088

147736

3435 3446  AGGTAGGAGAAG 1-10-1 MOE 963

398104

3503 3516  CAAGAAGACCTTAC 2-10-2 MOE 1065

147737

3591 3602  ACAGCCAGGTAG 1-10-1 MOE 1067

398105

3592 3605  TGCACAGGCAGGTT 2-10-2 MOE 1066

147719

3608 3619  CCAACTCCAACT 1-10-1 MOE 1116

147737

3617 3628  ACAGCCAGGTAG 1-10-1 MOE 1067

401398

3621 3634  CAAAGTCCCTTAGC 2-10-2 MOE 947

147079

3637 3648  TCCTTCCACTGA 1-10-1 MOE 1001

147080

3638 3649  CTCCTTCCACTG 1-10-1 MOE 1021

398095

3638 3651  CATCAGCAAGAGGC 2-10-2 MOE 1011

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398106

3672 3685  TGGAAAACTGCACC 2-10-2 MOE 1068

147733

3687 3698  TTCTTGATGTCC 1-10-1 MOE 891

147731

3688 3699 TTTCCTCTTGTC 1-10-1 MOE 934

147719

3716 3727  CCAACTCCAACT 1-10-1 MOE 1116

147745

3728 3739  TTGACCAGGAAG 1-10-1 MOE 1058

147683

3740 3751  GCTTACGATTGT 1-10-1 MOE 922

147079

3745 3756  TCCTTCCACTGA 1-10-1 MOE 1001

147080

3746 3757  CTCCTTCCACTG 1-10-1 MOE 1021

398108

3775 3788  GGAATGTCTGAGTT 2-10-2 MOE 1136

147733

3795 3806  TTCTTGATGTCC 1-10-1 MOE 891

147731

3796 3807 TTTCCTCTTGTC 1-10-1 MOE 934

147691

3806 3817  GAGGTGGGAAAA 1-10-1 MOE 966

147738

3853 3864  TGGGTGGCCGGG 1-10-1 MOE 1069

398167

3926 3937  CAGGCCATGTGG 1-10-1 MOE 1059

147691

3978 3989  GAGGTGGGAAAA 1-10-1 MOE 966

398167

4034 4045  CAGGCCATGTGG 1-10-1 MOE 1059

147091

4085 4096  GTTCCCTCTACA 1-10-1 MOE 1004

147691

4086 4097  GAGGTGGGAAAA 1-10-1 MOE 966

398111

4168 4181  GTGAAAATGCTGGC 2-10-2 MOE 904

398166

4197 4208  GGGCTTCTTCCA 1-10-1 MOE 1070

147091

4223 4234  GTTCCCTCTACA 1-10-1 MOE 1004

147092

4224 4235  TGTTCCCTCTAC 1-10-1 MOE 901

398112

4282 4295  CAGCCTGGCACCTA 2-10-2 MOE 1072

147746

4315 4326  TAAAAACAACAA 1-10-1 MOE 1073

398113

4391 4404  AGGAGGTTAAACCA 2-10-2 MOE 905

147723

4422 4433  GACTCCAAAGTC 1-10-1 MOE 892

398114

4468 4481  AGGCATATAGCAGA 2-10-2 MOE 1075

398115

4484 4497  AGTAAATATTGGCT 2-10-2 MOE 1076

390030

4491 4502 TTTATAAAACTG 1-10-1 MOE 1074

398116

4497 4510  TAATGACCTGATGA 2-10-2 MOE 1137

147723

4530 4541  GACTCCAAAGTC 1-10-1 MOE 892

390030

4599 4610 TTTATAAAACTG 1-10-1 MOE 1074

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398124

4761 4774  CACATGAGCTATTC 2-10-2 MOE 1089

398124

4869 4882  CACATGAGCTATTC 2-10-2 MOE 1089

147703

4926 4937  TGGCTTCATGTC 1-10-1 MOE 971

147692

4928 4939  CTCACCTTCATG 1-10-1 MOE 1113

147696

4975 4986  TGGATGATTGGC 1-10-1 MOE 906

147703

5034 5045  TGGCTTCATGTC 1-10-1 MOE 971

147692

5036 5047  CTCACCTTCATG 1-10-1 MOE 1113

147098

5173 5184  AGTTGTTGTTCC 1-10-1 MOE 1112

398125

5183 5196 CAGTAAGGAATTTT 2-10-2 MOE 913

398126

5216 5229  GTGAAGTGAGTCAT 2-10-2 MOE 1090

147098

5281 5292  AGTTGTTGTTCC 1-10-1 MOE 1112

398127

5283 5296  GGTCACTCAAGATG 2-10-2 MOE 1091

398126

5324 5337  GTGAAGTGAGTCAT 2-10-2 MOE 1090

398128

5335 5348 CTAAATTTAGTTCA 2-10-2 MOE 911

398127

5391 5404  GGTCACTCAAGATG 2-10-2 MOE 1091

398128

5443 5456 CTAAATTTAGTTCA 2-10-2 MOE 911

147712

5474 5485  ACACCATCTCCC 1-10-1 MOE 1005

147736

5600 5611  AGGTAGGAGAAG 1-10-1 MOE 963

147746

5606 5617  TAAAAACAACAA 1-10-1 MOE 1073

398129

5628 5641 TTTGAGGAGCTATT 2-10-2 MOE 1106

147085

5654 5665  TCTACACCAGGT 1-10-1 MOE 961

147736

5708 5719  AGGTAGGAGAAG 1-10-1 MOE 963

398129

5736 5749 TTTGAGGAGCTATT 2-10-2 MOE 1106

147679

5934 5945  CAAAAGGATCCC 1-10-1 MOE 907

147723

6229 6240  GACTCCAAAGTC 1-10-1 MOE 892

147723

6338 6349  GACTCCAAAGTC 1-10-1 MOE 892

390030

6803 6814 TTTATAAAACTG 1-10-1 MOE 1074

398142

6885 6898  CCAGCACACTGGAA 2-10-2 MOE 923

390030

6912 6923 TTTATAAAACTG 1-10-1 MOE 1074

398142

6994 7007  CCAGCACACTGGAA 2-10-2 MOE 923

147695

7054 7065  TCATTCCCCACT 1-10-1 MOE 984

147695

7163 7174  TCATTCCCCACT 1-10-1 MOE 984

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398166

7197 7208  GGGCTTCTTCCA 1-10-1 MOE 1070

398166

7306 7317  GGGCTTCTTCCA 1-10-1 MOE 1070

147684

7442 7453  ACCCAGTCAGGG 1-10-1 MOE 964

398130

7694 7707  TTAGTATGACAGCT 2-10-2 MOE 925

398131

7711 7724  GGACTCACTCAGCA 2-10-2 MOE 1092

398130

7802 7815  TTAGTATGACAGCT 2-10-2 MOE 925

398125

7804 7817 CAGTAAGGAATTTT 2-10-2 MOE 913

398131

7819 7832  GGACTCACTCAGCA 2-10-2 MOE 1092

390030

7877 7888 TTTATAAAACTG 1-10-1 MOE 1074

398125

7912 7925 CAGTAAGGAATTTT 2-10-2 MOE 913

390030

7985 7996 TTTATAAAACTG 1-10-1 MOE 1074

398132

8031 8044  TCAGGGCTACTCAT 2-10-2 MOE 1093

398132

8139 8152  TCAGGGCTACTCAT 2-10-2 MOE 1093

147684

8148 8159  ACCCAGTCAGGG 1-10-1 MOE 964

147684

8256 8267  ACCCAGTCAGGG 1-10-1 MOE 964

398163

8365 8376  ATGTCAACCGGC 1-10-1 MOE 908

398166

8447 8458  GGGCTTCTTCCA 1-10-1 MOE 1070

398163

8473 8484  ATGTCAACCGGC 1-10-1 MOE 908

398166

8555 8566  GGGCTTCTTCCA 1-10-1 MOE 1070

147718

8631 8642  TAATATGACTTG 1-10-1 MOE 998

147691

8698 8709  GAGGTGGGAAAA 1-10-1 MOE 966

147691

8806 8817  GAGGTGGGAAAA 1-10-1 MOE 966

147728

8835 8846 GCCAGACAGAAG 1-10-1 MOE 1013

147727

8876 8887  CAGTGGACCACA 1-10-1 MOE 1128

147728

8943 8954 GCCAGACAGAAG 1-10-1 MOE 1013

398169

8946 8957  TCAGCCAGACAG 1-10-1 MOE 909

147727

8984 8995  CAGTGGACCACA 1-10-1 MOE 1128

147742

9060 9071  AACTTCAGTGTC 1-10-1 MOE 1041

398133

9112 9125  CAGCACTAGATTCA 2-10-2 MOE 1094

384545

9135 9146  CAAGTAGGATGT 1-10-1 MOE 951

147742

9168 9179  AACTTCAGTGTC 1-10-1 MOE 1041

398133

9220 9233  CAGCACTAGATTCA 2-10-2 MOE 1094

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

384545

9243 9254  CAAGTAGGATGT 1-10-1 MOE 951

398125

9368 9381 CAGTAAGGAATTTT 2-10-2 MOE 913

398125

9476 9489 CAGTAAGGAATTTT 2-10-2 MOE 913

401409

9516 9529  ATTCTTAACACAGA 2-10-2 MOE 991

147096

9594 9605  TTGTTGTTCCCT 1-10-1 MOE 1107

147733

9597 9608  TTCTTGATGTCC 1-10-1 MOE 891

147720

9689 9700  GATCTCTCGAGT 1-10-1 MOE 1117

147096

9702 9713  TTGTTGTTCCCT 1-10-1 MOE 1107

147733

9705 9716  TTCTTGATGTCC 1-10-1 MOE 891

147720

9797 9808  GATCTCTCGAGT 1-10-1 MOE 1117

147746

9963 9974  TAAAAACAACAA 1-10-1 MOE 1073

147746

9966 9977  TAAAAACAACAA 1-10-1 MOE 1073

147746

9969 9980  TAAAAACAACAA 1-10-1 MOE 1073

147746

9991 10002  TAAAAACAACAA 1-10-1 MOE 1073

147746

10071 10082  TAAAAACAACAA 1-10-1 MOE 1073

147746

10074 10085  TAAAAACAACAA 1-10-1 MOE 1073

147746

10077 10088  TAAAAACAACAA 1-10-1 MOE 1073

147746

10099 10110  TAAAAACAACAA 1-10-1 MOE 1073

398134

10153 10166  TAGCTTAATGTAAC 2-10-2 MOE 1095

147085

10221 10232  TCTACACCAGGT 1-10-1 MOE 961

398134

10261 10274  TAGCTTAATGTAAC 2-10-2 MOE 1095

390030

10278 10289 TTTATAAAACTG 1-10-1 MOE 1074

147084

10328 10339  CTACACCAGGTC 1-10-1 MOE 993

147711

10684 10695  AAGGGCCCTGGG 1-10-1 MOE 1040

398128

11333 11346 CTAAATTTAGTTCA 2-10-2 MOE 911

398128

11340 11353 CTAAATTTAGTTCA 2-10-2 MOE 911

147730

11783 11794  CTTGTCCATCAG 1-10-1 MOE 1121

147731

11789 11800 TTTCCTCTTGTC 1-10-1 MOE 934

147730

11790 11801  CTTGTCCATCAG 1-10-1 MOE 1121

147731

11796 11807 TTTCCTCTTGTC 1-10-1 MOE 934

147707

11960 11971  TAGTCATTATCT 1-10-1 MOE 977

147090

12008 12019  TTCCCTCTACAC 1-10-1 MOE 955

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147091

12009 12020  GTTCCCTCTACA 1-10-1 MOE 1004

147091

12014 12025  GTTCCCTCTACA 1-10-1 MOE 1004

398096

12141 12154 GGAGAAGCGCAGCT 2-10-2 MOE 1015

147735

12143 12154 GGAGAAGCGCAG 1-10-1 MOE 1016

398096

12146 12159 GGAGAAGCGCAGCT 2-10-2 MOE 1015

147735

12148 12159 GGAGAAGCGCAG 1-10-1 MOE 1016

398166

12209 12220  GGGCTTCTTCCA 1-10-1 MOE 1070

398166

12214 12225  GGGCTTCTTCCA 1-10-1 MOE 1070

398135

12303 12316 GACTACATTTTACA 2-10-2 MOE 912

147741

12389 12400  CACCCACTGGTG 1-10-1 MOE 1055

147741

12394 12405  CACCCACTGGTG 1-10-1 MOE 1055

398125

12431 12444 CAGTAAGGAATTTT 2-10-2 MOE 913

147714

12585 12596  TTCTGCTCCCAC 1-10-1 MOE 986

147718

12594 12605  TAATATGACTTG 1-10-1 MOE 998

398125

12612 12625 CAGTAAGGAATTTT 2-10-2 MOE 913

147737

12803 12814  ACAGCCAGGTAG 1-10-1 MOE 1067

147746

12876 12887  TAAAAACAACAA 1-10-1 MOE 1073

147691

12900 12911  GAGGTGGGAAAA 1-10-1 MOE 966

398136

12915 12928  TTGTGACATCTAGG 2-10-2 MOE 1096

147737

12984 12995  ACAGCCAGGTAG 1-10-1 MOE 1067

147746

13057 13068  TAAAAACAACAA 1-10-1 MOE 1073

147691

13081 13092  GAGGTGGGAAAA 1-10-1 MOE 966

398136

13096 13109  TTGTGACATCTAGG 2-10-2 MOE 1096

398138

13254 13267  AACATCAAGCTTGA 2-10-2 MOE 931

398138

13435 13448  AACATCAAGCTTGA 2-10-2 MOE 931

147691

13488 13499  GAGGTGGGAAAA 1-10-1 MOE 966

147681

13659 13670  ATGTCATTAAAC 1-10-1 MOE 965

147691

13669 13680  GAGGTGGGAAAA 1-10-1 MOE 966

389965

13839 13850  CTGCAACATGAT 1-10-1 MOE 1018

389764

13839 13850  CTGCAACATGAT 1-9-2 MOE 1018

147681

13840 13851  ATGTCATTAAAC 1-10-1 MOE 965

389965

14020 14031  CTGCAACATGAT 1-10-1 MOE 1018

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

389764

14020 14031  CTGCAACATGAT 1-9-2 MOE 1018

389948

14067 14078  CCGTTGGACCCC 1-10-1 MOE 915

147736

14123 14134  AGGTAGGAGAAG 1-10-1 MOE 963

389948

14248 14259  CCGTTGGACCCC 1-10-1 MOE 915

147738

14279 14290  TGGGTGGCCGGG 1-10-1 MOE 1069

147736

14304 14315  AGGTAGGAGAAG 1-10-1 MOE 963

147731

14411 14422 TTTCCTCTTGTC 1-10-1 MOE 934

147738

14461 14472  TGGGTGGCCGGG 1-10-1 MOE 1069

147692

14475 14486  CTCACCTTCATG 1-10-1 MOE 1113

147731

14593 14604 TTTCCTCTTGTC 1-10-1 MOE 934

389950

14614 14625  CCCTGAAGGTTC 1-10-1 MOE 1063

147692

14657 14668  CTCACCTTCATG 1-10-1 MOE 1113

147717

14750 14761  ATCTTCAGAGAT 1-10-1 MOE 996

147698

14754 14765 CCCGCCACCACC 1-10-1 MOE 928

389950

14796 14807  CCCTGAAGGTTC 1-10-1 MOE 1063

398112

14863 14876  CAGCCTGGCACCTA 2-10-2 MOE 1072

398121

14875 14888  GTGCCTAGCACAGA 2-10-2 MOE 1097

147717

14932 14943  ATCTTCAGAGAT 1-10-1 MOE 996

398112

15045 15058  CAGCCTGGCACCTA 2-10-2 MOE 1072

398121

15057 15070  GTGCCTAGCACAGA 2-10-2 MOE 1097

147730

15117 15128  CTTGTCCATCAG 1-10-1 MOE 1121

147730

15299 15310  CTTGTCCATCAG 1-10-1 MOE 1121

401407

15339 15352  CAGCTTAGGCAGAG 2-10-2 MOE 983

398167

15556 15567  CAGGCCATGTGG 1-10-1 MOE 1059

147736

16444 16455  AGGTAGGAGAAG 1-10-1 MOE 963

147746

16510 16521  TAAAAACAACAA 1-10-1 MOE 1073

147738

16590 16601  TGGGTGGCCGGG 1-10-1 MOE 1069

147736

16610 16621  AGGTAGGAGAAG 1-10-1 MOE 963

398167

16631 16642  CAGGCCATGTGG 1-10-1 MOE 1059

401411

16657 16670 AGCCGCCTGAAGTG 2-10-2 MOE 999

147746

16676 16687  TAAAAACAACAA 1-10-1 MOE 1073

398144

16745 16758  GACAGCTTCTATAA 2-10-2 MOE 916

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147738

16756 16767  TGGGTGGCCGGG 1-10-1 MOE 1069

398167

16797 16808  CAGGCCATGTGG 1-10-1 MOE 1059

398144

16911 16924  GACAGCTTCTATAA 2-10-2 MOE 916

389965

17096 17107  CTGCAACATGAT 1-10-1 MOE 1018

389764

17096 17107  CTGCAACATGAT 1-9-2 MOE 1018

389965

17264 17275  CTGCAACATGAT 1-10-1 MOE 1018

389764

17264 17275  CTGCAACATGAT 1-9-2 MOE 1018

147709

17406 17417 CCATTTTTATCA 1-10-1 MOE 978

147745

17443 17454  TTGACCAGGAAG 1-10-1 MOE 1058

147746

17497 17508  TAAAAACAACAA 1-10-1 MOE 1073

147720

17589 17600  GATCTCTCGAGT 1-10-1 MOE 1117

147745

17611 17622  TTGACCAGGAAG 1-10-1 MOE 1058

147695

17634 17645  TCATTCCCCACT 1-10-1 MOE 984

147746

17665 17676  TAAAAACAACAA 1-10-1 MOE 1073

147088

17707 17718  CCCTCTACACCA 1-10-1 MOE 1050

147720

17757 17768  GATCTCTCGAGT 1-10-1 MOE 1117

147711

17808 17819  AAGGGCCCTGGG 1-10-1 MOE 1040

147711

17976 17987  AAGGGCCCTGGG 1-10-1 MOE 1040

398139

18049 18062  AGTGACTGACCACA 2-10-2 MOE 917

398139

18217 18230  AGTGACTGACCACA 2-10-2 MOE 917

398140

18596 18609  GTAGCATAGAGCCT 2-10-2 MOE 918

398140

18764 18777  GTAGCATAGAGCCT 2-10-2 MOE 918

398167

18927 18938  CAGGCCATGTGG 1-10-1 MOE 1059

398167

19095 19106  CAGGCCATGTGG 1-10-1 MOE 1059

147724

19147 19158  GAAATTGAGGAA 1-10-1 MOE 1139

147746

19207 19218  TAAAAACAACAA 1-10-1 MOE 1073

147724

19315 19326  GAAATTGAGGAA 1-10-1 MOE 1139

147740

19348 19359  TGTGAGGCTCCA 1-10-1 MOE 1062

147746

19375 19386  TAAAAACAACAA 1-10-1 MOE 1073

147729

19386 19397  GTAAGAGGCAGG 1-10-1 MOE 920

147701

19503 19514  CCATGGCGGGAC 1-10-1 MOE 921

147711

19508 19519  AAGGGCCCTGGG 1-10-1 MOE 1040

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147740

19516 19527  TGTGAGGCTCCA 1-10-1 MOE 1062

147718

19617 19628  TAATATGACTTG 1-10-1 MOE 998

390030

19618 19629 TTTATAAAACTG 1-10-1 MOE 1074

147679

19635 19646  CAAAAGGATCCC 1-10-1 MOE 907

147711

19676 19687  AAGGGCCCTGGG 1-10-1 MOE 1040

147694

19747 19758  CAGCCTACCAGT 1-10-1 MOE 1098

147718

19785 19796  TAATATGACTTG 1-10-1 MOE 998

390030

19786 19797 TTTATAAAACTG 1-10-1 MOE 1074

147679

19803 19814  CAAAAGGATCCC 1-10-1 MOE 907

147698

19852 19863 CCCGCCACCACC 1-10-1 MOE 928

147694

19915 19926  CAGCCTACCAGT 1-10-1 MOE 1098

147704

20011 20022  TTGTTCTTAGGA 1-10-1 MOE 1012

147698

20020 20031 CCCGCCACCACC 1-10-1 MOE 928

398142

20485 20498  CCAGCACACTGGAA 2-10-2 MOE 923

147078

20514 20525  CCTTCCACTGAT 1-10-1 MOE 1044

147079

20515 20526  TCCTTCCACTGA 1-10-1 MOE 1001

147080

20516 20527  CTCCTTCCACTG 1-10-1 MOE 1021

398143

20561 20574  GTCAGTCCCAGCTA 2-10-2 MOE 924

389965

20620 20631  CTGCAACATGAT 1-10-1 MOE 1018

389764

20620 20631  CTGCAACATGAT 1-9-2 MOE 1018

398142

20653 20666  CCAGCACACTGGAA 2-10-2 MOE 923

147078

20682 20693  CCTTCCACTGAT 1-10-1 MOE 1044

147079

20683 20694  TCCTTCCACTGA 1-10-1 MOE 1001

147080

20684 20695  CTCCTTCCACTG 1-10-1 MOE 1021

147080

20704 20715  CTCCTTCCACTG 1-10-1 MOE 1021

147081

20705 20716  GCTCCTTCCACT 1-10-1 MOE 1006

398143

20729 20742  GTCAGTCCCAGCTA 2-10-2 MOE 924

389965

20788 20799  CTGCAACATGAT 1-10-1 MOE 1018

389764

20788 20799  CTGCAACATGAT 1-9-2 MOE 1018

147746

20870 20881  TAAAAACAACAA 1-10-1 MOE 1073

147080

20872 20883  CTCCTTCCACTG 1-10-1 MOE 1021

147081

20873 20884  GCTCCTTCCACT 1-10-1 MOE 1006

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147746

21038 21049  TAAAAACAACAA 1-10-1 MOE 1073

147717

21080 21091  ATCTTCAGAGAT 1-10-1 MOE 996

147076

21222 21233  TTCCACTGATCC 1-10-1 MOE 1029

147076

21390 21401  TTCCACTGATCC 1-10-1 MOE 1029

398094

21441 21454  ATCAGCCAGACAGA 2-10-2 MOE 1010

147746

21465 21476  TAAAAACAACAA 1-10-1 MOE 1073

398094

21609 21622  ATCAGCCAGACAGA 2-10-2 MOE 1010

398169

21610 21621  TCAGCCAGACAG 1-10-1 MOE 909

147746

21633 21644  TAAAAACAACAA 1-10-1 MOE 1073

147738

21884 21895  TGGGTGGCCGGG 1-10-1 MOE 1069

147743

22045 22056  AGGGCTTCCAGT 1-10-1 MOE 1042

147738

22052 22063  TGGGTGGCCGGG 1-10-1 MOE 1069

147683

22107 22118  GCTTACGATTGT 1-10-1 MOE 922

147743

22213 22224  AGGGCTTCCAGT 1-10-1 MOE 1042

147681

22566 22577  ATGTCATTAAAC 1-10-1 MOE 965

389950

22619 22630  CCCTGAAGGTTC 1-10-1 MOE 1063

147681

22734 22745  ATGTCATTAAAC 1-10-1 MOE 965

147736

22759 22770  AGGTAGGAGAAG 1-10-1 MOE 963

389950

22787 22798  CCCTGAAGGTTC 1-10-1 MOE 1063

389949

22794 22805 GCGCGAGCCCGA 1-10-1 MOE 1061

147736

22927 22938  AGGTAGGAGAAG 1-10-1 MOE 963

389949

22962 22973 GCGCGAGCCCGA 1-10-1 MOE 1061

398144

22962 22975  GACAGCTTCTATAA 2-10-2 MOE 916

398142

23008 23021  CCAGCACACTGGAA 2-10-2 MOE 923

147727

23019 23030  CAGTGGACCACA 1-10-1 MOE 1128

398169

23064 23075  TCAGCCAGACAG 1-10-1 MOE 909

398144

23130 23143  GACAGCTTCTATAA 2-10-2 MOE 916

398145

23154 23167  ACATGTCAGTAATT 2-10-2 MOE 1099

398142

23176 23189  CCAGCACACTGGAA 2-10-2 MOE 923

147727

23187 23198  CAGTGGACCACA 1-10-1 MOE 1128

147735

23243 23254 GGAGAAGCGCAG 1-10-1 MOE 1016

398145

23322 23335  ACATGTCAGTAATT 2-10-2 MOE 1099

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147735

23411 23422 GGAGAAGCGCAG 1-10-1 MOE 1016

398146

23478 23491  CTCATGGACACAAA 2-10-2 MOE 1100

398146

23646 23659  CTCATGGACACAAA 2-10-2 MOE 1100

398147

23784 23797  CTACAGGACAATAC 2-10-2 MOE 957

398114

23853 23866  AGGCATATAGCAGA 2-10-2 MOE 1075

398147

23952 23965  CTACAGGACAATAC 2-10-2 MOE 957

398114

24021 24034  AGGCATATAGCAGA 2-10-2 MOE 1075

147702

24319 24330  CTGGTAAATAGC 1-10-1 MOE 898

147702

24487 24498  CTGGTAAATAGC 1-10-1 MOE 898

389965

24543 24554  CTGCAACATGAT 1-10-1 MOE 1018

389764

24543 24554  CTGCAACATGAT 1-9-2 MOE 1018

147713

24602 24613  CTCCCACACCAT 1-10-1 MOE 985

389965

24711 24722  CTGCAACATGAT 1-10-1 MOE 1018

389764

24711 24722  CTGCAACATGAT 1-9-2 MOE 1018

147684

24918 24929  ACCCAGTCAGGG 1-10-1 MOE 964

147684

25086 25097  ACCCAGTCAGGG 1-10-1 MOE 964

398148

25152 25165  TCATAACTATTAAG 2-10-2 MOE 981

398144

25192 25205  GACAGCTTCTATAA 2-10-2 MOE 916

147746

25216 25227  TAAAAACAACAA 1-10-1 MOE 1073

147736

25313 25324  AGGTAGGAGAAG 1-10-1 MOE 963

398148

25320 25333  TCATAACTATTAAG 2-10-2 MOE 981

398143

25337 25350  GTCAGTCCCAGCTA 2-10-2 MOE 924

398144

25360 25373  GACAGCTTCTATAA 2-10-2 MOE 916

147746

25384 25395  TAAAAACAACAA 1-10-1 MOE 1073

147691

25442 25453  GAGGTGGGAAAA 1-10-1 MOE 966

147736

25481 25492  AGGTAGGAGAAG 1-10-1 MOE 963

398130

25504 25517  TTAGTATGACAGCT 2-10-2 MOE 925

147691

25610 25621  GAGGTGGGAAAA 1-10-1 MOE 966

147721

25662 25673  AATGCAGGATCT 1-10-1 MOE 1118

398130

25672 25685  TTAGTATGACAGCT 2-10-2 MOE 925

147688

25750 25761  TCCCAAACAAAT 1-10-1 MOE 990

147746

25810 25821  TAAAAACAACAA 1-10-1 MOE 1073

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147721

25830 25841  AATGCAGGATCT 1-10-1 MOE 1118

147688

25918 25929  TCCCAAACAAAT 1-10-1 MOE 990

147746

25978 25989  TAAAAACAACAA 1-10-1 MOE 1073

147746

26172 26183  TAAAAACAACAA 1-10-1 MOE 1073

147746

26340 26351  TAAAAACAACAA 1-10-1 MOE 1073

398149

26492 26505 GGAAGTTTTCAAGT 2-10-2 MOE 1101

398150

26526 26539  GAAT-CTGGAGGTAA 2-10-2 MOE 1102

398149

26641 26654 GGAAGTTTTCAAGT 2-10-2 MOE 1101

398150

26675 26688  GAATCTGGAGGTAA 2-10-2 MOE 1102

147729

26712 26723  GTAAGAGGCAGG 1-10-1 MOE 920

398151

26718 26731  TCAGTGTAGGAAGA 2-10-2 MOE 926

147729

26861 26872  GTAAGAGGCAGG 1-10-1 MOE 920

398151

26867 26880  TCAGTGTAGGAAGA 2-10-2 MOE 926

147728

26917 26928 GCCAGACAGAAG 1-10-1 MOE 1013

147728

27066 27077 GCCAGACAGAAG 1-10-1 MOE 1013

147076

27258 27269  TTCCACTGATCC 1-10-1 MOE 1029

147731

27267 27278 TTTCCTCTTGTC 1-10-1 MOE 934

147076

27407 27418  TTCCACTGATCC 1-10-1 MOE 1029

147731

27416 27427 TTTCCTCTTGTC 1-10-1 MOE 934

398152

27559 27572  TGAATATACAGATG 2-10-2 MOE 927

398152

27708 27721  TGAATATACAGATG 2-10-2 MOE 927

147696

28265 28276  TGGATGATTGGC 1-10-1 MOE 906

147696

28414 28425  TGGATGATTGGC 1-10-1 MOE 906

147698

28481 28492 CCCGCCACCACC 1-10-1 MOE 928

147720

28662 28673  GATCTCTCGAGT 1-10-1 MOE 1117

389965

28714 28725  CTGCAACATGAT 1-10-1 MOE 1018

389764

28714 28725  CTGCAACATGAT 1-9-2 MOE 1018

389965

28861 28872  CTGCAACATGAT 1-10-1 MOE 1018

389764

28861 28872  CTGCAACATGAT 1-9-2 MOE 1018

398153

28980 28993 ATTTCTCTTACAGG 2-10-2 MOE 948

398153

29126 29139 ATTTCTCTTACAGG 2-10-2 MOE 948

147719

29570 29581  CCAACTCCAACT 1-10-1 MOE 1116

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398154

29692 29705  AGCCCCTTGGCCGT 2-10-2 MOE 1103

147719

29715 29726  CCAACTCCAACT 1-10-1 MOE 1116

398155

29785 29798 TGTTTTTACACAGA 2-10-2 MOE 970

398154

29837 29850  AGCCCCTTGGCCGT 2-10-2 MOE 1103

401384

29905 29918  TGAACACATCACTA 2-10-2 MOE 933

398155

29930 29943 TGTTTTTACACAGA 2-10-2 MOE 970

390030

29945 29956 TTTATAAAACTG 1-10-1 MOE 1074

390030

30090 30101 TTTATAAAACTG 1-10-1 MOE 1074

398156

30141 30154  GAATACTTCAAATC 2-10-2 MOE 1104

398156

30286 30299  GAATACTTCAAATC 2-10-2 MOE 1104

389948

30384 30395  CCGTTGGACCCC 1-10-1 MOE 915

389948

30530 30541  CCGTTGGACCCC 1-10-1 MOE 915

398142

30591 30604  CCAGCACACTGGAA 2-10-2 MOE 923

147744

30654 30665  AGGAAGGGCTTC 1-10-1 MOE 1043

147093

30689 30700  TTGTTCCCTCTA 1-10-1 MOE 929

398142

30738 30751  CCAGCACACTGGAA 2-10-2 MOE 923

147744

30801 30812  AGGAAGGGCTTC 1-10-1 MOE 1043

398168

31082 31093 TCGGACTTTGAA 1-10-1 MOE 1008

147746

31105 31116  TAAAAACAACAA 1-10-1 MOE 1073

398168

31230 31241 TCGGACTTTGAA 1-10-1 MOE 1008

390030

31329 31340 TTTATAAAACTG 1-10-1 MOE 1074

147736

31458 31469  AGGTAGGAGAAG 1-10-1 MOE 963

390030

31477 31488 TTTATAAAACTG 1-10-1 MOE 1074

147736

31606 31617  AGGTAGGAGAAG 1-10-1 MOE 963

147698

31713 31724 CCCGCCACCACC 1-10-1 MOE 928

384545

31829 31840  CAAGTAGGATGT 1-10-1 MOE 951

147698

31861 31872 CCCGCCACCACC 1-10-1 MOE 928

147723

31941 31952  GACTCCAAAGTC 1-10-1 MOE 892

384545

31977 31988  CAAGTAGGATGT 1-10-1 MOE 951

147692

32061 32072  CTCACCTTCATG 1-10-1 MOE 1113

147723

32089 32100  GACTCCAAAGTC 1-10-1 MOE 892

147692

32209 32220  CTCACCTTCATG 1-10-1 MOE 1113

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147089

32535 32546  TCCCTCTACACC 1-10-1 MOE 956

401396

32569 32582  TGCAGGATGTTGAG 2-10-2 MOE 945

147730

32714 32725  CTTGTCCATCAG 1-10-1 MOE 1121

398165

32854 32865  GTTCTTAGGAAG 1-10-1 MOE 968

147730

32862 32873  CTTGTCCATCAG 1-10-1 MOE 1121

389950

32949 32960  CCCTGAAGGTTC 1-10-1 MOE 1063

398165

33002 33013  GTTCTTAGGAAG 1-10-1 MOE 968

147736

33012 33023  AGGTAGGAGAAG 1-10-1 MOE 963

368352

33056 33069  CTGATCCTGCACTG 2-10-2 MOE 1105

147081

33073 33084  GCTCCTTCCACT 1-10-1 MOE 1006

368360

33073 33086  AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

33074 33085  AGCTCCTTCCAC 1-10-1 MOE 1036

389950

33097 33108  CCCTGAAGGTTC 1-10-1 MOE 1063

147736

33160 33171  AGGTAGGAGAAG 1-10-1 MOE 963

368352

33204 33217  CTGATCCTGCACTG 2-10-2 MOE 1105

147081

33221 33232  GCTCCTTCCACT 1-10-1 MOE 1006

147082

33222 33233  AGCTCCTTCCAC 1-10-1 MOE 1036

398138

33244 33257  AACATCAAGCTTGA 2-10-2 MOE 931

147746

33250 33261  TAAAAACAACAA 1-10-1 MOE 1073

398138

33392 33405  AACATCAAGCTTGA 2-10-2 MOE 931

147746

33398 33409  TAAAAACAACAA 1-10-1 MOE 1073

147732

33652 33663 GGGTCTTTCCTC 1-10-1 MOE 1122

147724

33733 33744  GAAATTGAGGAA 1-10-1 MOE 1139

147732

33800 33811 GGGTCTTTCCTC 1-10-1 MOE 1122

147724

33881 33892  GAAATTGAGGAA 1-10-1 MOE 1139

147719

33976 33987  CCAACTCCAACT 1-10-1 MOE 1116

147746

34034 34045  TAAAAACAACAA 1-10-1 MOE 1073

398129

34045 34058 TTTGAGGAGCTATT 2-10-2 MOE 1106

147719

34124 34135  CCAACTCCAACT 1-10-1 MOE 1116

147721

34156 34167  AATGCAGGATCT 1-10-1 MOE 1118

398129

34193 34206 TTTGAGGAGCTATT 2-10-2 MOE 1106

147721

34304 34315  AATGCAGGATCT 1-10-1 MOE 1118

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147746

34606 34617  TAAAAACAACAA 1-10-1 MOE 1073

398165

34704 34715  GTTCTTAGGAAG 1-10-1 MOE 968

147746

34754 34765  TAAAAACAACAA 1-10-1 MOE 1073

398165

34852 34863  GTTCTTAGGAAG 1-10-1 MOE 968

147717

34893 34904  ATCTTCAGAGAT 1-10-1 MOE 996

147719

34976 34987  CCAACTCCAACT 1-10-1 MOE 1116

147092

34987 34998  TGTTCCCTCTAC 1-10-1 MOE 901

147719

35124 35135  CCAACTCCAACT 1-10-1 MOE 1116

147092

35135 35146  TGTTCCCTCTAC 1-10-1 MOE 901

147736

35248 35259  AGGTAGGAGAAG 1-10-1 MOE 963

147738

35391 35402  TGGGTGGCCGGG 1-10-1 MOE 1069

147736

35396 35407  AGGTAGGAGAAG 1-10-1 MOE 963

147738

35539 35550  TGGGTGGCCGGG 1-10-1 MOE 1069

147691

35554 35565  GAGGTGGGAAAA 1-10-1 MOE 966

147691

35702 35713  GAGGTGGGAAAA 1-10-1 MOE 966

147746

35814 35825  TAAAAACAACAA 1-10-1 MOE 1073

147733

35889 35900  TTCTTGATGTCC 1-10-1 MOE 891

147733

35923 35934  TTCTTGATGTCC 1-10-1 MOE 891

147746

35962 35973  TAAAAACAACAA 1-10-1 MOE 1073

147726

35978 35989  TGACTCTCGGAC 1-10-1 MOE 1120

147733

36037 36048  TTCTTGATGTCC 1-10-1 MOE 891

147733

36071 36082  TTCTTGATGTCC 1-10-1 MOE 891

147726

36126 36137  TGACTCTCGGAC 1-10-1 MOE 1120

147736

36359 36370  AGGTAGGAGAAG 1-10-1 MOE 963

147691

36360 36371  GAGGTGGGAAAA 1-10-1 MOE 966

147736

36507 36518  AGGTAGGAGAAG 1-10-1 MOE 963

147691

36508 36519  GAGGTGGGAAAA 1-10-1 MOE 966

147746

36564 36575  TAAAAACAACAA 1-10-1 MOE 1073

147723

36575 36586  GACTCCAAAGTC 1-10-1 MOE 892

147731

36620 36631 TTTCCTCTTGTC 1-10-1 MOE 934

147723

36723 36734  GACTCCAAAGTC 1-10-1 MOE 892

147731

36768 36779 TTTCCTCTTGTC 1-10-1 MOE 934

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398169

37174 37185  TCAGCCAGACAG 1-10-1 MOE 909

147688

37380 37391  TCCCAAACAAAT 1-10-1 MOE 990

147688

37528 37539  TCCCAAACAAAT 1-10-1 MOE 990

147714

37881 37892  TTCTGCTCCCAC 1-10-1 MOE 986

147714

38029 38040  TTGTGCTCCCAC 1-10-1 MOE 986

147681

38364 38375  ATGTCATTAAAC 1-10-1 MOE 965

147736

38766 38777  AGGTAGGAGAAG 1-10-1 MOE 963

147738

38909 38920  TGGGTGGCCGGG 1-10-1 MOE 1069

147736

38914 38925  AGGTAGGAGAAG 1-10-1 MOE 963

147738

39057 39068  TGGGTGGCCGGG 1-10-1 MOE 1069

390030

39249 39260 TTTATAAAACTG 1-10-1 MOE 1074

390030

39397 39408 TTTATAAAACTG 1-10-1 MOE 1074

147717

39545 39556  ATCTTCAGAGAT 1-10-1 MOE 996

147717

39693 39704  ATCTTCAGAGAT 1-10-1 MOE 996

147746

39729 39740  TAAAAACAACAA 1-10-1 MOE 1073

147746

39789 39800  TAAAAACAACAA 1-10-1 MOE 1073

147691

39829 39840  GAGGTGGGAAAA 1-10-1 MOE 966

147746

39877 39888  TAAAAACAACAA 1-10-1 MOE 1073

147691

39977 39988  GAGGTGGGAAAA 1-10-1 MOE 966

147727

39983 39994  CAGTGGACCACA 1-10-1 MOE 1128

147727

40131 40142  CAGTGGACCACA 1-10-1 MOE 1128

147746

40333 40344  TAAAAACAACAA 1-10-1 MOE 1073

147719

40457 40468  CCAACTCCAACT 1-10-1 MOE 1116

147679

40467 40478  CAAAAGGATCCC 1-10-1 MOE 907

147746

40478 40489  TAAAAACAACAA 1-10-1 MOE 1073

147741

40565 40576  CACCCACTGGTG 1-10-1 MOE 1055

398166

40589 40600  GGGCTTCTTCCA 1-10-1 MOE 1070

147719

40605 40616  CCAACTCCAACT 1-10-1 MOE 1116

147679

40615 40626  CAAAAGGATCCC 1-10-1 MOE 907

147746

40626 40637  TAAAAACAACAA 1-10-1 MOE 1073

147735

40662 40673 GGAGAAGCGCAG 1-10-1 MOE 1016

147746

40706 40717  TAAAAACAACAA 1-10-1 MOE 1073

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147741

40713 40724  CACCCACTGGTG 1-10-1 MOE 1055

398166

40737 40748  GGGCTTCTTCCA 1-10-1 MOE 1070

147735

40810 40821 GGAGAAGCGCAG 1-10-1 MOE 1016

147746

40854 40865  TAAAAACAACAA 1-10-1 MOE 1073

147718

41218 41229  TAATATGACTTG 1-10-1 MOE 998

147717

41221 41232  ATCTTCAGAGAT 1-10-1 MOE 996

147717

41369 41380  ATCTTCAGAGAT 1-10-1 MOE 996

147723

41627 41638  GACTCCAAAGTC 1-10-1 MOE 892

147717

41747 41758  ATCTTCAGAGAT 1-10-1 MOE 996

147723

41775 41786  GACTCCAAAGTC 1-10-1 MOE 892

390030

41908 41919 TTTATAAAACTG 1-10-1 MOE 1074

390030

42056 42067 TTTATAAAACTG 1-10-1 MOE 1074

398153

42157 42170 ATTTCTCTTACAGG 2-10-2 MOE 948

398153

42305 42318 ATTTCTCTTACAGG 2-10-2 MOE 948

147690

42423 42434  TGAAGTTAATTC 1-10-1 MOE 1138

147695

42521 42532  TCATTCCCCACT 1-10-1 MOE 984

147710

42543 42554  TATAGCTCCTCT 1-10-1 MOE 994

147690

42571 42582  TGAAGTTAATTC 1-10-1 MOE 1138

147695

42669 42680  TCATTCCCCACT 1-10-1 MOE 984

147078

43321 43332  CCTTCCACTGAT 1-10-1 MOE 1044

147079

43322 43333  TCCTTCCACTGA 1-10-1 MOE 1001

147716

43329 43340  TTAACGAGCCTT 1-10-1 MOE 949

147078

43469 43480  CCTTCCACTGAT 1-10-1 MOE 1044

147079

43470 43481  TCCTTCCACTGA 1-10-1 MOE 1001

147080

43471 43482  CTCCTTCCACTG 1-10-1 MOE 1021

398102

43837 43850 CTACCRGAGGATTT 2-10-2 MOE 899

147074

43848 43859  CCACTGATCCTG 1-10-1 MOE 845

401408

43871 43884  CAATGAAGCACAGG 2-10-2 MOE 989

398102

43985 43998 CTACCTGAGGATTT 2-10-2 MOE 899

147736

44137 44148  AGGTAGGAGAAG 1-10-1 MOE 963

147746

44140 44151  TAAAAACAACAA 1-10-1 MOE 1073

147687

44206 44217 CGACACGGGAAC 1-10-1 MOE 950

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147743

44223 44234  AGGGCTTCCAGT 1-10-1 MOE 1042

384545

44242 44253  CAAGTAGGATGT 1-10-1 MOE 951

147736

44285 44296  AGGTAGGAGAAG 1-10-1 MOE 963

147743

44371 44382  AGGGCTTCCAGT 1-10-1 MOE 1042

384545

44390 44401  CAAGTAGGATGT 1-10-1 MOE 951

147728

44589 44600 GCCAGACAGAAG 1-10-1 MOE 1013

389948

44628 44639  CCGTTGGACCCC 1-10-1 MOE 915

147720

44703 44714  GATCTCTCGAGT 1-10-1 MOE 1117

147728

44729 44740 GCCAGACAGAAG 1-10-1 MOE 1013

147728

44737 44748 GCCAGACAGAAG 1-10-1 MOE 1013

389948

44776 44787  CCGTTGGACCCC 1-10-1 MOE 915

147720

44851 44862  GATCTCTCGAGT 1-10-1 MOE 1117

398110

44861 44874 GTTCCCTTTGCAGG 2-10-2 MOE 952

147728

44877 44888 GCCAGACAGAAG 1-10-1 MOE 1013

147705

45092 45103 CGGTTTTTGTTC 1-10-1 MOE 1002

147705

45240 45251 CGGTTTTTGTTC 1-10-1 MOE 1002

147681

45337 45348  ATGTCATTAAAC 1-10-1 MOE 965

147681

45485 45496  ATGTCATTAAAC 1-10-1 MOE 965

147096

45660 45671  TTGTTGTTCCCT 1-10-1 MOE 1107

147096

45808 45819  TTGTTGTTCCCT 1-10-1 MOE 1107

368368

45976 45989  TCCACTGATCCTTA 2-10-2 MOE 1127

147074

45977 45988  CCACTGATCCTG 1-10-1 MOE 845

147075

45978 45989  TCCACTGATCCT 1-10-1 MOE 1026

147076

45979 45990  TTCCACTGATCC 1-10-1 MOE 1029

368368

46124 46137  TCCACTGATCCTTA 2-10-2 MOE 1127

147075

46126 46137  TCCACTGATCCT 1-10-1 MOE 1026

147076

46127 46138  TTCCACTGATCC 1-10-1 MOE 1029

147705

46555 46566 CGGTTTTTGTTC 1-10-1 MOE 1002

147714

46685 46696  TTCTGCTCCCAC 1-10-1 MOE 986

147705

46703 46714 CGGTTTTTGTTC 1-10-1 MOE 1002

147714

46833 46844  TTCTGCTCCCAC 1-10-1 MOE 986

390030

47007 47018 TTTATAAAACTG 1-10-1 MOE 1074

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147746

47023 47034  TAAAAACAACAA 1-10-1 MOE 1073

147746

47171 47182  TAAAAACAACAA 1-10-1 MOE 1073

147085

47607 47618  TCTACACCAGGT 1-10-1 MOE 961

147746

47609 47620  TAAAAACAACAA 1-10-1 MOE 1073

147089

47611 47622  TCCCTCTACACC 1-10-1 MOE 956

147091

47613 47624  GTTCCCTCTACA 1-10-1 MOE 1004

401384

47689 47702  TGAACACATCACTA 2-10-2 MOE 933

147691

47729 47740  GAGGTGGGAAAA 1-10-1 MOE 966

147085

47755 47766  TCTACACCAGGT 1-10-1 MOE 961

147087

47757 47768  CCTCTACACCAG 1-10-1 MOE 982

147090

47760 47771  TTCCCTCTACAC 1-10-1 MOE 955

147091

47761 47772  GTTCCCTCTACA 1-10-1 MOE 1004

147099

47770 47781  GAGTTGTTGTTC 1-10-1 MOE 1108

147100

47771 47782  CGAGTTGTTGTT 1-10-1 MOE 1109

390030

47847 47858 TTTATAAAACTG 1-10-1 MOE 1074

147691

47877 47888  GAGGTGGGAAAA 1-10-1 MOE 966

147099

47918 47929  GAGTTGTTGTTC 1-10-1 MOE 1108

147100

47919 47930  CGAGTTGTTGTT 1-10-1 MOE 1109

390030

47995 48006 TTTATAAAACTG 1-10-1 MOE 1074

147074

48222 48233  CCACTGATCCTG 1-10-1 MOE 845

147731

48340 48351 TTTCCTCTTGTC 1-10-1 MOE 934

147691

48393 48404  GAGGTGGGAAAA 1-10-1 MOE 966

147731

48488 48499 TTTCCTCTTGTC 1-10-1 MOE 934

147691

43541 48552  GAGGTGGGAAAA 1-10-1 MOE 966

398147

48887 48900  CTACAGGACAATAC 2-10-2 MOE 957

398147

49035 49048  CTACAGGACAATAC 2-10-2 MOE 957

147074

49525 49536  CCACTGATCCTG 1-10-1 MOE 845

398168

49742 49753 TCGGACTTTGAA 1-10-1 MOE 1008

384545

49858 49869  CAAGTAGGATGT 1-10-1 MOE 951

398168

49890 49901 TCGGACTTTGAA 1-10-1 MOE 1008

147724

49974 49985  GAAATTGAGGAA 1-10-1 MOE 1139

384545

50006 50017  CAAGTAGGATGT 1-10-1 MOE 951

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147689

50084 50095  CAGAGAAGGTCT 1-10-1 MOE 987

147687

50102 50113 CGACACGGGAAC 1-10-1 MOE 950

147724

50122 50133  GAAATTGAGGAA 1-10-1 MOE 1139

147687

50250 50261 CGACACGGGAAC 1-10-1 MOE 950

398117

50389 50402 TTTCCACTTGGGTG 2-10-2 MOE 960

147736

50436 50447  AGGTAGGAGAAG 1-10-1 MOE 963

147736

50582 50593  AGGTAGGAGAAG 1-10-1 MOE 963

398168

50703 50714 TCGGACTTTGAA 1-10-1 MOE 1008

401397

50822 50835  CTGGTCAGCATTGA 2-10-2 MOE 946

147746

51019 51030  TAAAAACAACAA 1-10-1 MOE 1073

147708

51101 51112  TTGATATAGTCA 1-10-1 MOE 997

147746

51165 51176  TAAAAACAACAA 1-10-1 MOE 1073

147746

51185 51196  TAAAAACAACAA 1-10-1 MOE 1073

147708

51247 51258  TTGATATAGTCA 1-10-1 MOE 997

147081

51287 51298  GCTCCTTCCACT 1-10-1 MOE 1006

147082

51288 51299  AGCTCCTTCCAC 1-10-1 MOE 1036

147746

51324 51335  TAAAAACAACAA 1-10-1 MOE 1073

147746

51331 51342  TAAAAACAACAA 1-10-1 MOE 1073

147728

51376 51387 GCCAGACAGAAG 1-10-1 MOE 1013

147729

51406 51417  GTAAGAGGCAGG 1-10-1 MOE 920

147081

51433 51444  GCTCCTTCCACT 1-10-1 MOE 1006

147082

51434 51445  AGCTCCTTCCAC 1-10-1 MOE 1036

147728

51492 51503 GCCAGACAGAAG 1-10-1 MOE 1013

147728

51522 51533 GCCAGACAGAAG 1-10-1 MOE 1013

147729

51552 51563  GTAAGAGGCAGG 1-10-1 MOE 920

368360

51633 51646  AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

51634 51645  AGCTCCTTCCAC 1-10-1 MOE 1036

368361

51635 51648  GAAAGCTCCTTCCA 2-10-2 MOE 962

147728

51638 51649 GCCAGACAGAAG 1-10-1 MOE 1013

147695

51644 51655  TCATTCCCCACT 1-10-1 MOE 984

147736

51713 51724  AGGTAGGAGAAG 1-10-1 MOE 963

147684

51721 51732  ACCCAGTCAGGG 1-10-1 MOE 964

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147081

51779 51790  GCTCCTTCCACT 1-10-1 MOE 1006

368360

51779 51792  AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

51780 51791  AGCTCCTTCCAC 1-10-1 MOE 1036

368361

51781 51794  GAAAGCTCCTTCCA 2-10-2 MOE 962

147695

51790 51801  TCATTCCCCACT 1-10-1 MOE 984

147736

51859 51870  AGGTAGGAGAAG 1-10-1 MOE 963

147077

51988 51999  CTTCCACTGATC 1-10-1 MOE 1047

147079

51990 52001  TCCTTCCACTGA 1-10-1 MOE 1001

147746

52064 52075  TAAAAACAACAA 1-10-1 MOE 1073

147681

52085 52096  ATGTCATTAAAC 1-10-1 MOE 965

147077

52134 52145  CTTCCACTGATC 1-10-1 MOE 1047

147079

52136 52147  TCCTTCCACTGA 1-10-1 MOE 1001

147691

52166 52177  GAGGTGGGAAAA 1-10-1 MOE 966

147719

52252 52263  CCAACTCCAACT 1-10-1 MOE 1116

147691

52312 52323  GAGGTGGGAAAA 1-10-1 MOE 966

147719

52398 52409  CCAACTCCAACT 1-10-1 MOE 1116

147728

52428 52439 GCCAGACAGAAG 1-10-1 MOE 1013

147729

52483 52494  GTAAGAGGCAGG 1-10-1 MOE 920

398167

52527 52538  CAGGCCATGTGG 1-10-1 MOE 1059

147682

52571 52582  CGGGTACTATGG 1-10-1 MOE 992

147728

52574 52585 GCCAGACAGAAG 1-10-1 MOE 1013

147724

52615 52626  GAAATTGAGGAA 1-10-1 MOE 1139

147729

52629 52640  GTAAGAGGCAGG 1-10-1 MOE 920

147703

52670 52681  TGGCTTCATGTC 1-10-1 MOE 971

398167

52673 52684  CAGGCCATGTGG 1-10-1 MOE 1059

398165

52708 52719  GTTCTTAGGAAG 1-10-1 MOE 968

147704

52710 52721  TTGTTCTTAGGA 1-10-1 MOE 1012

147705

52716 52727 CGGTTTTTGTTC 1-10-1 MOE 1002

147724

52761 52772  GAAATTGAGGAA 1-10-1 MOE 1139

398167

52762 52773  CAGGCCATGTGG 1-10-1 MOE 1059

147703

52816 52827  TGGCTTCATGTC 1-10-1 MOE 971

398165

52854 52865  GTTCTTAGGAAG 1-10-1 MOE 968

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147704

52856 52867  TTGTTCTTAGGA 1-10-1 MOE 1012

147705

52862 52873 CGGTTTTTGTTC 1-10-1 MOE 1002

398167

52908 52919  CAGGCCATGTGG 1-10-1 MOE 1059

147689

53063 53074  CAGAGAAGGTCT 1-10-1 MOE 987

147727

53111 53122  CAGTGGACCACA 1-10-1 MOE 1128

147727

53158 53169  CAGTGGACCACA 1-10-1 MOE 1128

147689

53209 53220  CAGAGAAGGTCT 1-10-1 MOE 987

147727

53257 53268  CAGTGGACCACA 1-10-1 MOE 1128

147727

53304 53315  CAGTGGACCACA 1-10-1 MOE 1128

147680

53638 53649  GTATGCACTGCT 1-10-1 MOE 988

147722

53650 53661  AAAGTCAGGCCA 1-10-1 MOE 1130

147083

53703 53714  TACACCAGGTCA 1-10-1 MOE 973

147085

53705 53716  TCTACACCAGGT 1-10-1 MOE 961

147086

53706 53717  CTCTACACCAGG 1-10-1 MOE 969

398167

53724 53735  CAGGCCATGTGG 1-10-1 MOE 1059

147684

53747 53758  ACCCAGTCAGGG 1-10-1 MOE 964

147680

53784 53795  GTATGCACTGCT 1-10-1 MOE 988

147722

53796 53807  AAAGTCAGGCCA 1-10-1 MOE 1130

147085

53851 53862  TCTACACCAGGT 1-10-1 MOE 961

398167

53870 53881  CAGGCCATGTGG 1-10-1 MOE 1059

147684

53893 53904  ACCCAGTCAGGG 1-10-1 MOE 964

398155

54026 54039 TGTTTTTACACAGA 2-10-2 MOE 970

147703

54137 54148  TGGCTTCATGTC 1-10-1 MOE 971

398155

54172 54185 TGIIII1ACACAGA 2-10-2 MOE 970

147705

54275 54286 CGGTTTTTGTTC 1-10-1 MOE 1002

147703

54283 54294  TGGCTTCATGTC 1-10-1 MOE 971

147705

54421 54432 CGGTTTTTGTTC 1-10-1 MOE 1002

147727

54853 54864  CAGTGGACCACA 1-10-1 MOE 1128

398165

54963 54974  GTTCTTAGGAAG 1-10-1 MOE 968

398090

54963 54976  TTGTTCTTAGGAAG 2-10-2 MOE 972

147704

54965 54976  TTGTTCTTAGGA 1-10-1 MOE 1012

147705

54971 54982 CGGTTTTTGTTC 1-10-1 MOE 1002

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147727

54999 55010  CAGTGGACCACA 1-10-1 MOE 1128

398165

55109 55120  GTTCTTAGGAAG 1-10-1 MOE 968

147704

55111 55122  TTGTTCTTAGGA 1-10-1 MOE 1012

147705

55117 55128 CGGTTTTTGTTC 1-10-1 MOE 1002

147083

55352 55363  TACACCAGGTCA 1-10-1 MOE 973

147705

55378 55389 CGGTTTTTGTTC 1-10-1 MOE 1002

147705

55524 55535 CGGTTTTTGTTC 1-10-1 MOE 1002

147712

55819 55830  ACACCATCTCCC 1-10-1 MOE 1005

147712

55965 55976  ACACCATCTCCC 1-10-1 MOE 1005

147733

56289 56300  TTCTTGATGTCC 1-10-1 MOE 891

147707

56300 56311  TAGTCATTATCT 1-10-1 MOE 977

147708

56306 56317  TTGATATAGTCA 1-10-1 MOE 997

390030

56321 56332 TTTATAAAACTG 1-10-1 MOE 1074

147081

56333 56344  GCTCCTTCCACT 1-10-1 MOE 1006

398166

56335 56346  GGGCTTCTTCCA 1-10-1 MOE 1070

147733

56435 56446  TTCTTGATGTCC 1-10-1 MOE 891

147707

56446 56457  TAGTCATTATCT 1-10-1 MOE 977

147708

56452 56463  TTGATATAGTCA 1-10-1 MOE 997

390030

56467 56478 TTTATAAAACTG 1-10-1 MOE 1074

147081

56479 56490  GCTCCTTCCACT 1-10-1 MOE 1006

398091

56479 56492  GGGCTTCTTCCATT 2-10-2 MOE 979

398166

56481 56492  GGGCTTCTTCCA 1-10-1 MOE 1070

368366

56518 56531  CTGATCCTTAGAAG 2-10-2 MOE 1019

147743

57612 57623  AGGGCTTCCAGT 1-10-1 MOE 1042

147700

57709 57720  GCGCTAGGCCGC 1-10-1 MOE 1110

147743

57758 57769  AGGGCTTCCAGT 1-10-1 MOE 1042

147700

57855 57866  GCGCTAGGCCGC 1-10-1 MOE 1110

398093

57963 57976 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

57965 57976 TCGGACTTTGAA 1-10-1 MOE 1008

147698

58105 58116 CCCGCCACCACC 1-10-1 MOE 928

398093

58109 58122 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

58111 58122 TCGGACTTTGAA 1-10-1 MOE 1008

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147698

58251 58262 CCCGCCACCACC 1-10-1 MOE 928

147735

58279 58290 GGAGAAGCGCAG 1-10-1 MOE 1016

147735

58425 58436 GGAGAAGCGCAG 1-10-1 MOE 1016

404135

58946 58959 CATTTCCATGGCCA 2-10-2 MOE 1056

390030

59326 59337 TTTATAAAACTG 1-10-1 MOE 1074

147711

59357 59368  AAGGGCCCTGGG 1-10-1 MOE 1040

147743

59382 59393  AGGGCTTCCAGT 1-10-1 MOE 1042

147711

59503 59514  AAGGGCCCTGGG 1-10-1 MOE 1040

147743

59528 59539  AGGGCTTCCAGT 1-10-1 MOE 1042

147695

59576 59587  TCATTCCCCACT 1-10-1 MOE 984

147713

59716 59727  CTCCCACACCAT 1-10-1 MOE 985

147714

59721 59732  TTCTGCTCCCAC 1-10-1 MOE 986

147715

59746 59757  GTTGAGCATGAC 1-10-1 MOE 1077

147716

59771 59782  TTAACGAGCCTT 1-10-1 MOE 949

147712

59857 59868  ACACCATCTCCC 1-10-1 MOE 1005

147714

59867 59878  TTCTGCTCCCAC 1-10-1 MOE 986

147715

59892 59903  GTTGAGCATGAC 1-10-1 MOE 1077

147716

59917 59928  TTAACGAGCCTT 1-10-1 MOE 949

390030

59993 60004 TTTATAAAACTG 1-10-1 MOE 1074

147690

60270 60281  TGAAGTTAATTC 1-10-1 MOE 1138

389949

60325 60336 GCGCGAGCCCGA 1-10-1 MOE 1061

147690

60416 60427  TGAAGTTAATTC 1-10-1 MOE 1138

389949

60471 60482 GCGCGAGCCCGA 1-10-1 MOE 1061

147746

60619 60630  TAAAAACAACAA 1-10-1 MOE 1073

384545

60676 60687  CAAGTAGGATGT 1-10-1 MOE 951

147746

60765 60776  TAAAAACAACAA 1-10-1 MOE 1073

384545

60822 60833  CAAGTAGGATGT 1-10-1 MOE 951

147689

60967 60978  CAGAGAAGGTCT 1-10-1 MOE 987

147689

61008 61019  CAGAGAAGGTCT 1-10-1 MOE 987

147689

61049 61060  CAGAGAAGGTCT 1-10-1 MOE 987

398105

61121 61134  TGCACAGGCAGGTT 2-10-2 MOE 1066

147689

61154 61165  CAGAGAAGGTCT 1-10-1 MOE 987

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147689

61195 61206  CAGAGAAGGTCT 1-10-1 MOE 987

398105

61267 61280  TGCACAGGCAGGTT 2-10-2 MOE 1066

147692

61365 61376  CTCACCTTCATG 1-10-1 MOE 1113

147692

61511 61522  CTCACCTTCATG 1-10-1 MOE 1113

147680

61619 61630  GTATGCACTGCT 1-10-1 MOE 988

147078

61755 61766  CCTTCCACTGAT 1-10-1 MOE 1044

147079

61756 61767  TCCTTCCACTGA 1-10-1 MOE 1001

147080

61757 61768  CTCCTTCCACTG 1-10-1 MOE 1021

147078

61901 61912  CCTTCCACTGAT 1-10-1 MOE 1044

147079

61902 61913  TCCTTCCACTGA 1-10-1 MOE 1001

147080

61903 61914  CTCCTTCCACTG 1-10-1 MOE 1021

147088

62361 62372  CCCTCTACACCA 1-10-1 MOE 1050

401384

62573 62586  TGAACACATCACTA 2-10-2 MOE 933

147688

62697 62708  TCCCAAACAAAT 1-10-1 MOE 990

147746

63102 63113  TAAAAACAACAA 1-10-1 MOE 1073

147721

63225 63236  AATGCAGGATCT 1-10-1 MOE 1118

147742

63226 63237  AACTTCAGTGTC 1-10-1 MOE 1041

147746

63248 63259  TAAAAACAACAA 1-10-1 MOE 1073

147682

63337 63348  CGGGTACTATGG 1-10-1 MOE 992

147721

63371 63382  AATGCAGGATCT 1-10-1 MOE 1118

147742

63372 63383  AACTTCAGTGTC 1-10-1 MOE 1041

147688

63401 63412  TCCCAAACAAAT 1-10-1 MOE 990

147097

63449 63460  GTTGTTGTTCCC 1-10-1 MOE 1111

147098

63450 63461  AGTTGTTGTTCC 1-10-1 MOE 1112

401409

63458 63471  ATTCTTAACACAGA 2-10-2 MOE 991

147084

63531 63542  CTACACCAGGTC 1-10-1 MOE 993

147688

63547 63558  TCCCAAACAAAT 1-10-1 MOE 990

147097

63595 63606  GTTGTTGTTCCC 1-10-1 MOE 1111

147098

63596 63607  AGTTGTTGTTCC 1-10-1 MOE 1112

147721

64086 64097  AATGCAGGATCT 1-10-1 MOE 1118

147721

64232 64243  AATGCAGGATCT 1-10-1 MOE 1118

147692

64233 64244  CTCACCTTCATG 1-10-1 MOE 1113

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147692

64379 64390  CTCACCTTCATG 1-10-1 MOE 1113

147729

64633 64644  GTAAGAGGCAGG 1-10-1 MOE 920

401403

64746 64759 TTTCCTAGGAGGTG 2-10-2 MOE 967

147729

64779 64790  GTAAGAGGCAGG 1-10-1 MOE 920

147746

65151 65162  TAAAAACAACAA 1-10-1 MOE 1073

147746

65297 65308  TAAAAACAACAA 1-10-1 MOE 1073

147689

65302 65313  CAGAGAAGGTCT 1-10-1 MOE 987

147689

65448 65459  CAGAGAAGGTCT 1-10-1 MOE 987

147717

65862 65873  ATCTTCAGAGAT 1-10-1 MOE 996

147717

65895 65906  ATCTTCAGAGAT 1-10-1 MOE 996

147729

66000 66011  GTAAGAGGCAGG 1-10-1 MOE 920

147717

66008 66019  ATCTTCAGAGAT 1-10-1 MOE 996

147717

66041 66052  ATCTTCAGAGAT 1-10-1 MOE 996

147708

66046 66057  TTGATATAGTCA 1-10-1 MOE 997

147718

66055 66066  TAATATGACTTG 1-10-1 MOE 998

147729

66146 66157  GTAAGAGGCAGG 1-10-1 MOE 920

147089

66236 66247  TCCCTCTACACC 1-10-1 MOE 956

368363

66281 66294  CTTAGAAGGCAGCA 2-10-2 MOE 1114

147727

66293 66304  CAGTGGACCACA 1-10-1 MOE 1128

147093

66319 66330  TTGTTCCCTCTA 1-10-1 MOE 929

147094

66320 66331  GTTGTTCCCTCT 1-10-1 MOE 1115

147089

66382 66393  TCCCTCTACACC 1-10-1 MOE 956

368363

66427 66440  CTTAGAAGGCAGCA 2-10-2 MOE 1114

147727

66439 66450  CAGTGGACCACA 1-10-1 MOE 1128

147719

66441 66452  CCAACTCCAACT 1-10-1 MOE 1116

147093

66465 66476  TTGTTCCCTCTA 1-10-1 MOE 929

147094

66466 66477  GTTGTTCCCTCT 1-10-1 MOE 1115

147075

66561 66572  TCCACTGATCCT 1-10-1 MOE 1026

368357

66562 66575  CCTTCCACTGATCC 2-10-2 MOE 1046

147076

66562 66573  TTCCACTGATCC 1-10-1 MOE 1029

368377

66562 66577  CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

66563 66574  CTTCCACTGATC 1-10-1 MOE 1047

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

368358

66563 66576  TCCTTCCACTGATC 2-10-2 MOE 1031

147078

66564 66575  CCTTCCACTGAT 1-10-1 MOE 1044

147079

66565 66576  TCCTTCCACTGA 1-10-1 MOE 1001

147080

66566 66577  CTCCTTCCACTG 1-10-1 MOE 1021

147081

66567 66578  GCTCCTTCCACT 1-10-1 MOE 1006

147719

66587 66598  CCAACTCCAACT 1-10-1 MOE 1116

147075

66707 66718  TCCACTGATCCT 1-10-1 MOE 1026

368377

66708 66723  CTCCTTCCACTGATCC 3-10-3 MOE 1030

147076

66708 66719  TTCCACTGATCC 1-10-1 MOE 1029

368357

66708 66721  CCTTCCACTGATCC 2-10-2 MOE 1046

147077

66709 66720  CTTCCACTGATC 1-10-1 MOE 1047

147078

66710 66721  CCTTCCACTGAT 1-10-1 MOE 1044

147079

66711 66722  TCCTTCCACTGA 1-10-1 MOE 1001

147080

66712 66723  CTCCTTCCACTG 1-10-1 MOE 1021

147081

66713 66724  GCTCCTTCCACT 1-10-1 MOE 1006

147089

66842 66853  TCCCTCTACACC 1-10-1 MOE 956

147089

66988 66999  TCCCTCTACACC 1-10-1 MOE 956

147075

66999 67010  TCCACTGATCCT 1-10-1 MOE 1026

147075

67145 67156  TCCACTGATCCT 1-10-1 MOE 1026

147705

67213 67224 CGGTTTTTGTTC 1-10-1 MOE 1002

401413

67301 67314  TGCAGCCATGTACT 2-10-2 MOE 1022

147737

67309 67320  ACAGCCAGGTAG 1-10-1 MOE 1067

147080

67430 67441  CTCCTTCCACTG 1-10-1 MOE 1021

147737

67455 67466  ACAGCCAGGTAG 1-10-1 MOE 1067

147080

67576 67587  CTCCTTCCACTG 1-10-1 MOE 1021

147082

67578 67589  AGCTCCTTCCAC 1-10-1 MOE 1036

147090

67582 67593  TTCCCTCTACAC 1-10-1 MOE 955

147091

67583 67594  GTTCCCTCTACA 1-10-1 MOE 1004

147742

67591 67602  AACTTCAGTGTC 1-10-1 MOE 1041

147090

67728 67739  TTCCCTCTACAC 1-10-1 MOE 955

147698

68036 68047 CCCGCCACCACC 1-10-1 MOE 928

147698

68182 68193 CCCGCCACCACC 1-10-1 MOE 928

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147681

68267 68278  ATGTCATTAAAC 1-10-1 MOE 965

147721

68386 68397  AATGCAGGATCT 1-10-1 MOE 1118

147681

68413 68424  ATGTCATTAAAC 1-10-1 MOE 965

147712

68527 68538  ACACCATCTCCC 1-10-1 MOE 1005

147721

68532 68543  AATGCAGGATCT 1-10-1 MOE 1118

147711

68760 68771  AAGGGCCCTGGG 1-10-1 MOE 1040

147711

68906 68917  AAGGGCCCTGGG 1-10-1 MOE 1040

147696

69045 69056  TGGATGATTGGC 1-10-1 MOE 906

147696

69191 69202  TGGATGATTGGC 1-10-1 MOE 906

147723

69194 69205  GACTCCAAAGTC 1-10-1 MOE 892

147723

69210 69221  GACTCCAAAGTC 1-10-1 MOE 892

389965

69271 69282  CTGCAACATGAT 1-10-1 MOE 1018

389764

69271 69282  CTGCAACATGAT 1-9-2 MOE 1018

147723

69340 69351  GACTCCAAAGTC 1-10-1 MOE 892

147723

69356 69367  GACTCCAAAGTC 1-10-1 MOE 892

398101

69357 69370 TTTGATAAAGCCCT 2-10-2 MOE 1064

389965

69417 69428  CTGCAACATGAT 1-10-1 MOE 1018

389764

69417 69428  CTGCAACATGAT 1-9-2 MOE 1018

398101

69503 69516 TTTGATAAAGCCCT 2-10-2 MOE 1064

368353

69519 69532  CACTGATCCTGCAC 2-10-2 MOE 1007

147074

69522 69533  CCACTGATCCTG 1-10-1 MOE 845

147081

69631 69642  GCTCCTTCCACT 1-10-1 MOE 1006

368353

69665 69678  CACTGATCCTGCAC 2-10-2 MOE 1007

147720

69729 69740  GATCTCTCGAGT 1-10-1 MOE 1117

147721

69736 69747  AATGCAGGATCT 1-10-1 MOE 1118

398167

69757 69768  CAGGCCATGTGG 1-10-1 MOE 1059

147722

69762 69773  AAAGTCAGGCCA 1-10-1 MOE 1130

147723

69768 69779  GACTCCAAAGTC 1-10-1 MOE 892

147080

69776 z69787  CTCCTTCCACTG 1-10-1 MOE 1021

147081

69777 69788  GCTCCTTCCACT 1-10-1 MOE 1006

398093

69811 69824 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

69813 69824 TCGGACTTTGAA 1-10-1 MOE 1008

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147725

69814 69825 CTCGGACTTTGA 1-10-1 MOE 1119

147726

69819 69830  TGACTCTCGGAC 1-10-1 MOE 1120

147727

69860 69871  CAGTGGACCACA 1-10-1 MOE 1128

147720

69875 69886  GATCTCTCGAGT 1-10-1 MOE 1117

147721

69882 69893  AATGCAGGATCT 1-10-1 MOE 1118

147728

69899 69910 GCCAGACAGAAG 1-10-1 MOE 1013

398094

69901 69914  ATCAGCCAGACAGA 2-10-2 MOE 1010

398167

69903 69914  CAGGCCATGTGG 1-10-1 MOE 1059

398092

69904 69917  AGTCAGGCCATGTG 2-10-2 MOE 1060

147722

69908 69919  AAAGTCAGGCCA 1-10-1 MOE 1130

147723

69914 69925  GACTCCAAAGTC 1-10-1 MOE 892

147729

69916 69927  GTAAGAGGCAGG 1-10-1 MOE 920

398095

69919 69932  CATCAGCAAGAGGC 2-10-2 MOE 1011

398093

69957 69970 TCGGACTTTGAAAA 2-10-2 MOE 1009

398168

69959 69970 TCGGACTTTGAA 1-10-1 MOE 1008

147725

69960 69971 CTCGGACTTTGA 1-10-1 MOE 1119

147726

69965 69976  TGACTCTCGGAC 1-10-1 MOE 1120

147704

69991 70002  TTGTTCTTAGGA 1-10-1 MOE 1012

147727

70006 70017  CAGTGGACCACA 1-10-1 MOE 1128

147728

70045 70056 GCCAGACAGAAG 1-10-1 MOE 1013

398094

70047 70060  ATCAGCCAGACAGA 2-10-2 MOE 1010

398169

70048 70059  TCAGCCAGACAG 1-10-1 MOE 909

147729

70062 70073  GTAAGAGGCAGG 1-10-1 MOE 920

398095

70065 70078  CATCAGCAAGAGGC 2-10-2 MOE 1011

147704

70137 70148  TTGTTCTTAGGA 1-10-1 MOE 1012

147697

70161 70172 CCCCAGCAGCGG 1-10-1 MOE 1000

147697

70307 70318 CCCCAGCAGCGG 1-10-1 MOE 1000

147728

70450 70461 GCCAGACAGAAG 1-10-1 MOE 1013

398164

70464 70475  TTGTCGATCTGC 1-10-1 MOE 1014

147730

70465 70476  CTTGTCCATCAG 1-10-1 MOE 1121

147731

70471 70482 TTTCCTCTTGTC 1-10-1 MOE 934

147732

70476 70487 GGGTCTTTCCTC 1-10-1 MOE 1122

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147733

70497 70508  TTCTTGATGTCC 1-10-1 MOE 891

398096

70562 70575 GGAGAAGCGCAGCT 2-10-2 MOE 1015

147735

70564 70575 GGAGAAGCGCAG 1-10-1 MOE 1016

147736

70569 70580  AGGTAGGAGAAG 1-10-1 MOE 963

147737

70575 70586  ACAGCCAGGTAG 1-10-1 MOE 1067

147728

70596 70607 GCCAGACAGAAG 1-10-1 MOE 1013

398164

70610 70621  TTGTCGATCTGC 1-10-1 MOE 1014

147730

70611 70622  CTTGTCCATCAG 1-10-1 MOE 1121

368349

70616 70629  CTGCACTGACGAGT 2-10-2 MOE 1017

147731

70617 70628 TTTCCTCTTGTC 1-10-1 MOE 934

147732

70622 70633 GGGTCTTTCCTC 1-10-1 MOE 1122

147733

70643 70654  TTCTTGATGTCC 1-10-1 MOE 891

398096

70708 70721 GGAGAAGCGCAGCT 2-10-2 MOE 1015

147735

70710 70721 GGAGAAGCGCAG 1-10-1 MOE 1016

147736

70715 70726  AGGTAGGAGAAG 1-10-1 MOE 963

147737

70721 70732  ACAGCCAGGTAG 1-10-1 MOE 1067

389764

70784 70795  CTGCAACATGAT 1-9-2 MOE 1018

389965

70784 70795  CTGCAACATGAT 1-10-1 MOE 1018

389965

70930 70941  CTGCAACATGAT 1-10-1 MOE 1018

389764

70930 70941  CTGCAACATGAT 1-9-2 MOE 1018

368386

70995 71010  CACTGATCCTTAGAAG 3-10-3 MOE 1123

368367

70997 71010  CACTGATCCTTAGA 2-10-2 MOE 1124

368387

70997 71012  TCCACTGATCCTTAGA 3-10-3 MOE 1125

368354

70999 71012  TCCACTGATCCTGC 2-10-2 MOE 1024

368374

70999 71014  CTTCCACTGATCCTGC 3-10-3 MOE 1126

368368

70999 71012  TCCACTGATCCTTA 2-10-2 MOE 1127

368388

70999 71014  CTTCCACTGATCCTTA 3-10-3 MOE 895

368355

71000 71013  TTCCACTGATCCTG 2-10-2 MOE 1025

147074

71000 71011  CCACTGATCCTG 1-10-1 MOE 845

368375

71000 71015  CCTTCCACTGATCCTG 3-10-3 MOE 1020

147075

71001 71012  TCCACTGATCCT 1-10-1 MOE 1026

368376

71001 71016  TCCTTCCACTGATCCT 3-10-3 MOE 1028

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147076

71002 71013  TTCCACTGATCC 1-10-1 MOE 1029

368357

71002 71015  CCTTCCACTGATCC 2-10-2 MOE 1046

368377

71002 71017  CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

71003 71014  CTTCCACTGATC 1-10-1 MOE 1047

368378

71003 71018  GCTCCTTCCACTGATC 3-10-3 MOE 1032

147078

71004 71015  CCTTCCACTGAT 1-10-1 MOE 1044

368359

71005 71018  GCTCCTTCCACTGA 2-10-2 MOE 1033

368379

71005 71020  AAGCTCCTTCCACTGA 3-10-3 MOE 1034

147079

71005 71016  TCCTTCCACTGA 1-10-1 MOE 1001

147080

71006 71017  CTCCTTCCACTG 1-10-1 MOE 1021

368360

71007 71020  AAGCTCCTTCCACT 2-10-2 MOE 1035

368380

71007 71022  GAAAGCTCCTTCCACT 3-10-3 MOE 896

147081

71007 71018  GCTCCTTCCACT 1-10-1 MOE 1006

147082

71008 71019  AGCTCCTTCCAC 1-10-1 MOE 1036

368361

71009 71022  GAAAGCTCCTTCCA 2-10-2 MOE 962

368381

71009 71024  GGGAAAGCTCCTTCCA 3-10-3 MOE 1037

147738

71067 71078  TGGGTGGCCGGG 1-10-1 MOE 1069

147739

71071 71082 CGTTTGGGTGGC 1-10-1 MOE 1023

147740

71088 71099  TGTGAGGCTCCA 1-10-1 MOE 1062

147741

71129 71140  CACCCACTGGTG 1-10-1 MOE 1055

368366

71141 71154  CTGATCCTTAGAAG 2-10-2 MOE 1019

368386

71141 71156  CACTGATCCTTAGAAG 3-10-3 MOE 1123

368367

71143 71156  CACTGATCCTTAGA 2-10-2 MOE 1124

368387

71143 71158  TCCACTGATCCTTAGA 3-10-3 MOE 1125

368374

71145 71160  CTTCCACTGATCCTGC 3-10-3 MOE 1126

368354

71145 71158  TCCACTGATCCTGC 2-10-2 MOE 1024

368368

71145 71158  TCCACTGATCCTTA 2-10-2 MOE 1127

368388

71145 71160  CTTCCACTGATCCTTA 3-10-3 MOE 895

368355

71146 71159  TTCCACTGATCCTG 2-10-2 MOE 1025

368375

71146 71161  CCTTCCACTGATCCTG 3-10-3 MOE 1020

147075

71147 71158  TCCACTGATCCT 1-10-1 MOE 1026

368356

71147 71160  CTTCCACTGATCCT 2-10-2 MOE 1027

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

368376

71147 71162  TCCTTCCACTGATCCT 3-10-3 MOE 1028

147076

71148 71159  TTCCACTGATCC 1-10-1 MOE 1029

368357

71148 71161  CCTTCCACTGATCC 2-10-2 MOE 1046

368377

71148 71163  CTCCTTCCACTGATCC 3-10-3 MOE 1030

147077

71149 71160  CTTCCACTGATC 1-10-1 MOE 1047

368358

71149 71162  TCCTTCCACTGATC 2-10-2 MOE 1031

368378

71149 71164  GCTCCTTCCACTGATC 3-10-3 MOE 1032

147078

71150 71161  CCTTCCACTGAT 1-10-1 MOE 1044

368359

71151 71164  GCTCCTTCCACTGA 2-10-2 MOE 1033

147079

71151 71162  TCCTTCCACTGA 1-10-1 MOE 1001

368379

71151 71166  AAGCTCCTTCCACTGA 3-10-3 MOE 1034

147080

71152 71163  CTCCTTCCACTG 1-10-1 MOE 1021

368380

71153 71168  GAAAGCTCCTTCCACT 3-10-3 MOE 896

147081

71153 71164  GCTCCTTCCACT 1-10-1 MOE 1006

368360

71153 71166  AAGCTCCTTCCACT 2-10-2 MOE 1035

147082

71154 71165  AGCTCCTTCCAC 1-10-1 MOE 1036

368381

71155 71170  GGGAAAGCTCCTTCCA 3-10-3 MOE 1037

368361

71155 71168  GAAAGCTCCTTCCA 2-10-2 MOE 962

398097

71158 71171 GGCAGTCTTTATCC 2-10-2 MOE 897

147738

71213 71224  TGGGTGGCCGGG 1-10-1 MOE 1069

147739

71217 71228 CGTTTGGGTGGC 1-10-1 MOE 1023

147740

71234 71245  TGTGAGGCTCCA 1-10-1 MOE 1062

147741

71275 71286  CACCCACTGGTG 1-10-1 MOE 1055

398097

71304 71317 GGCAGTCTTTATCC 2-10-2 MOE 897

147727

71702 71713  CAGTGGACCACA 1-10-1 MOE 1128

147727

71848 71859  CAGTGGACCACA 1-10-1 MOE 1128

390030

71986 71997 TTTATAAAACTG 1-10-1 MOE 1074

147102

72015 72026  TGCGAGTTGTTG 1-10-1 MOE 1129

390030

72132 72143 TTTATAAAACTG 1-10-1 MOE 1074

147102

72161 72172  TGCGAGTTGTTG 1-10-1 MOE 1129

147722

72199 72210  AAAGTCAGGCCA 1-10-1 MOE 1130

147696

72232 72243  TGGATGATTGGC 1-10-1 MOE 906

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147741

72254 72265  CACCCACTGGTG 1-10-1 MOE 1055

147722

72345 72356  AAAGTCAGGCCA 1-10-1 MOE 1130

147696

72378 72389  TGGATGATTGGC 1-10-1 MOE 906

147741

72400 72411  CACCCACTGGTG 1-10-1 MOE 1055

147711

72446 72457  AAGGGCCCTGGG 1-10-1 MOE 1040

398098

72574 72587  TAACTTCAGTGTCT 2-10-2 MOE 1131

147742

72575 72586  AACTTCAGTGTC 1-10-1 MOE 1041

147698

72595 72606 CCCGCCACCACC 1-10-1 MOE 928

147743

72690 72701  AGGGCTTCCAGT 1-10-1 MOE 1042

398099

72690 72703  GAAGGGCTTCCAGT 2-10-2 MOE 1132

147744

72694 72705  AGGAAGGGCTTC 1-10-1 MOE 1043

398100

72697 72710  TGACCAGGAAGGGC 2-10-2 MOE 1133

147745

72700 72711  TTGACCAGGAAG 1-10-1 MOE 1058

398098

72720 72733  TAACTTCAGTGTCT 2-10-2 MOE 1131

147742

72721 72732  AACTTCAGTGTC 1-10-1 MOE 1041

147698

72741 72752 CCCGCCACCACC 1-10-1 MOE 928

398157

72757 72770  GGAAACATACCCTG 2-10-2 MOE 1045

147743

72836 72847  AGGGCTTCCAGT 1-10-1 MOE 1042

398099

72836 72849  GAAGGGCTTCCAGT 2-10-2 MOE 1132

147744

72840 72851  AGGAAGGGCTTC 1-10-1 MOE 1043

398100

72843 72856  TGACCAGGAAGGGC 2-10-2 MOE 1133

147745

72846 72857  TTGACCAGGAAG 1-10-1 MOE 1058

147076

72898 72909  TTCCACTGATCC 1-10-1 MOE 1029

368357

72898 72911  CCTTCCACTGATCC 2-10-2 MOE 1046

147077

72899 72910  CTTCCACTGATC 1-10-1 MOE 1047

147078

72900 72911  CCTTCCACTGAT 1-10-1 MOE 1044

398157

72903 72916  GGAAACATACCCTG 2-10-2 MOE 1045

398158

72983 72996  AGGCCCTGAGATTA 2-10-2 MOE 1134

398159

72988 73001  GGTTAAGGCCCTGA 2-10-2 MOE 1135

398160

72993 73006  GAATAGGTTAAGGC 2-10-2 MOE 1048

147076

73044 73055  TTCCACTGATCC 1-10-1 MOE 1029

368357

73044 73057  CCTTCCACTGATCC 2-10-2 MOE 1046

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147077

73045 73056  CTTCCACTGATC 1-10-1 MOE 1047

147078

73046 73057  CCTTCCACTGAT 1-10-1 MOE 1044

147746

73052 73063  TAAAAACAACAA 1-10-1 MOE 1073

398161

73092 73105  AACAATGTGTTGTA 2-10-2 MOE 1049

147746

73101 73112  TAAAAACAACAA 1-10-1 MOE 1073

398158

73129 73142  AGGCCCTGAGATTA 2-10-2 MOE 1134

398159

73134 73147  GGTTAAGGCCCTGA 2-10-2 MOE 1135

398160

73139 73152  GAATAGGTTAAGGC 2-10-2 MOE 1048

147746

73198 73209  TAAAAACAACAA 1-10-1 MOE 1073

398161

73238 73251  AACAATGTGTTGTA 2-10-2 MOE 1049

147746

73247 73258  TAAAAACAACAA 1-10-1 MOE 1073

147088

73273 73284  CCCTCTACACCA 1-10-1 MOE 1050

398105

73401 73414  TGCACAGGCAGGTT 2-10-2 MOE 1066

398105

73547 73560  TGCACAGGCAGGTT 2-10-2 MOE 1066

147741

73559 73570  CACCCACTGGTG 1-10-1 MOE 1055

147741

73705 73716  CACCCACTGGTG 1-10-1 MOE 1055

398162

73968 73981  ACCAAACAGTTCAG 2-10-2 MOE 1057

147745

73991 74002  TTGACCAGGAAG 1-10-1 MOE 1058

398167

74008 74019  CAGGCCATGTGG 1-10-1 MOE 1059

398092

74009 74022  AGTCAGGCCATGTG 2-10-2 MOE 1060

398162

74114 74127  ACCAAACAGTTCAG 2-10-2 MOE 1057

147745

74137 74148  TTGACCAGGAAG 1-10-1 MOE 1058

398167

74154 74165  CAGGCCATGTGG 1-10-1 MOE 1059

147089

74280 74291  TCCCTCTACACC 1-10-1 MOE 956

147090

74281 74292  TTCCCTCTACAC 1-10-1 MOE 955

389949

74310 74321 GCGCGAGCCCGA 1-10-1 MOE 1061

147740

74339 74350  TGTGAGGCTCCA 1-10-1 MOE 1062

389950

74381 74392  CCCTGAAGGTTC 1-10-1 MOE 1063

147089

74426 74437  TCCCTCTACACC 1-10-1 MOE 956

147090

74427 74438  TTCCCTCTACAC 1-10-1 MOE 955

389949

74456 74467 GCGCGAGCCCGA 1-10-1 MOE 1061

147685

74490 74501  GGCTGACATTCA 1-10-1 MOE 975

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398101

74510 74523 TTTGATAAAGCCCT 2-10-2 MOE 1064

398102

74536 74549 CTACCTGAGGATTT 2-10-2 MOE 899

398103

74543 74556  CCCAGTACTACCTG 2-10-2 MOE 900

147685

74636 74647  GGCTGACATTCA 1-10-1 MOE 975

398102

74682 74695 CTACCTGAGGATTT 2-10-2 MOE 899

398103

74689 74702  CCCAGTACTACCTG 2-10-2 MOE 900

147736

74737 74748  AGGTAGGAGAAG 1-10-1 MOE 963

398104

74805 74818  CAAGAAGACCTTAC 2-10-2 MOE 1065

147736

74883 74894  AGGTAGGAGAAG 1-10-1 MOE 963

147737

74893 74904  ACAGCCAGGTAG 1-10-1 MOE 1067

398105

74894 74907  TGCACAGGCAGGTT 2-10-2 MOE 1066

147737

74919 74930  ACAGCCAGGTAG 1-10-1 MOE 1067

398095

74940 74953  CATCAGCAAGAGGC 2-10-2 MOE 1011

398104

74951 74964  CAAGAAGACCTTAC 2-10-2 MOE 1065

398106

74974 74987  TGGAAAACTGCACC 2-10-2 MOE 1068

398107

74980 74993  TATTCCTGGAAAAC 2-10-2 MOE 902

147745

75030 75041  TTGACCAGGAAG 1-10-1 MOE 1058

147737

75039 75050  ACAGCCAGGTAG 1-10-1 MOE 1067

398105

75040 75053  TGCACAGGCAGGTT 2-10-2 MOE 1066

147737

75065 75076  ACAGCCAGGTAG 1-10-1 MOE 1067

398108

75077 75090  GGAATGTCTGAGTT 2-10-2 MOE 1136

398095

75086 75099  CATCAGCAAGAGGC 2-10-2 MOE 1011

147691

75108 75119  GAGGTGGGAAAA 1-10-1 MOE 966

398106

75120 75133  TGGAAAACTGCACC 2-10-2 MOE 1068

398107

75126 75139  TATTCCTGGAAAAC 2-10-2 MOE 902

147738

75155 75166  TGGGTGGCCGGG 1-10-1 MOE 1069

147745

75176 75187  TTGACCAGGAAG 1-10-1 MOE 1058

398108

75223 75236  GGAATGTCTGAGTT 2-10-2 MOE 1136

398109

75247 75260  CAAGAAGTGTGGTT 2-10-2 MOE 903

147691

75254 75265  GAGGTGGGAAAA 1-10-1 MOE 966

147738

75301 75312  TGGGTGGCCGGG 1-10-1 MOE 1069

398110

75385 75398 GTTCCCTTTGCAGG 2-10-2 MOE 952

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147091

75387 75398  GTTCCCTCTACA 1-10-1 MOE 1004

398109

75393 75406  CAAGAAGTGTGGTT 2-10-2 MOE 903

398111

75470 75483  GTGAAAATGCTGGC 2-10-2 MOE 904

401385

75494 75507 CCCAGTGGGTTTGA 2-10-2 MOE 890

398166

75499 75510  GGGCTTCTTCCA 1-10-1 MOE 1070

147091

75525 75536  GTTCCCTCTACA 1-10-1 MOE 1004

147092

75526 75537  TGTTCCCTCTAC 1-10-1 MOE 901

398110

75531 75544 GTTCCCTTTGCAGG 2-10-2 MOE 952

147091

75533 75544  GTTCCCTCTACA 1-10-1 MOE 1004

147706

75540 75551  GCTGACATCTCG 1-10-1 MOE 1071

398112

75584 75597  CAGCCTGGCACCTA 2-10-2 MOE 1072

398111

75616 75629  GTGAAAATGCTGGC 2-10-2 MOE 904

147746

75617 75628  TAAAAACAACAA 1-10-1 MOE 1073

398166

75645 75656  GGGCTTCTTCCA 1-10-1 MOE 1070

147091

75671 75682  GTTCCCTCTACA 1-10-1 MOE 1004

147092

75672 75683  TGTTCCCTCTAC 1-10-1 MOE 901

398113

75693 75706  AGGAGGTTAAACCA 2-10-2 MOE 905

398112

75730 75743  CAGCCTGGCACCTA 2-10-2 MOE 1072

147746

75763 75774  TAAAAACAACAA 1-10-1 MOE 1073

398114

75770 75783  AGGCATATAGCAGA 2-10-2 MOE 1075

398115

75786 75799  AGTAAATATTGGCT 2-10-2 MOE 1076

398116

75799 75812  TAATGACCTGATGA 2-10-2 MOE 1137

398113

75839 75852  AGGAGGTTAAACCA 2-10-2 MOE 905

390030

75839 75850 TTTATAAAACTG 1-10-1 MOE 1074

398115

75932 75945  AGTAAATATTGGCT 2-10-2 MOE 1076

398116

75945 75958  TAATGACCTGATGA 2-10-2 MOE 1137

398106

75982 75995  TGGAAAACTGCACC 2-10-2 MOE 1068

390030

75985 75996 TTTATAAAACTG 1-10-1 MOE 1074

398106

76127 76140  TGGAAAACTGCACC 2-10-2 MOE 1068

147690

76196 76207  TGAAGTTAATTC 1-10-1 MOE 1138

147690

76341 76352  TGAAGTTAATTC 1-10-1 MOE 1138

147724

76740 76751  GAAATTGAGGAA 1-10-1 MOE 1139

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147089

76873 76884  TCCCTCTACACC 1-10-1 MOE 956

147679

76881 76892  CAAAAGGATCCC 1-10-1 MOE 907

147724

76885 76896  GAAATTGAGGAA 1-10-1 MOE 1139

147089

77018 77029  TCCCTCTACACC 1-10-1 MOE 956

147679

77026 77037  CAAAAGGATCCC 1-10-1 MOE 907

147693

77240 77251  GTGCGCTCCCAT 1-10-1 MOE 1078

147697

77759 77770 CCCCAGCAGCGG 1-10-1 MOE 1000

In certain embodiments, a target region is nucleotides 177-190 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 177-190 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Nucleotide targeting 177-190 comprises a nucleotide sequence selected from SEQ ID

No. 886, 859 or 853. In certain such embodiments, a short antisense compound directed to nucleotides 177-190 of SEQ ID NO: 1 is selected from No. Isis 147022, 147023 or 147024.

In certain embodiments, a target region is nucleotides 195-228 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 195-228 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Nucleotide targeting 195-228 comprises a nucleotide sequence selected from SEQ ID

10 No. 877, 868, 882, 886, 859, 853, 865, 835, 843, 846, 842, 848, 874, 849, 863, 855, 850, 864 or 834. In certain of said embodiments, a short antisense compound targeting nucleotides 195-228 of SEQ ID NO: 11 is selected from No. Isis 147019, 147020, 147021, 147022, 147023, 147024, 147025, 147026, 147027, 147028, 147073, 147029, 147030, 147036, 147037, 147038 , 147039, 147040 or 147041.

In certain embodiments, a target region is nucleotides 323-353 of SEQ ID No. 11. In certain embodiments, a

15 short antisense compound targeting nucleotides 323-353 of SEQ ID No. 11. In certain embodiments, a short antisense compound targeting nucleotides 323-353 comprises a nucleotide sequence selected from SEQ ID NO: 866, 881, 869, 883, 858, 833, 875, 837, 829, 871, 884, 887, 839, 830, 840, 861 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 323-353 of SEQ ID NO. 11 is selected from No. Isis 147042, 147043, 147044, 147045, 147046, 147047, 147051, 147052, 147053, 147054, 147055, 147056, 147057,

20 147058, 147059, 147060 or 147061.

In certain embodiments, a target region is nucleotides 322-353 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 322-353 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 322-353 comprises a nucleotide sequence selected from SEQ ID NO: 842, 866, 881, 869, 883, 858, 833, 875, 837, 829, 871, 884, 887, 839, 830, 840, 861, or 879. In certain of said 25 embodiments, a short antisense compound directed to nucleotides 322-353 of SEQ ID NO: 11 is selected from No. Isis 147073, 147042, 147043, 147044, 147045, 147046, 147047, 147051 , 147052, 147053, 147054, 147055, 147056, 147057, 147058, 147059, 147060 or 147061. In certain embodiments, a target region is nucleotides 679-799 of SEQ ID NO. 11. In certain embodiments, a short targeted antisense compound. to nucleotides 679-799 of SEQ ID NO.

11. In certain embodiments, a short antisense compound directed to nucleotides 679-799 comprises a sequence

30 of nucleotides selected from SEQ ID NOS. 883, 858, 883 or 858. In certain such embodiments, a short antisense compound directed to nucleotides 679-799 of SEQ ID N ° 11 is selected from No. Isis 147045, 147046, 147045 or 147046.

In certain embodiments, a target region is nucleotides 679-827 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 679-827 of SEQ ID No. 11. In certain embodiments, a compound

Short antisense directed at nucleotides 679-827 comprises a nucleotide sequence selected from SEQ ID NO. 883, 858, 883, 858 or 851. In certain such embodiments, a short antisense compound directed at nucleotides 679-827 of the SEQ ID NO. 11 is selected from No. Isis 147045, 147046, 147045, 147046 or 147066.

In certain embodiments, a target region is nucleotides 1024-1046 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1024-1046 of SEQ ID No. 11. In certain embodiments, an antisense compound. Short nucleotide targeting 1024-1046 comprises a nucleotide sequence selected from SEQ ID Nos. 841, 862, 880, 857, 851, 876, 838, 860, 878, 856, 832 or 842. In certain such embodiments, a short antisense compound targeting nucleotides 1024-1046 of SEQ ID NO: 11 is selected from No. Isis 147062,

147063, 147064, 147065, 147066, 147067, 147068, 147069, 147070, 147071, 147072 or 147073.

In certain embodiments, a target region is nucleotides 992-1046 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 992-1046 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Nucleotide targeting 992-1046 comprises a nucleotide sequence selected from SEQ ID Nos. 831, 841, 862, 880, 857, 851, 876, 838, 860, 878, 856, 832 or 842. In certain such embodiments, A short antisense compound targeting nucleotides 992-1046 of SEQ ID NO: 11 is selected from No. Isis 404131, 147062, 147063, 147064, 147065, 147066, 147067, 147068, 147069, 147070, 147071, 147072 or 147073.

In certain embodiments, a target region is nucleotides 1868-1881 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1868-1881 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 1868-1881 comprises a nucleotide sequence selected from SEQ ID NO. 886, 859 or 853. In certain such embodiments, a short antisense compound directed to nucleotides 1868-1881 of SEQ ID NO: 11 is selected from No. Isis 147022, 147023 or 147024.

In certain embodiments, a target region is nucleotides 1886-1919 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1886-1919 of SEQ ID No. 11. In certain embodiments, a short antisense compound. targeting nucleotides 1886-1919 comprises a nucleotide sequence selected from SEQ ID NO: 877, 868, 882, 886, 859, 865, 843, 846, 874, 863, 855, 864 or 834. In certain such embodiments, A short antisense compound targeting nucleotides 1886-1919 of SEQ ID NO: 11 is selected from No. Isis 147019, 147020, 147021, 147022, 147023, 147025, 147027, 147028, 147030, 147037, 147038, 147040 or 147041.

In certain embodiments, a target region is nucleotides 1869-1919 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1869-1919 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Nucleotide targeting 1869-1919 comprises a nucleotide sequence selected from SEQ ID Nos. 859, 853, 877, 868, 882, 886, 859, 865, 843, 846, 874, 863, 855, 864 or 834. In certain of said embodiments, a short antisense compound targeting nucleotides 1869-1919 of SEQ ID NO: 11 is selected from No. Isis 147023, 147024, 147019, 147020, 147021, 147022, 147023, 147025, 147027, 147028, 147030, 147037 , 147038, 147040 or 147041.

In certain embodiments, a target region is nucleotides 1976-1989 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1976-1989 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Directed to nucleotides 1976-1989 comprises a nucleotide sequence selected from SEQ ID NO. 886, 859 or 853. In certain such embodiments, a short antisense compound directed to nucleotides 1976-1989 of SEQ ID NO: 11 is selected from No. Isis 147022, 147023 or 147024.

In certain embodiments, a target region is nucleotides 1995-2027 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 1995-2027 of SEQ ID No. 11. In certain embodiments, a short antisense compound. Nucleotide targeting 1995-2027 comprises a nucleotide sequence selected from SEQ ID Nos. 868, 882, 886, 859, 853, 865, 835, 843, 846, 848, 874, 849, 863, 855, 850, 864 or 834. In certain such embodiments, a short antisense compound targeting nucleotides 1995-2027 of SEQ ID NO: 11 is selected from No. Isis 147020, 147021, 147022, 147023, 147024, 147025, 147026, 147027, 147028, 147029 , 147030, 147036, 147037, 147038, 147039, 147040 or 147041.

In certain embodiments, a target region is nucleotides 2366-2382 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 2366-2382 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 2366-2382 comprises a nucleotide sequence selected from SEQ ID NO. 867 or 873. In certain such embodiments, a short antisense compound directed to nucleotides 2366-2382 of SEQ ID NO: 11 is selected from Isis No. 404199 or 404134.

In certain embodiments, a target region is nucleotides 6220-6233 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 6220-6233 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 6220-6233 comprises a nucleotide sequence selected from SEQ ID NO: 870, 836 or 844. In certain such embodiments, a short antisense compound directed to nucleotides 6220-6233 of SEQ ID NO: 11 is selected from No. Isis 147032, 147033 or 147034.

In certain embodiments, a target region is nucleotides 6288-6300 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 6288-6300 of SEQ ID No. 11. In certain embodiments, a short antisense compound. targeting nucleotides 6288-6300 comprises a nucleotide sequence selected from SEQ ID NO. 869 or 883. In certain such embodiments, a short antisense compound targeting nucleotides 6288-6300 of SEQ ID NO: 11 is selected from No. Isis. 147044 or 147045.

In certain embodiments, a target region is nucleotides 6329-6342 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 6329-6342 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 6329-6342 comprises a nucleotide sequence selected from SEQ ID No. 870, 836 or 844. In certain such embodiments, a short antisense compound targeting nucleotides 6329-6342 of SEQ ID No. 11 is select from No. Isis 147032, 147033 or 147034.

In certain embodiments, a target region is nucleotides 6397-6409 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 6397-6409 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 6397-6409 comprises a nucleotide sequence selected from SEQ ID NO. 869 or 883. In certain such embodiments, a short antisense compound directed to nucleotides 6397-6409 of SEQ ID NO: 11 is selected from No. Isis. 147044 or 147045.

In certain embodiments, a target region is nucleotides 7057-7178 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 7057-7178 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 7057-7178 comprises a nucleotide sequence selected from SEQ ID NO: 830, 840, 861, 830 or 840. In certain such embodiments, a short antisense compound directed to nucleotides 7057-7178 of SEQ ID NO. 11 is selected from No. Isis 147058, 147059, 147060, 147058 or 147059.

In certain embodiments, a target region is nucleotides 8630-8750 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 8630-8750 of SEQ ID No. 11. In certain such embodiments, a compound short antisense targeting nucleotides 8630-8750 comprises a nucleotide sequence selected from SEQ ID NO. 843, 846, 843 or 846. In certain such embodiments, a short antisense compound targeting nucleotides 8630-8750 of SEQ ID NO. 11 is selected from No. Isis 147027, 147028, 147027 or 147028.

In certain embodiments, a target region is nucleotides 10957-11077 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 10957-11077 of SEQ ID No. 11. In certain such embodiments, a compound short antisense directed to nucleotides 10957-11077 comprises a nucleotide sequence selected from SEQ ID NO. 881, 869, 881 or 869. In certain such embodiments, a short antisense compound directed to nucleotides 10957-11077 of SEQ ID NO. 11 is selected from No. Isis 147043, 147044, 147043 or 147044.

In certain embodiments, a target region is nucleotides 11605-11623 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 11605-11623 of SEQ ID No. 11. In certain such embodiments, a compound short antisense targeting nucleotides 11605-11623 comprises a nucleotide sequence selected from SEQ ID NO. 856, 878 or 856. In certain such embodiments, a short antisense compound targeting nucleotides 11605-11623 of SEQ ID No. 11 is select from No. Isis 147071, 147070 or 147071.

In certain embodiments, a target region is nucleotides 12805-12817 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 12805-12817 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 12805-12817 comprises a nucleotide sequence selected from SEQ ID NO: 874 or 885. In certain such embodiments, a short antisense compound directed to nucleotides 12805-12817 of SEQ ID NO: 11 is selected from No. Isis 147030 or 147031.

In certain embodiments, a target region is nucleotides 12986-12998 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 12986-12998 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 12986-12998 comprises a nucleotide sequence selected from SEQ ID NO: 874 or 885. In certain such embodiments, a short antisense compound directed to nucleotides 12986-12998 of SEQ ID NO: 11 is selected from No. Isis 147030 or 147031.

In certain embodiments, a target region is nucleotides 15560-15572 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 15560-15572 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 15560-15572 comprises a nucleotide sequence selected from SEQ ID NO: 876 or 838. In certain such embodiments, a short antisense compound directed to nucleotides 15560-15572 of SEQ ID NO: 11 is selected from No. Isis 147067 or 147068.

In certain embodiments, a target region is nucleotides 17787-17941 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 17787-17941 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 17787-17941 comprises a nucleotide sequence selected from SEQ ID NO: 874 or 880. In certain such embodiments, a short antisense compound directed to nucleotides 17787-17941 of SEQ ID NO: 11 is selected from No. Isis 147030 or 147064.

In certain embodiments, a target region is nucleotides 21190-21202 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 21190-21202 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 21190-21202 comprises a nucleotide sequence selected from SEQ ID NO: 843 or 846. In certain such embodiments, a short antisense compound directed to nucleotides 21190-21202 of SEQ ID NO: 11 is selected from No. Isis 147027 or 147028.

In certain embodiments, a target region is nucleotides 21358-21370 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 21358-21370 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 21358-21370 comprises a nucleotide sequence selected from SEQ ID NO. 843 or 846. In certain such embodiments, a short antisense compound directed to nucleotides 21358-21370 of SEQ ID NO: 11 is selected from No. Isis 017027 or 147028.

In certain embodiments, a target region is nucleotides 24318-24332 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 24318-24332 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 24318-24332 comprises a nucleotide sequence selected from SEQ ID NO. 881, 869, 883 or 858. In certain such embodiments, a short antisense compound directed to nucleotides 24318-24332 of SEQ ID NO: 11 is select from No. Isis 147043, 147044, 147045 or 147046.

In certain embodiments, a target region is nucleotides 24486-24501 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 24486-24501 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to nucleotides 24486-24501 comprises a nucleotide sequence selected from SEQ ID NO. 881, 869, 858 or 833. In certain such embodiments, a short antisense compound directed to nucleotides 24486-24501 of SEQ ID NO. 11 is selected from No. Isis 147043, 147044, 147046 or 147047.

In certain embodiments, a target region is nucleotides 25065-25077 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 25065-25077 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 25065-25077 comprises a nucleotide sequence selected from SEQ ID NO. 864 or 834. In certain such embodiments, a short antisense compound directed to nucleotides 25065-25077 of SEQ ID NO: 11 is selected from No. Isis 147040 or 147041.

In certain embodiments, a target region is nucleotides 25232-25245 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 25232-25245 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to nucleotides 25232-25245 comprises a nucleotide sequence selected from SEQ ID NO. 850, 864 or 834. In certain such embodiments, a short antisense compound directed to nucleotides 25232-25245 of SEQ ID NO: 11 is select from Isis No. 147039, 147040 or 147041.

In certain embodiments, a target region is nucleotides 25508-25523 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 25508-25523 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 25508-25523 comprises a nucleotide sequence selected from SEQ ID NO: 839 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 25508-25523 of SEQ ID NO: 11 is selected from No. Isis 147057 or 147061.

In certain embodiments, a target region is nucleotides 25676-28890 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 25676-28890 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed at nucleotides 25676-28890 comprises a nucleotide sequence selected from SEQ ID NO. 839, 860 or 878. In certain such embodiments, a short antisense compound directed at nucleotides 25676-28890 of SEQ ID No. 11 is select from No. Isis 147057, 147069 or 147070.

In certain embodiments, a target region is nucleotides 33056-33069 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33056-33069 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 33056-33069 comprises a nucleotide sequence selected from SEQ ID NO. 860, 878 or 856. In certain such embodiments, a short antisense compound targeting nucleotides 33056-33069 of SEQ ID No. 11 is select from No. Isis 147069, 147070 or 147071.

In certain embodiments, a target region is nucleotides 33205-33217 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33205-33217 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 33205-33217 comprises a nucleotide sequence selected from SEQ ID NO: 878 or 856. In certain of said embodiments, a short antisense compound directed to nucleotides 33205-33217 of SEQ ID NO: 11 is selected from No. Isis 14707 or 147071.

In certain embodiments, a target region is nucleotides 33318-33334 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33318-33334 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 33318-33334 comprises a nucleotide sequence selected from SEQ ID NO. 858, 854 or 875. In certain such embodiments, a short antisense compound targeting nucleotides 33318-33334 of SEQ ID NO: 11 is select from Isis No. 147046, 147049 or 147051.

In certain embodiments, a target region is nucleotides 33466-33482 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33466-33482 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 33466-33482 comprises a nucleotide sequence selected from SEQ ID NO. 858, 833 or 875. In certain such embodiments, a short antisense compound targeting nucleotides 33466-33482 of SEQ ID NO: 11 is select from Isis No. 147046, 147047 or 147051.

In certain embodiments, a target region is nucleotides 33640-33656 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33640-33656 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 33640-33656 comprises a nucleotide sequence selected from SEQ ID NO: 858 or 875. In certain such embodiments, a short antisense compound directed to nucleotides 33640-33656 of SEQ ID NO: 11 is selected from No. Isis 147046 or 147051.

In certain embodiments, a target region is nucleotides 33788-33804 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 33788-33804 of SEQ ID No. 11. In certain embodiments, a short antisense compound. targeting nucleotides 33788-33804 comprises a nucleotide sequence selected from SEQ ID NO. 858 or 875. In certain such embodiments, a short antisense compound targeting nucleotides 33788-33804 of SEQ ID NO: 11 is selected from No. Isis. 147046 or 147051.

In certain embodiments, a target region is nucleotides 35437-35449 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 35437-35449 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 35437-35449 comprises a nucleotide sequence selected from SEQ ID NO: 840 or 861. In certain such embodiments, a short antisense compound directed to nucleotides 35437-35449 of SEQ ID NO: 11 is selected from No. Isis 147059 or 147060.

In certain embodiments, a target region is nucleotides 40353-40373 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 40353-40373 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 40353-40373 comprises a nucleotide sequence selected from SEQ ID No. 879 or 881. In certain such embodiments, a short antisense compound directed to nucleotides 40353-40373 of SEQ ID No. 11 is selected from No. Isis 147061 or 147043.

In certain embodiments, a target region is nucleotides 42527-42541 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 42527-42541 of SEQ ID No. 11. In certain such embodiments, a compound short antisense targeting nucleotides 42527-42541 comprises a nucleotide sequence selected from SEQ ID NO. 885, 870 or 844. In certain such embodiments, a short antisense compound targeting nucleotides 42527-42541 of SEQ ID No. 11 is select from Isis No. 147031, 147032 or 147034.

In certain embodiments, a target region is nucleotides 42675-42689 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 42675-42689 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 42675-42689 comprises a nucleotide sequence selected from SEQ ID NO. 885, 870, 836 or 844. In certain such embodiments, a short antisense compound directed to nucleotides 42675-42689 of SEQ ID NO: 11 is select from No. Isis 147031, 147032, 147033 or 147034.

In certain embodiments, a target region is nucleotides 46313-46328 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 46313-46328 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 46313-46328 comprises a nucleotide sequence selected from SEQ ID NO: 839, 830, 840 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 46313-46328 of SEQ ID NO: 11 is select from No. Isis 147057, 147058, 147059 or 147061.

In certain embodiments, a target region is nucleotides 46461-46476 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 46461-46476 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 46461-46476 comprises a nucleotide sequence selected from SEQ ID NO. 839, 840 or 879. In certain such embodiments, a short antisense compound targeting nucleotides 46461-46476 of SEQ ID NO: 11 is select from No. Isis 147057, 147059 or 147061.

In certain embodiments, a target region is nucleotides 48369-48381 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 48369-48381 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 48369-48381 comprises a nucleotide sequence selected from SEQ ID NO: 842 or 845. In certain such embodiments, a short antisense compound directed to nucleotides 48369-48381 of SEQ ID NO: 11 is selected from No. Isis 147073 or 147074.

In certain embodiments, a target region is nucleotides 48714-48726 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 48714-48726 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 48714-48726 comprises a nucleotide sequence selected from SEQ ID NO: 843 or 846. In certain such embodiments, a short antisense compound directed to nucleotides 48714-48726 of SEQ ID NO: 11 is selected from No. Isis 147027 or 147028.

In certain embodiments, a target region is nucleotides 49050-49062 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 49050-49062 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 49050-49062 comprises a nucleotide sequence selected from SEQ ID NO: 876 or 838. In certain such embodiments, a short antisense compound directed to nucleotides 49050-49062 of SEQ ID NO: 11 is selected from No. Isis 147067 or 147068.

In certain embodiments, a target region is nucleotides 49672-49684 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 49672-49684 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 49672-49684 comprises a nucleotide sequence selected from SEQ ID NO. 842 or 845. In certain such embodiments, a short antisense compound directed to nucleotides 49672-49684 of SEQ ID NO: 11 is selected from No. Isis. 147073 or 147074.

In certain embodiments, a target region is nucleotides 52292-52304 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 52292-52304 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 52292-52304 comprises a nucleotide sequence selected from SEQ ID NO: 849 or 863. In certain such embodiments, a short antisense compound directed to nucleotides 52292-52304 of SEQ ID NO: 11 is selected from No. Isis 147036 or 147037.

In certain embodiments, a target region is nucleotides 52438-52450 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 52438-52450 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to 52438-53450 comprises a nucleotide sequence selected from SEQ ID NO. 849 or 863. In certain such embodiments, a short antisense compound directed to nucleotides 52438-52450 of SEQ ID NO: 11 is selected from No. Isis. 147036 or 147037.

In certain embodiments, a target region is nucleotides 53445-53458 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 53445-53458 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 53445-53458 comprises a nucleotide sequence selected from SEQ ID NO: 866, 881 or 869. In certain such embodiments, a short antisense compound directed to nucleotides 53445-53458 of SEQ ID NO: 11 is selected from No. Isis 147042, 147043 or 147044.

In certain embodiments, a target region is nucleotides 53591-53604 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 53591-53604 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 53591-53604 comprises a nucleotide sequence selected from SEQ ID NO: 866, 874, 881, 885 or 869. In certain such embodiments, a short antisense compound directed to nucleotides 53591-53604 of SEQ ID NO. 11 is selected from No. Isis 147042, 147030, 147043, 147031 or 147044.

In certain embodiments, a target region is nucleotides 53738-53750 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 53738-53750 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 53738-53750 comprises a nucleotide sequence selected from SEQ ID NO: 874 or 885. In certain such embodiments, a short antisense compound directed to nucleotides 53738-53750 of SEQ ID NO: 11 is selected from No. Isis 147030 or 147031.

In certain embodiments, a target region is nucleotides 53783-53795 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 53783-53795 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 53783-53795 comprises a nucleotide sequence selected from SEQ ID NO: 864 or 834. In certain such embodiments, a short antisense compound directed to nucleotides 53783-53795 of SEQ ID NO: 11 is selected from No. Isis 147040 or 147041.

In certain embodiments, a target region is nucleotides 55008-55020 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 55008-55020 of SEQ ID No. 11. In certain embodiments, a short antisense compound. targeting nucleotides 55008-55020 comprises a nucleotide sequence selected from SEQ ID NO: 866 or 881. In certain such embodiments, a short antisense compound targeting nucleotides 55008-55020 of SEQ ID NO: 11 is selected from No. Isis 147042 or 147043.

In certain embodiments, a target region is nucleotides 55154-55166 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 55154-55166 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 55154-55166 comprises a nucleotide sequence selected from SEQ ID NO: 866 or 881. In certain such embodiments, a short antisense compound directed to nucleotides 55154-55166 of SEQ ID NO: 11 is selected from No. Isis 147042 or 147043.

In certain embodiments, a target region is nucleotides 55682-55695 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 55682-55695 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 55682-55695 comprises a nucleotide sequence selected from SEQ ID NO. 877 or 882. In certain such embodiments, a short antisense compound directed to nucleotides 55682-55695 of SEQ ID NO: 11 is selected from No. Isis. 147019 or 147021.

In certain embodiments, a target region is nucleotides 56275-56293 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 56275-56293 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 56275-56293 comprises a nucleotide sequence selected from SEQ ID Nos. 871, 884, 887, 830, 840.861 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 56275-56293 of the SEC ID No. 11 is selected from No. Isis 147054, 147055, 147056, 147058, 147059, 147060 or 147061.

In certain embodiments, a target region is nucleotides 56418-56439 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 56418-56439 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to nucleotides 56418-56439 comprises a nucleotide sequence selected from SEQ ID Nos. 875, 829, 871, 884, 887, 839, 830 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 56418-56439 of SEQ ID NO: 11 is selected from No. Isis 147051, 147053, 147054, 147055, 147056, 147057, 147058 or 147061.

In certain embodiments, a target region is nucleotides 57264-57276 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 57264-57276 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 57264-57276 comprises a nucleotide sequence selected from SEQ ID NO. 883 or 858. In certain such embodiments, a short antisense compound directed to nucleotides 57264-57276 of SEQ ID NO: 11 is selected from No. Isis 147045 or 147046.

In certain embodiments, a target region is nucleotides 61276-61293 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 61276-61293 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 61276-61293 comprises a nucleotide sequence selected from SEQ ID Nos. 856, 847, 849, 863, 855, 850 or 864. In certain such embodiments, a short antisense compound directed to nucleotides 61276-61293 of SEQ ID No. 11 is selected from No. Isis 147071, 147035, 147036, 147037, 147038, 147039 or 147040.

In certain embodiments, a target region is nucleotides 61257-61320 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 61257-61320 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to nucleotides 61257-61320 comprises a nucleotide sequence selected from SEQ ID NO: 881, 856, 847, 849, 863, 855, 850, 864 or 886. In certain of said embodiments, a short antisense compound directed to nucleotides 61257-61320 of SEQ ID NO: 11 is selected from No. Isis 147043, 147071, 147035, 147036, 147037, 147038, 147039, 147040 or 147071.

In certain embodiments, a target region is nucleotides 61422-61439 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 61422-61439 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 61422-61439 comprises a nucleotide sequence selected from SEQ ID NO: 844, 847, 849, 863, 855 or 864. In certain such embodiments, a short antisense compound directed to nucleotides 61422-61439 of SEC ID No. 11 is selected from No. Isis 147034, 147035, 147036, 147037, 147038, or 147040.

In certain embodiments, a target region is nucleotides 61422-61466 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 61422-61466 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 61422-61466 comprises a nucleotide sequence selected from SEQ ID NO: 844, 847, 849, 863, 855, 864 or 856. In certain such embodiments, a short antisense compound directed to nucleotides 61422-61466 of SEQ ID No. 11 is selected from No. Isis 147034, 147035, 147036, 147037, 147038, 147040 or 147071.

In certain embodiments, a target region is nucleotides 63065-63078 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 63065-63078 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 63065-63078 comprises a nucleotide sequence selected from SEQ ID NO. 851 or 838. In certain such embodiments, a short antisense compound directed to nucleotides 63065-63078 of SEQ ID NO: 11 is selected from No. Isis 147066 or 147068.

In certain embodiments, a target region is nucleotides 63207-63222 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 63207-63222 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 63207-63222 comprises a nucleotide sequence selected from SEQ ID NO. 841 or 851. In certain such embodiments, a short antisense compound directed to nucleotides 63207-63222 of SEQ ID NO: 11 is selected from No. Isis. 147062 or 147066.

In certain embodiments, a target region is nucleotides 64538-64550 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 64538-64550 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 64538-64550 comprises a nucleotide sequence selected from SEQ ID NO: 849 or 863. In certain such embodiments, a short antisense compound directed to nucleotides 64538-64550 of SEQ ID NO: 11 is selected from No. Isis 147036 or 147037.

In certain embodiments, a target region is nucleotides 64864-64876 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 64864-64876 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 64864-64876 comprises a nucleotide sequence selected from SEQ ID NO: 851 or 876. In certain such embodiments, a short antisense compound directed to nucleotides 64864-64876 of SEQ ID NO: 11 is selected from No. Isis 147066 or 147067.

In certain embodiments, a target region is nucleotides 65010-65028 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 65010-65028 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 65010-65028 comprises a nucleotide sequence selected from SEQ ID NO. 851, 876 or 883. In certain such embodiments, a short antisense compound directed to nucleotides 65010-65028 of SEQ ID NO: 11 is selected from No. Isis 147066, 147067 or 147045.

In certain embodiments, a target region is nucleotides 65163-65175 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 65163-65175 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 65163-65175 comprises a nucleotide sequence selected from SEQ ID NO. 883 or 858. In certain such embodiments, a short antisense compound directed to nucleotides 65163-65175 of SEQ ID NO: 11 is selected from No. Isis 147045 or 147046.

In certain embodiments, a target region is nucleotides 65408-65422 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 65408-65422 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 65408-65422 comprises a nucleotide sequence selected from SEQ ID NO. 883 or 856. In certain such embodiments, a short antisense compound directed to nucleotides 65408-65422 of SEQ ID NO: 11 is selected from Isis No. 147068 or 147071.

In certain embodiments, a target region is nucleotides 65549-65568 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 65549-65568 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 65549-65568 comprises a nucleotide sequence selected from SEQ ID NO: 860, 838 or 856. In certain such embodiments, a short antisense compound directed to nucleotides 65549-65568 of SEQ ID NO: 11 is selected from No. Isis 147069, 147068 or 147071.

In certain embodiments, a target region is nucleotides 67741-67754 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 67741-67754 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 67741-67754 comprises a nucleotide sequence selected from SEQ ID NO: 848, 874 or 885. In certain such embodiments, a short antisense compound directed to nucleotides 67741-67754 of SEQ ID NO: 11 is selected from No. Isis 147029, 147030 or 147031.

In certain embodiments, a target region is nucleotides 67886-67900 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 67886-67900 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 67886-67900 comprises a nucleotide sequence selected from SEQ ID NO. 846, 848, 874 or 885. In certain such embodiments, a short antisense compound targeting nucleotides 67886-67900 of SEQ ID NO. 11 is selected from No. Isis 147028, 147029, 147030 or 147031.

In certain embodiments, a target region is nucleotides 68867-68880 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 68867-68880 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense targeting nucleotides 68867-68880 comprises a nucleotide sequence selected from SEQ ID NO. 881, 869 or 883. In certain such embodiments, a short antisense compound targeting nucleotides 68867-68880 of SEQ ID No. 11 is select from No. Isis 147043, 147044 or 147045.

In certain embodiments, a target region is nucleotides 69013-69532 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 69013-69532 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 69013-69532 comprises a nucleotide sequence selected from SEQ ID Nos. 881, 869, 883, 858, 856, 832 or 842. In certain such embodiments, a short antisense compound directed to nucleotides 69013-69532 of SEQ ID No. 11 is selected from No. Isis 147043, 147044, 147045, 147046, 147071, 147072 or 147073.

In certain embodiments, a target region is nucleotides 69665-69880 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 69665-69880 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 69665-69880 comprises a nucleotide sequence selected from SEQ ID NO: 856, 832, 842, 845 or 851. In certain such embodiments, a short antisense compound directed to nucleotides 69665-69880 of SEQ ID NO. 11 is selected from No. Isis 147071, 147072, 147073, 147074 or 147066.

In certain embodiments, a target region is nucleotides 70611-70630 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 70611-70630 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 70611-70630 comprises a nucleotide sequence selected from SEQ ID Nos. 859, 841, 862, 880, 857 or 851. In certain such embodiments, a short antisense compound directed to nucleotides 70611-70630 of SEC ID No. 11 is selected from No. Isis 147023, 147062, 147063, 147064, 147065, or 147066.

In certain embodiments, a target region is nucleotides 70762-70776 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 70762-70776 of SEQ ID No. 11. In certain such embodiments, a compound short antisense targeting nucleotides 70762-70776 comprises a nucleotide sequence selected from SEQ ID NO. 862, 880, 857 or 851. In certain such embodiments, a short antisense compound targeting nucleotides 70762-70776 of SEQ ID NO. 11 is selected from No. Isis 147063, 147064, 147065 or 147066.

In certain embodiments, a target region is nucleotides 70998-71010 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 70998-71010 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 70998-71010 comprises a nucleotide sequence selected from SEQ ID NO: 832 or 842. In certain such embodiments, a short antisense compound directed to nucleotides 70998-71010 of SEQ ID NO: 11 is selected from No. Isis 147072 or 147073.

In certain embodiments, a target region is nucleotides 71144-714364 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 71144-714364 of SEQ ID No. 11. In certain embodiments, a short antisense compound. directed to nucleotides 71144-714364 comprises a nucleotide sequence selected from SEQ ID NO: 832, 842, 845, 863, 855 or 850. In certain such embodiments, a short antisense compound directed to nucleotides 71144-714364 of the SEC ID No. 11 is selected from No. Isis 147072, 147073, 147074, 147037, 147038, or 147039.

In certain embodiments, a target region is nucleotides 71497-71652 of SEQ ID No. 11. In certain embodiments, a short antisense compound directed to nucleotides 71497-71652 of SEQ ID No. 11. In certain of said embodiments, a compound short antisense directed to nucleotides 71497-71652 comprises a nucleotide sequence selected from SEQ ID NO. 863, 855, 850 or 879. In certain such embodiments, a short antisense compound directed to nucleotides 71497-71652 of SEQ ID NO. 11 is selected from No. Isis 147037, 147038, 147039 or 147061.

In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 8 to 16 in length, preferably 9 to 15, more preferably 9 to 14, more preferably 10 to 14 nucleotides in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 9 to 14 nucleotides in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 10 to 14 nucleotides in length. In certain embodiments, said short antisense compounds are short antisense oligonucleotides.

In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid are short captamers. In certain of said embodiments, short captamers directed to a PTP1B nucleic acid comprise at least one high affinity modification in one or more wings of the compound. In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid comprise 1 to 3 high affinity modifications in each wing. In certain of said embodiments, the nucleosides or nucleotides of the wing comprise a 2 'modification. In certain embodiments, the wing monomers are BNA. In certain of said embodiments, the wing monomers are selected from α-L-methyloxy (4'-CH2-O-2 ') BNA, ß-D-methyloxy (4'-CH2-O-2') BNA, ethyleneoxy (4 '- (CH2) 2-O-2') BNA, aminooxy (4'-CH2-ON (R) -2 ') BNA and oxyamino (4'-CH2-N (R) -O-2') BNA In certain embodiments, the monomers of a wing comprise a substituent in the 2 'position selected from allyl, amino, azido, thio, O-allyl, O-C1-C10 alkyl, -OCF3, O- (CH2) 2-O- CH3, 2'-O (CH2) 2SCH3, O- (CH2) 2-ON (Rm) (Rn), and O-CH2-C (= O) -N (Rm) (Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. In certain embodiments, the monomers of a wing are 2’MOE nucleotides.

In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid comprise a gap between the 5 'wing and the 3' wing. In certain embodiments, the gap comprises five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen monomers. In certain embodiments, the hollow monomers are unmodified deoxyribonucleotides. In certain embodiments, the hollow monomers are unmodified ribonucleotides. In certain embodiments, modifications of the gap (if any) result in an antisense compound that, when bound to its target nucleic acid, supports cleavage by an RNase, including, among others, RNase H.

In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid have monomeric bonds. In certain of said embodiments, said links are all phosphorothioate bonds. In certain embodiments, the links are all phosphodiester bonds. In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid have mixed skeletons.

In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 8 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 9 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 10 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 11 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid have a monomer length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 13 monomers in length. In certain embodiments, short antisense compounds targeting a PTP1B nucleic acid are 14 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 15 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid are 16 monomers in length. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid comprise 9 to 15 monomers. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid comprise 10 to 15 monomers. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid comprise 12 to 14 monomers. In certain embodiments, short antisense compounds directed to a PTP1B nucleic acid comprise 12 to 14 nucleotides or nucleosides.

In certain embodiments, methods of modulating the expression of PTP1B are disclosed herein. In certain embodiments, said methods comprise the use of one or more short antisense compounds targeting a PTP1B nucleic acid, wherein the short antisense compound targeting a PTP1B nucleic acid is about 8 to about 16 in length, preferably of 9 to 15, more preferably 9 to 14, more preferably 10 to 14 monomers (ie, about 8 to about 16 attached monomers). One skilled in the art will appreciate that this comprises methods of modulating the expression of PTP1B using one

or more short antisense compounds directed to a PTP1B nucleic acid of 8, 9, 10, 11, 12, 13, 14, 15 or 16 monomers.

In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 8 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 9 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 10 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 11 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 12 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 13 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 14 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 15 monomers in length. In certain embodiments, the PTP1B modulation methods comprise the use of a short antisense compound directed to a PTP1B nucleic acid that is 16 monomers in length.

In certain embodiments, the methods of modulating the expression of PTP1B comprise the use of a short antisense compound directed to a PTP1B nucleic acid comprising 9 to 15 monomers. In certain embodiments, the methods of modulating the expression of PTP1B comprise the use of a short antisense compound directed to a PTP1B nucleic acid comprising 10 to 15 monomers. In certain embodiments, the methods of modulating the expression of PTP1B comprise the use of a short antisense compound directed to a PTP1B nucleic acid comprising 12 to 14 monomers. In certain embodiments, the methods of modulating the expression of PTP1B comprise the use of a short antisense compound directed to a PTB1B nucleic acid comprising 12 or 14 nucleotides or nucleosides.

10. PTEN

In certain embodiments, short antisense compounds directed to a nucleic acid encoding PTEN are disclosed herein. In certain embodiments, said compounds are used to modulate PTEN expression in cells. In certain of said embodiments, short antisense compounds directed to a PTEN nucleic acid are administered to an animal. In certain embodiments, short antisense compounds targeting a PTEN nucleic acid are useful for studying PTEN, for studying certain nucleases and / or for evaluating antisense activity. In certain of said embodiments, short antisense compounds targeting PTEN nucleic acids are useful for evaluating certain chemical motifs and / or modifications. In certain embodiments, administration of a short antisense compound directed to a PTEN nucleic acid to an animal results in a measurable phenotypic change.

Short antisense compounds directed to PTEN may have any one or more properties or characteristics of short antisense compounds generally described herein. In certain embodiments, short antisense compounds targeting a PTEN nucleic acid have a motif (wing-deoxy-wing) selected from 1-12-1, 1-1-10-2, 2-10-1-1, 3-10-3, 2-10-3, 2-10-2, 1-10-1,1-10-2, 3-8-3, 2-8-2, 1-8-1, 3- 6-3 or 1-6-1, more

5 preferably 1-10-1, 2-10-2, 3-10-3 and 1-9-2

Certain short antisense compounds targeting a PTEN nucleic acid

In certain embodiments, short antisense compounds are directed to a PTEN nucleic acid having the registration number sequence in GENBANK® NM 000314.4, incorporated herein as SEQ ID NO.

14. In certain embodiments, short antisense compounds are directed to a PTEN nucleic acid having the

10 nucleotide sequence 8063255 to 8167140 of registration number in GENBANK® NT 033890.3, incorporated herein as SEQ ID No. 15. In certain such embodiments, a short antisense compound directed to SEQ ID No. 14 is at least 90 % complementary to SEQ ID No. 14. In certain of said embodiments, a short antisense compound directed to SEQ ID No. 14 is at least 95% complementary to SEQ ID No. 14. In certain such embodiments, a short antisense compound addressed to SEQ ID No. 15 EN 100% complementary to SEQ ID No. 15. In

In certain of said embodiments, a short antisense compound directed to SEQ ID No. 15 is at least 90% complementary to SEQ ID No. 15. In certain such embodiments, a short antisense compound directed to SEQ ID No. 15 is at minus 95% complementary to SEQ ID No. 15. In certain such embodiments, a short antisense compound directed to SEQ ID No. 15 IS 100% complementary to SEQ ID No. 15.

In certain embodiments, a short antisense compound directed to SEQ ID NO: 14 comprises a sequence of

20 nucleotides selected from the nucleotide sequences indicated in Tables 20 and 21. In certain embodiments, a short antisense compound directed to SEQ ID NO: 15 comprises a nucleotide sequence selected from the nucleotide sequences indicated in Tables 22 and 23.

Each nucleotide sequence indicated in Tables 20, 21, 22 and 23 is independent of any modification of a sugar moiety, an internucleoside bond or a nucleotide base. As such, short antisense compounds that

25 comprise a nucleotide sequence as indicated in Tables 20, 21, 22 and 23 may independently comprise one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base. The antisense compounds described by the Isis Number (No. Isis) indicate a combination of nucleotide base sequence and one or more modifications in a sugar moiety, an internucleoside bond or a nucleotide base.

Table 20 illustrates short antisense compounds that are 100% complementary to SEQ ID NO: 14. Table 22 illustrates

30 short antisense compounds that are 100% complementary to SEQ ID NO. 15. The column called "capper motif" indicates the wing-hollow-wing motif of each short antisense compound. The hollow segment comprises 2'deoxynucleotides and each nucleotide of each wing segment comprises a 2 'modified sugar. The sugar modified in 2 'concrete is also indicated in the column “gápmero motif”. For example, ‘2-10-2 MOE’ means a 2-10-2 catheter motif, in which a gap segment of ten 2’-deoxynucleotides is flanked by wing segments

35 of two nucleotides, in which the nucleotides of the wing segments are 2’-MOE nucleotides. The internucleoside bonds are phosphorothioate. Short antisense compounds comprise 5-methylcytidine instead of unmodified cytosine, unless "unmodified cytosine" is listed in the column of the catheter motif, in which case the indicated cytosines are unmodified cytosines. For example, "5-mC only in gap" indicates that the gap segment has 5-methylcytosines, while the wing segments have unmodified cytosines.

40 The 2 ’modified nucleotides and their abbreviations include: 2’-O-methoxyethyl (MOE); 2’-O-methyl (OMe); 2’-O- (2,2,3,3,3pentafluoropropyl) (PentaF); 2’-O - [(2-methoxy) ethyl] -4’-uncle (2’-MOE-4’-uncle); (R) -CMOE-BNA. As illustrated in Tables 20 and 22, a wing may comprise monomers comprising more than one type of 2 ′ substituent. For example, -2-10-2 MOE / PentaF / MOE indicates a nucleotide modified with MOE, followed by two nucleotides modified by PentaF, followed by a gap of ten deoxynucleotides, followed by two nucleotides modified with PentaF. For example, -1-10

45 22 ′ - (butyl-acetomide) -palmitamide Methylene oxy BNA / Methylene oxy BNA indicates that the nucleotide more in 5 ’is 2’ (butylaceceptide) -palmitamide, the second nucleotide is methyloxy BNA nucleotide and the 3 ′ wing is methylene methoxy BNA. Unless otherwise indicated, cytosines are 5-methylcytosines and internucleoside bonds are phosphorothioate.

Table 20: Short antisense compounds directed to SEQ ID No. 14

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

390092

5530 5541 AGAATGAGACTT 1-10-1 MOE 1514

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

390091

5435 5446 TGAGGCATTATC 1-10-1 MOE 1522

390090

5346 5357 AGAGTATCTGAA 1-10-1 MOE 1227

390088

5162 5173 CACATTAACAGT 1-10-1 MOE 1511

390087

5126 5137 GTGGCAACCACA 1-10-1 MOE 1501

390085

5031 5042 ATTTGATGCTGC  1-10-1 MOE 1505

390084

4982 4993 CAAAGAATGGTG 1-10-1 MOE 1215

390082

4910 4921 AGGACTTGGGAT 1-10-1 MOE 1503

390080

4833 4844 TGCTGCACATCC 1-10-1 MOE 1150

392067

4832 4845 CTGCTGCACATCCA 2-10-2 Methyloxy BNA unmodified cytosines in the hollow 1510

390078

4714 4725 CTTTCAGTCATA  1-10-1 MOE 1520

390077

4693 4704 GTCAAATTCTAT 1-10-1 MOE 1252

390076

4599 4610 TTCCAATGACTA 1-10-1 MOE 1506

390075

4576 4587 GTAAGCAAGGCT 1-10-1 MOE # N / A

390074

4533 4544 ACCCTCATTCAG 1-10-1 MOE 1513

390068

4191 4202 GTAAATCCTAAG 1-10-1 MOE 1515

390064

4001 4012 ACCACAGCTAGT 1-10-1 MOE 1498

390063

3977 3988 CACCAATAAGTT 1-10-1 MOE 1219

390058

3828 3839 AGTAGTTGTACT 1-10-1 MOE 1192

390056

3793 3804 GGGCATATCAAA 1-10-1 MOE 1521

390054

3705 3716 AACACTGCACAT 1-10-1 MOE 1493

390052

3623 3634 GACAATTTCTAC  1-10-1 MOE 1492

390050

3503 3514 GTATTCAAGTAA 1-10-1 MOE 1140

390049

3479 3490 GTTAATGACATT 1-10-1 MOE 1491

390047

3428 3439 TGTGTAAGGTCA 1-10-1 MOE 1490

390041

3175 3186 TTAGCACTGGCC 1-10-1 MOE 1489

398076

3171 3182 CACTGGCCTTGA 1-10-1 MOE 1488

398009

3170 3183 GCACTGGCCTTGAT 2-10-2 MOE 1487

398075

3111 3122 AAATCATTGTCA 1-10-1 MOE 1233

398008

3110 3123 TAAATCATTGTCAA 2-10-2 MOE 1486

398074

2913 2924 GCACCAATATGC 1-10-1 MOE 1248

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398007

2912 2925 AGCACCAATATGCT 2-10-2 MOE 1247

398073

2681 2692 TTAGCCAACTGC 1-10-1 MOE 1485

398006

2680 2693 CTTAGCCAACTGCA 2-10-2 MOE 1484

390033

2679 2690 AGCCAACTGCAA 1-10-1 MOE 1483

398072

2671 2682 GCAAACTTATCT 1-10-1 MOE 1482

398005

2670 2683 TGCAAACTTATCTG 2-10-2 MOE 1481

390030

2534 2545 TTTATAAAACTG 1-10-1 MOE 1074

398071

2533 2544 TTATAAAACTGG 1-10-1 MOE 1480

398004

2532 2545 TTTATAAAACTGGA 2-10-2 MOE 1479

390029

2510 2521 AAAGTGCCATCT 1-10-1 MOE 1478

390028

2491 2502 TCCTAATTGAAT 1-10-1 MOE 1477

398070

2481 2492 ATTTTAAATGTC  1-10-1 MOE 1476

398003

2480 2493 AATTTTAAATGTCC  2-10-2 MOE 1475

390027

2455 2466 AGGTATATACAT 1-10-1 MOE 1206

398069

2451 2462 ATATACATGACA 1-10-1 MOE 1474

398002

2450 2463 TATATACATGACAC 2-10-2 MOE 1473

398068

2440 2451 ACAGCTACACAA 1-10-1 MOE 1472

398001

2439 2452 CACAGCTACACAAC 2-10-2 MOE 1471

390026

2438 2449 AGCTACACAACC 1-10-1 MOE 1470

390025

2406 2417 GTGTCAAAACCC 1-10-1 MOE 1211

398067

2405 2416 TGTCAAAACCCT 1-10-1 MOE 1210

398000

2404 2417 GTGTCAAAACCCTG 2-10-2 MOE 1469

398066

2372 2383 AGATTGGTCAGG 1-10-1 MOE 1468

397999

2371 2384 AAGATTGGTCAGGA 2-10-2 MOE 1467

398065

2349 2360 GTTCCTATAACT 1-10-1 MOE 1466

397998

2348 2361 TGTTCCTATAACTG 2-10-2 MOE 1465

398064

2331 2342 CTGACACAATGT 1-10-1 MOE 1464

397997

2330 2343 TCTGACACAATGTC 2-10-2 MOE 1463

398063

2321 2332 GTCCTATTGCCA 1-10-1 MOE 1205

397996

2320 2333 TGTCCTATTGCCAT 2-10-2 MOE 1462

390022

2286 2297 CAGTTTATTCAA  1-10-1 MOE 1142

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336221

2230 2243 TCAGACTTTTGTAA  3-8-3 MOE 1461

336220

2224 2237 TTTTGTAATTTGTG  3-8-3 MOE 1460

336219

2209 2222 ATGCTGATCTTCAT 3-8-3 MOE 1459

390021

2203 2214 CTTCATCAAAAG 1-10-1 MOE 1458

336218

2201 2214 CTTCATCAAAAGGT 3-8-3 MOE 1457

389779

2201 2212 TCATCAAAAGGT 1-9-2 MOE 1176

389979

2201 2212 TCATCAAAAGGT 1-10-1 MOE 1176

397995

2200 2213 TTCATCAAAAGGTT 2-10-2 MOE 1456

336217

2192 2205 AAGGTTCATTCTCT 3-8-3 MOE 1455

390020

2183 2194 TCTGGATCAGAG 1-10-1 MOE 1149

336216

2182 2195 CTCTGGATCAGAGT 3-8-3 MOE 1454

336215

2169 2182 TCAGTGGTGTCAGA 3-8-3 MOE 1453

398062

2166 2177 GGTGTCAGAATA 1-10-1 MOE 1255

397994

2165 2178 TGGTGTCAGAATAT 2-10-2 MOE 1452

390019

2163 2174 GTCAGAATATCT 1-10-1 MOE 1173

336214

2157 2170 GAATATCTATAATG 3-8-3 MOE 1573

398061

2151 2162 ATAATGATCAGG 1-10-1 MOE 1451

397993

2150 2163 TATAATGATCAGGT 2-10-2 MOE 1450

336213

2146 2159 ATGATCAGGTTCAT 3-8-3 MOE 1449

389778

2144 2155 TCAGGTTCATTG 1-9-2 MOE 1448

389978

2144 2155 TCAGGTTCATTG 1-10-1 MOE 1448

398060

2137 2148 CATTGTCACTAA 1-10-1 MOE 1447

336212

2136 2149 TCATTGTCACTAAC 3-8-3 MOE 1446

397992

2136 2149 TCATTGTCACTAAC 2-10-2 MOE 1446

336211

2112 2125 ACAGAAGTTGAACT 3-8-3 MOE 1445

390017

2111 2122 GAAGTTGAACTG 1-10-1 MOE 1444

398059

2108 2119 GTTGAACTGCTA 1-10-1 MOE 1443

397991

2107 2120 AGTTGAACTGCTAG 2-10-2 MOE 1442

336210

2104 2117 TGAACTGCTAGCCT 3-8-3 MOE 1441

335340

2104 2118 TTGAACTGCTAGCCT 1-10-4 MOE 1440

335339

2103 2117 TGAACTGCTAGCCTC 1-10-4 MOE 1439

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

335338

2102 2116 GAACTGCTAGCCTCT 1-10-4 MOE 1438

335337

2101 2115 AACTGCTAGCCTCTG 1-10-4 MOE 1437

335336

2100 2114 ACTGCTAGCCTCTGG 1-10-4 MOE 1436

390430

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines 1163

390431

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines C in wing 9- (aminoethoxy) phenoxazine 1163

390432

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE 1163

390433

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 6 is 9- (aminoethoxy) phenoxazine 1163

390434

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 7 is 9- (aminoethoxy) phenoxazine 1163

390435

2099 2111 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 9 is 9- (aminoethoxy) phenoxazine 1163

335335

2099 2113 CTGCTAGCCTCTGGA 1-10-4 MOE 1435

389777

2098 2109 TAGCCTCTGGAT 1-9-2 MOE 1434

389954

2098 2109 TAGCCTCTGGAT 1-10-1 MOE 1434

335334

2098 2112 TGCTAGCCTCTGGAT 1-10-4 MOE 1433

331429

2097 2110 CTAGCCTCTGGATT 2-10-2 MOE 1431

335349

2097 2110 CTAGCCTCTGGATT 2-10-2 MOE 1431

335367

2097 2110 CTAGCCTCTGGATT 2-10-2 Methylene BNA 1431

335378

2097 2110 CTAGCCTCTGGATT 2-10-2 Methylene BNA 1431

392061

2097 2110 CTAGCCTCTGGATT 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1431

383991

2097 2109 TAGCCTCTGGATT 1-10-2 2 ’- (acetylamino-butyl-acetamido) cholesterol / MOE 1432

383992

2097 2109 TAGCCTCTGGATT 1-10-2 2 ’- (acetylamino-butyl-acetamido) colic acid / MOE 1432

386970

2097 2109 TAGCCTCTGGATT 1-10-2 MOE 1432

390578

2097 2109 TAGCCTCTGGATT 1-10-2 MOE Unmodified cytosines The T in the wings are 2-thiothymines 1432

390614

2097 2109 TAGCCTCTGGATT 1-10-2 PentaF 1432

335333

2097 2111 GCTAGCCTCTGGATT 1-10-4 MOE 1430

386683

2097 2109 TAGCCTCTGGATT 1-10-2 2 ’- (butylacetamide) -palmitamide / MOE 1432

371975

2096 2110 CTAGCCTCTGGATTT 3-10-2 MOE 1429

335341

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

335350

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

335368

2096 2111 GCTAGCCTCTGGATTT 3-10-3 Menyloxy BNA Phosphodiester links on the wings 1428

335379

2096 2111 GCTAGCCTCTGGATTT 3-10-3 Methylene BNA 1428

383739

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE 5-methylcytosine in the hollow 1428

384071

2096 2,111 GCTAGCCTCTGGATTT 3-10-3 OMe 5-methylcytosine in the hollow 1428

384073

2096 2111 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA 5-methylcytosine in the hollow 1428

390576

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE 5-methylcytosine in the hollow T in the wings are 2-thiothymines 1428

390580

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE Pyrimidines in the wings are 5 thiazole Unmodified cytosines in the hollow 1428

390581

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE Unmodified cytosines in the hole 1428

391863

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE Unmodified cytosines 1428

391864

2096 2111 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA Unmodified cytosines in the hole 1428

391865

2096 2111 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA Unmodified cytosines 1428

375560

2096 2110 CTAGCCTCTGGATTT 2-10-3 MOE 1429

391172

2096 2110 CTAGCCTCTGGATTT 2-10-2 Methyloxy BNA Unmodified cytosines 1429

391175

2096 2110 CTAGCCTCTGGATTT 2-10-3 Methylene BNA 1429

391449

2096 2110 CTAGCCTCTGGATTT 2-10-3 MOE Unmodified cytosines 1429

392054

2096 2110 CTAGCCTCTGGATTT 2-10-Menyloxy BNA Cytosines not modified in the hollow 1429

392055

2096 2110 CTAGCCTCTGGATTT 2-10-3 MOE Unmodified cytosines in the hollow 1429

362977

2096 2111 GCTAGCCTCTGGATTT 2-12-2 MOE 1428

386770

2096 2109 TAGCCTCTGGATTT 1-11-2 MOE 1427

390577

2096 2109 TAGCCTCTGGATTT 1-10-3 MOE Unmodified cytosines T on the wings are 2-thiothymines 1427

335332

2096 2110 CTAGCCTCTGGATTT 1-10-4 MOE 1429

390579

2096 2111 GCTAGCCTCTGGATTT 1-1-1-10-3 MOE / 4'-thio / 2'-O - [(2-methoxy) ethyl] 4'-thio / 2'-O - [(2-methoxy) ethyl] -4 ' -thio Unmodified cytosines on the wings Phosphodiester bonds on the wings 1428

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

391173

2096 2110 CTAGCCTCTGGATTT 2-10-3 (5’R) -5’-methyl-Methyloxy BNA Unmodified cytosines 1429

391174

2096 2110 CTAGCCTCTGGATTT 2-10-3 (5’S) -5’-methyl-Methyloxy BNA Unmodified cytosines 1429

390607

2096 2111 GCTAGCCTCTGGATTT 3-10-3 MOE / pentaF Unmodified cytosines in the wing 1428

390609

2096 2111 GCTAGCCTCTGGATTT 3-10-2-1 MOE / MOE / pentaF Unmodified cytosines in the wing 1428

384072

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines in the wings 1428

390606

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines in the wing 1428

390608

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines in the wing 1428

391869

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 Methylene BNA / (5’S) -5’-methyl-Methylene BNA / (5’S) -5’-methyl-Methylene BNA Unmodified cytosines 1428

385036

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 OMe / 2’-O-methyl-4’tio / 2’-O-methyl-4’tio Unmodified cytosines in the wing 1428

385871

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 OMe / 2’-O - [(2methoxy) ethyl] -4’-uncle / 2’O - [(2-methoxy) ethyl] -4’-uncle Unmodified cytosines in the wing 1428

386682

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 2 ’- (butylacetamide) -palmitamide / MOE / MOE 1428

390582

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 MOE / 2'-O - [(2-methoxy) ethyl] -4'-thio / 2'-O - [(2-methoxy) ethyl] -4'-thio Unmodified cytosines in the wings Phosphodiester links on the wings 1428

391868

2096 2111 GCTAGCCTCTGGATTT 1-2-10-3 (5’R) -5’-methi-Menyloxy BNA / Methyloxy BNA / (5’R) -5’-methyl-Methylene-BNA Unmodified cytosines 1428

336209

2095 2108 AGCCTCTGGATTTG  3-8-3 MOE 1425

335331

2095 2109 TAGCCTCTGGATTTG  1-10-4 MOE 1426

335376

2095 2109 TAGCCTCTGGATTTG  1-10-4 Menyloxy BNA 1426

335377

2095 2109 TAGCCTCTGGATTTG  1-10-4 Methylene BNA Phosphodiester on the 3 ’wing 1426

335330

2094 2108 AGCCTCTGGATTTGA  1-10-4 MOE 1424

336208

2079 2092 GGCTCCTCTACTGT 3-8-3 MOE 1423

336207

2073 2086 TCTACTGTTTTTGT 3-8-3 MOE 1422

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336206

2047 2060 CACCTTAAAATTTG  3-8-3 MOE 1518

389776

2046 2057 CTTAAAATTTGG 1-9-2 MOE 1421

389977

2046 2057 CTTAAAATTTGG 1-10-1 MOE 1421

397990

2045 2058 CCTTAAAATTTGGA 2-10-2 MOE 1420

336205

2043 2056 TTAAAATTTGGAGA 3-8-3 MOE 1419

398058

2029 2040 AGTATCGGTTGG 1-10-1 MOE 1418

336204

2028 2041 AAGTATCGGTTGGC 3-8-3 MOE 1417

397989

2028 2041 AAGTATCGGTTGGC 2-10-2 MOE 1417

336203

2002 2015 TGCTTTGTCAAGAT  3-8-3 MOE 1416

389775

2002 2013 CTTTGTCAAGAT  1-9-2 MOE 1177

389976

2002 2013 CTTTGTCAAGAT  1-10-1 MOE 1177

397988

2001 2014 GCTTTGTCAAGATC  2-10-2 MOE 1415

336202

1959 1972 TCCTTGTCATTATC 3-8-3 MOE 1414

389774

1945 1956 CACGCTCTATAC 1-9-2 MOE 1413

389975

1945 1956 CACGCTCTATAC 1-10-1 MOE 1413

336201

1944 1957 GCACGCTCTATACT 3-8-3 MOE 1412

336200

1929 1942 CAAATGCTATCGAT 3-8-3 MOE 1411

389773

1904 1915 AGACTTCCATTT 1-9-2 MOE 1410

389974

1904 1915 AGACTTCCATTT 1-10-1 MOE 1410

336199

1902 1915 AGACTTCCATTTTC  3-8-3 MOE 1409

336198

1884 1897 TTTTCTGAGGTTTC  3-8-3 MOE 1408

398057

1878 1889 GGTTTCCTCTGG 1-10-1 MOE 1407

397987

1877 1890 AGGTTTCCTCTGGT  2-10-2 MOE 1406

336197

1873 1886 TTCCTCTGGTCCTG 3-8-3 MOE 1405

390015

1868 1879 GGTCCTGGTATG 1-10-1 MOE 1404

398056

1865 1876 CCTGGTATGAAG 1-10-1 MOE 1403

336196

1864 1877 TCCTGGTATGAAGA 3-8-3 MOE 1402

397986

1864 1877 TCCTGGTATGAAGA 2-10-2 MOE 1402

398055

1849 1860 TATTTACCCAAA 1-10-1 MOE 1401

397985

1848 1861 GTATTTACCCAAAA 2-10-2 MOE 1400

336195

1847 1860 TATTTACCCAAAAG 3-8-3 MOE 1399

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

389772

1846 1857 TTACCCAAAAGT 1-9-2 MOE 1398

389973

1846 1857 TTACCCAAAAGT 1-10-1 MOE 1398

336194

1838 1851 AAAAGTGAAACATT 3-8-3 MOE 1145

398054

1836 1847 GTGAAACATTTT 1-10-1 MOE 1144

397984

1835 1848 AGTGAAACATTTTG  2-10-2 MOE 1397

336193

1828 1841 CATTTTGTCCTTTT 3-8-3 MOE 1182

336192

1810 1823 CATCTTGTTCTGTT 3-8-3 MOE 1396

336191

1800 1813 TGTTTGTGGAAGAA  3-8-3 MOE 1395

398053

1796 1807 TGGAAGAACTCT 1-10-1 MOE 1394

397983

1795 1808 GTGGAAGAACTCTA 2-10-2 MOE 1393

389771

1794 1805 GAAGAACTCTAC 1-9-2 MOE 1392

389972

1794 1805 GAAGAACTCTAC 1-10-1 MOE 1392

336190

1789 1802 GAACTCTACTTTGA  3-8-3 MOE 1391

336189

1773 1786 TCACCACACACAGG 3-8-3 MOE 1390

336188

1754 1767 GCTGAGGGAACTCA 3-8-3 MOE 1389

398052

1751 1762 GGGAACTCAAAG 1-10-1 MOE 1388

389770

1750 1761 GGAACTCAAAGT 1-9-2 MOE 1386

389971

1750 1761 GGAACTCAAAGT 1-10-1 MOE 1386

397982

1750 1763 AGGGAACTCAAAGT 2-10-2 MOE 1387

336187

1747 1760 GAACTCAAAGTACA 3-8-3 MOE 1385

390012

1745 1756 TCAAAGTACATG 1-10-1 MOE 1384

336186

1688 1701 TCTTCACCTTTAGC  3-8-3 MOE 1383

398051

1684 1695 CCTTTAGCTGGC  1-10-1 MOE 1220

397981

1683 1696 ACCTTTAGCTGGCA  2-10-2 MOE 1382

336185

1677 1690 AGCTGGCAGACCAC 3-8-3 MOE 1381

389769

1676 1687 TGGCAGACCACA 1-9-2 MOE 1249

389970

1676 1687 TGGCAGACCACA 1-10-1 MOE 1249

392060

1675 1688 CTGGCAGACCACAA 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1380

398050

1672 1683 AGACCACAAACT 1-10-1 MOE 1379

397980

1671 1684 CAGACCACAAACTG 2-10-2 MOE 1378

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

390011

1658 1669 GGATTGCAAGTT 1-10-1 MOE 1238

336184

1655 1668 GATTGCAAGTTCCG 3-8-3 MOE 1508

336183

1644 1657 CCGCCACTGAACAT 3-8-3 MOE 1377

390010

1643 1654 CCACTGAACATT 1-10-1 MOE 1240

398049

1641 1652 ACTGAACATTGG 1-10-1 MOE 1376

397979

1640 1653 CACTGAACATTGGA 2-10-2 MOE 1375

336182

1633 1646 CATTGGAATAGTTT 3-8-3 MOE 1374

389768

1630 1641 GAATAGTTTCAA  1-9-2 MOE 1373

389969

1630 1641 GAATAGTTTCAA  1-10-1 MOE 1373

398048

1626 1637 AGTTTCAAACAT 1-10-1 MOE 1372

397978

1625 1638 TAGTTTCAAACATC  2-10-2 MOE 1371

336181

1623 1636 GTTTCAAACATCAT 3-8-3 MOE 1370

398047

1614 1625 CATCTTGTGAAA 1-10-1 MOE 1369

336180

1613 1626 TCATCTTGTGAAAC 3-8-3 MOE 1368

390009

1613 1624 ATCTTGTGAAAC 1-10-1 MOE 1175

397977

1613 1626 TCATCTTGTGAAAC 2-10-2 MOE 1368

390007

1563 1574 CAGGTAGCTATA 1-10-1 MOE 1367

336179

1561 1574 CAGGTAGCTATAAT 3-8-3 MOE 1366

336178

1541 1554 CATAGCGCCTCTGA 3-8-3 MOE 1365

336177

1534 1547 CCTCTGACTGGGAA 3-8-3 MOE 1364

389767

1534 1545 TCTGACTGGGAA 1-9-2 MOE 1151

389968

1534 1545 TCTGACTGGGAA 1-10-1 MOE 1151

335344

1503 1516 TCTCTGGTCCTTAC 2-10-2 MOE 1363

335355

1503 1516 TCTCTGGTCCTTAC 2-10-2 MOE Phosphodiester link on the wings 1363

335370

1503 1516 TCTCTGGTCCTTAC 2-10-2 Menyloxy BNA Phosphodiester bond on the wings 1363

335381

1503 1516 TCTCTGGTCCTTAC 2-10-2 Methylene BNA 1363

335411

1503 1516 TCTCTGGTCCTTAC 2-10-2 MOE 3 ’C is 9- (aminoethoxy) phenoxazine 1363

335412

1503 1516 TCTCTGGTCCTTAC 2-10-2 MOE C in the 5 ’wing is 9 (aminoethoxy) phenoxazine 1363

335413

1503 1516 TCTCTGGTCCTTAC 2-10-2 MOE C in the wings are 9 (aminoethoxy) phenoxazine 1363

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336176

1502 1515 CTCTGGTCCTTACT 3-8-3 MOE 1361

335345

1502 1517 GTCTCTGGTCCTTACT 3-10-3 MOE 1362

335356

1502 1517 GTCTCTGGTCCTTACT 3-10-3 MOE Phosphodiester link on the wings 1362

335371

1502 1517 GTCTCTGGTCCTTACT 3-10-3 Menyloxy BNA Phosphodiester bond on the wings 1362

335382

1502 1517 GTCTCTGGTCCTTACT 3-10-3 Methylene BNA 1362

335414

1502 1517 GTCTCTGGTCCTTACT 3-10-3 MOE C in the 3 ’wing is 9 (aminoethoxy) phenoxazine 1362

335415

1502 1517 GTCTCTGGTCCTTACT 3-10-3 MOE C at 5 ’the wing is 9 (aminoethoxy) phenoxazine 1362

335416

1502 1517 GTCTCTGGTCCTTACT 3-10-3 MOE C in the wings are 9 (aminoethoxy) phenoxazine 1362

336175

1495 1508 CCTTACTTCCCCAT 3-8-3 MOE 1360

336174

1472 1485 GGGCCTCTTGTGCC 3-8-3 MOE 1359

336173

1465 1478 TTGTGCCTTTAAAA 3-8-3 MOE 1358

398046

1465 1476 GTGCCTTTAAAA 1-10-1 MOE 1199

389766

1464 1475 TGCCTTTAAAAA 1-9-2 MOE 1217

389967

1464 1475 TGCCTTTAAAAA 1-10-1 MOE 1217

397976

1464 1477 TGTGCCTTTAAAAA 2-10-2 MOE 1357

336172

1437 1450 AATAAATATGCACA 3-8-3 MOE 1356

398045

1423 1434 TCATTACACCAG 1-10-1 MOE 1355

336171

1422 1435 ATCATTACACCAGT 3-8-3 MOE 1354

389765

1422 1433 CATTACACCAGT 1-9-2 MOE 1353

389966

1422 1433 CATTACACCAGT 1-10-1 MOE 1353

397975

1422 1435 ATCATTACACCAGT 2-10-2 MOE 1354

390005

1400 1411 CCAGCTTTACAG  1-10-1 MOE 1352

336170

1392 1405 TTACAGTGAATTGC 3-8-3 MOE 1351

398044

1382 1393 GCTGCAACATGA 1-10-1 MOE 1350

336169

1381 1394 TGCTGCAACATGAT 3-8-3 MOE 1349

389764

1381 1392 CTGCAACATGAT 1-9-2 MOE 1018

389965

1381 1392 CTGCAACATGAT 1-10-1 MOE 1018

397974

1381 1394 TGCTGCAACATGAT 2-10-2 MOE 1349

336168

1362 1375 TCTTCACTTAGCCA 3-8-3 MOE 1348

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

390004

1362 1373 TTCACTTAGCCA 1-10-1 MOE 1208

336167

1353 1366 AGCCATTGGTCAAG 3-8-3 MOE 1347

398043

1345 1356 CAAGATCTTCAC 1-10-1 MOE 1244

336166

1344 1357 TCAAGATCTTCACA 3-8-3 MOE 1346

390003

1344 1355 AAGATCTTCACA 1-10-1 MOE 1243

397973

1344 1357 TCAAGATCTTCACA 2-10-2 MOE 1346

336165

1329 1342 AAGGGTTTGATAAG  3-8-3 MOE 1345

390002

1322 1333 ATAAGTTCTAGC 1-10-1 MOE 1344

336164

1318 1331 AAGTTCTAGCTGTG 3-8-3 MOE 1343

398042

1305 1316 TGGGTTATGGTC 1-10-1 MOE 1214

336163

1304 1317 GTGGGTTATGGTCT 3-8-3 MOE 1342

397972

1304 1317 GTGGGTTATGGTCT 2-10-2 MOE 1342

398089

1298 1309 TGGTCTTCAAAA 1-10-1 MOE 1341

389763

1296 1307 GTCTTCAAAAGG 1-9-2 MOE 1197

389964

1296 1307 GTCTTCAAAAGG 1-10-1 MOE 1197

398041

1294 1305 CTTCAAAAGGAT 1-10-1 MOE 1196

336162

1293 1306 TCTTCAAAAGGATA 3-8-3 MOE 1340

397971

1293 1306 TCTTCAAAAGGATA 2-10-2 MOE 1340

398040

1279 1290 GTGCAACTCTGC 1-10-1 MOE 1236

336161

1278 1291 TGTGCAACTCTGCA 3-8-3 MOE 1235

397970

1278 1291 TGTGCAACTCTGCA 2-10-2 MOE 1235

398039

1264 1275 TAAATTTGGCGG 1-10-1 MOE 1339

397969

1263 1276 TTAAATTTGGCGGT  2-10-2 MOE 1338

336160

1261 1274 AAATTTGGCGGTGT  3-8-3 MOE 1337

336159

1253 1266 CGGTGTCATAATGT 3-8-3 MOE 1336

398038

1252 1263 TGTCATAATGTC 1-10-1 MOE 1200

390000

1251 1262 GTCATAATGTCT 1-10-1 MOE 1194

397968

1251 1264 GTGTCATAATGTCT 2-10-2 MOE 1195

336158

1227 1240 AGATTGTATATCTT 3-8-3 MOE 1335

389762

1220 1231 ATCTTGTAATGG 1-9-2 MOE 1334

389963

1220 1231 ATCTTGTAATGG 1-10-1 MOE 1334

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336157

1215 1228 TTGTAATGGTTTTT 3-8-3 MOE 1333

336156

1202 1215 TATGCTTTGAATCC  3-8-3 MOE 1332

389998

1199 1210 TTTGAATCCAAA 1-10-1 MOE 1331

397967

1198 1211 CTTTGAATCCAAAA 2-10-2 MOE 1330

336155

1190 1203 CCAAAAACCTTACT 3-8-3 MOE 1500

336154

1176 1189 ACATCATCAATATT 3-8-3 MOE 1329

389761

1171 1182 CAATATTGTTCC 1-9-2 MOE 1328

389962

1171 1182 CAATATTGTTCC 1-10-1 MOE 1328

398037

1170 1181 AATATTGTTCCT 1-10-1 MOE 1202

397966

1169 1182 CAATATTGTTCCTG 2-10-2 MOE 1327

336153

1164 1177 TTGTTCCTGTATAC 3-8-3 MOE 1326

336152

1149 1162 CCTTCAAGTCTTTC  3-8-3 MOE 1325

389996

1141 1152 TTTCTGCAGGAA  1-10-1 MOE 1165

336151

1138 1151 TTCTGCAGGAAATC 3-8-3 MOE 1324

398036

1138 1149 CTGCAGGAAATC 1-10-1 MOE 1323

397965

1137 1150 TCTGCAGGAAATCC 2-10-2 MOE 1322

389760

1129 1140 ATCCCATAGCAA 1-9-2 MOE 1321

389961

1129 1140 ATCCCATAGCAA 1-10-1 MOE 1321

398035

1126 1137 CCATAGCAATAA 1-10-1 MOE 1320

336150

1125 1138 CCCATAGCAATAAT 3-8-3 MOE 1319

397964

1125 1138 CCCATAGCAATAAT 2-10-2 MOE 1319

336149

1110 1123 TTTGGATAAATATA 3-8-3 MOE 1496

389995

1106 1117 TAAATATAGGTC 1-10-1 MOE 1516

336148

1100 1113 TATAGGTCAAGTCT 3-8-3 MOE 1495

398034

1099 1110 AGGTCAAGTCTA 1-10-1 MOE 1300

397963

1098 1111 TAGGTCAAGTCTAA 2-10-2 MOE 1494

389994

1095 1106 CAAGTCTAAGTC 1-10-1 MOE 1299

336147

1090 1103 GTCTAAGTCGAATC 3-8-3 MOE 1298

389993

1083 1094 GAATCCATCCTC 1-10-1 MOE 1297

336146

1080 1093 AATCCATCCTCTTG 3-8-3 MOE 1296

398033

1077 1088 ATCCTCTTGATA 1-10-1 MOE 1198

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

397962

1076 1089 CATCCTCTTGATAT 2-10-2 MOE 1295

336145

1070 1083 CTTGATATCTCCTT 3-8-3 MOE 1294

336144

1057 1070 TTTGTTTCTGCTAA  3-8-3 MOE 1293

389759

1056 1067 GTTTCTGCTAAC  1-9-2 MOE 1292

389960

1056 1067 GTTTCTGCTAAC  1-10-1 MOE 1292

392059

1055 1068 TGTTTCTGCTAACG  2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1291

336143

1044 1057 ACGATCTCTTTGAT  3-8-3 MOE 1290

398032

1038 1049 TTTGATGATGGC  1-10-1 MOE 1222

397961

1037 1050 CTTTGATGATGGCT 2-10-2 MOE 1289

389992

1036 1047 TGATGATGGCTG 1-10-1 MOE 1288

336142

1032 1045 ATGATGGCTGTCAT 3-8-3 MOE 1287

389991

1021 1032 TGTCTGGGAGCC 1-10-1 MOE 1286

392058

1020 1033 ATGTCTGGGAGCCT 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1285

397960

1020 1033 ATGTCTGGGAGCCT 2-10-2 MOE 1285

389990

1007 1018 TGGCTGAAGAAA 1-10-1 MOE 1284

397959

1006 1019 GTGGCTGAAGAAAA 2-10-2 MOE 1283

398031

987 998 GAGAGATGGCAG 1-10-1 MOE 1282

397958

986 999 AGAGAGATGGCAGA 2-10-2 MOE 1281

389758

983 994 GATGGCAGAAGC 1-9-2 MOE 1280

389959

983 994 GATGGCAGAAGC 1-10-1 MOE 1280

398030

976 987 GAAGCTGCTGGT 1-10-1 MOE 1143

397957

975 988 AGAAGCTGCTGGTG 2-10-2 MOE 1279

389989

953 964 TTCTGCAGGATG 1-10-1 MOE 1170

389757

941 952 GAAATGGCTCTG 1-9-2 MOE 1278

389958

941 952 GAAATGGCTCTG 1-10-1 MOE 1278

397956

940 953 GGAAATGGCTCTGG 2-10-2 MOE 1277

398029

931 942 TGGACTTGGCGG 1-10-1 MOE 1186

397955

930 943 CTGGACTTGGCGGT 2-10-2 MOE 1276

398028

914 925 GATGCCCCTCGC 1-10-1 MOE 1275

397954

913 926 TGATGCCCCTCGCT 2-10-2 MOE 1274

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398027

883 894 GGACCGCAGCCG  1-10-1 MOE 1155

397953

882 895 TGGACCGCAGCCGG 2-10-2 MOE 1273

389756

874 885 CCGGGTAATGGC 1-9-2 MOE 1272

389957

874 885 CCGGGTAATGGC 1-10-1 MOE 1272

398026

867 878 ATGGCTGCTGCG 1-10-1 MOE 1160

397952

866 879 AATGGCTGCTGCGG 2-10-2 MOE 1271

389987

848 859 CTGGATGGTTGC 1-10-1 MOE 1270

389755

806 817 AGAGGCCTGGCA 1-9-2 MOE 1269

389956

806 817 AGAGGCCTGGCA 1-10-1 MOE 1269

389985

584 595 ATGGTGACAGGC 1-10-1 MOE 1268

398025

581 592 GTGACAGGCGAC 1-10-1 MOE 1267

397951

580 593 GGTGACAGGCGACT 2-10-2 MOE 1266

389754

312 323 TGCTCACAGGCG 1-9-2 MOE 1158

389955

312 323 TGCTCACAGGCG 1-10-1 MOE 1158

398024

231 242 CAGCGGCTCAAC 1-10-1 MOE 1265

397950

230 243 ACAGCGGCTCAACT 2-10-2 MOE 1264

389982

205 216 CATGGCTGCAGC 1-10-1 MOE 1161

392056

204 217 TCATGGCTGCAGCT 2-10-2 Methylene BNA 1263

394424

204 217 TCATGGCTGCAGCT 2-10-2 MOE 1263

396007

204 217 TCATGGCTGCAGCT 2-10-2 (R) -CMOE BNA Unmodified cytosines 1263

396008

204 217 TCATGGCTGCAGCT 2-10-2 (S) -CMOE BNA Unmodified cytosines 1263

396009

204 217 TCATGGCTGCAGCT 2-10-2 α-L-menyloxy BNA Unmodified cytosines 1263

396566

204 217 TCATGGCTGCAGCT 2-10-2 Oxiamino BNA Unmodified cytosines 1263

396567

204 217 TCATGGCTGCAGCT 2-10-2 N-Methyl-Oxyamino BNA Unmodified cytosines 1263

396568

204 217 TCATGGCTGCAGCT 2-10-2 (6R) -6-Methyl Methyloxy BNA Unmodified cytosines 1263

397913

204 217 TCATGGCTGCAGCT 2-10-2 OMe Unmodified cytosines in the hole 1263

401974

204 217 TCATGGCTGCAGCT 2-10-2 OMe Unmodified cytosines 1263

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

403737

204 217 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-thiazolo nucleotide bases on the wings 1263

404121

204 217 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-methylcytosine in the gaps in 3 ’Terminal THF phosphorothioate 1263

404228

204 217 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-methylcytosine in the holes in the 5′-terminal reverse inverse 1263

396024

204 217 TCATGGCTGCAGCT 2-10-2 (6’S) -6’-methyl-Methyloxy BNA Unmodified cytosines 1263

396569

204 217 TCATGGCTGCAGCT 2-10-2 (5’S) -5’-methyl-Methyloxy BNA Unmodified cytosines 1263

396577

204 217 TCATGGCTGCAGCT 2-10-1-1 Methylene BNA / Methylene BNA / 2 ’- (butylacetamide) -palmitamide / Unmodified cytosines in the hole 1263

396576

204 217 TCATGGCTGCAGCT 1-1-10-2 2 ’- (butylacetamide) -palmitamide / Methyloxy BNA / Methyloxy BNA Cytosines not modified in the recess 1263

398023

191 202 CCGAGAGGAGAG 1-10-1 MOE 1262

397949

190 203 TCCGAGAGGAGAGA 2-10-2 MOE 1261

398022

126 137 AAGAGTCCCGCC 1-10-1 MOE 1260

397948

125 138 AAAGAGTCCCGCCA  2-10-2 MOE 1259

Table 22: Short antisense compounds directed to SEQ ID No. 15

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

397948

525 538 AAAGAGTCCCGCCA  2-10-2 MOE 1259

398022

526 537 AAGAGTCCCGCC 1-10-1 MOE 1260

397949

590 603 TCCGAGAGGAGAGA 2-10-2 MOE 1261

398023

591 602 CCGAGAGGAGAG 1-10-1 MOE 1262

394424

604 617 TCATGGCTGCAGCT 2-10-2 MOE 1263

397913

604 617 TCATGGCTGCAGCT 2-10-2 OMe Unmodified cytosines in the hole 1263

401974

604 617 TCATGGCTGCAGCT 2-10-2 Ome Unmodified cytosines 1263

403737

604 617 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-thiazole nucleotide bases on the wings 1263

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

392056

604 617 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1263

396576

604 617 TCATGGCTGCAGCT 1-1-10-2 2 ’- (butylacetamide) -palmitamide / Methyloxy BNA / Methyloxy BNA Cytosines not modified in the recess 1263

396577

604 617 TCATGGCTGCAGCT 2-10-1-2 Methylene BNA / Methylene BNA / 2 ’- (butylacetamide) -palmitamide / Unmodified cytosines in the hole 1263

404121

604 617 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-methylcytosine in gaps 3 ’Terminal THF phosphorothioate 1263

404228

604 617 TCATGGCTGCAGCT 2-10-2 Methyloxy BNA 5-methylcytosine in the 5′-terminal reverse inverse holes 1263

396007

604 617 TCATGGCTGCAGCT 2-10-2 (R) -CMOE BNA Unmodified cytosines 1263

396008

604 617 TCATGGCTGCAGCT 2-10-2 (S) -CMOE BNA Unmodified cytosines 1263

396009

604 617 TCATGGCTGCAGCT 2-10-2 α-L-Methylene methoxy BNA Unmodified cytosines 1263

396024

604 617 TCATGGCTGCAGCT 2-10-2 (6’S) -6’-methyl-Methyloxy BNA Unmodified cytosines 1263

396566

604 617 TCATGGCTGCAGCT 2-10-2 Oxiamino BNA Unmodified cytosines 1263

396567

604 617 TCATGGCTGCAGCT 2-10-2 N-Methyl-Oxyamino BNA Unmodified cytosines 1263

396568

604 617 TCATGGCTGCAGCT 2-10-2 (6R) -6-Methyl Methyloxy BNA Unmodified cytosines 1263

396569

604 617 TCATGGCTGCAGCT 2-10-2 (5’S) -5’-methyl-Methyloxy BNA Unmodified cytosines 1263

389982

605 616 CATGGCTGCAGC 1-10-1 MOE 1161

397950

630 643 ACAGCGGCTCAACT 2-10-2 MOE 1264

398024

631 642 CAGCGGCTCAAC 1-10-1 MOE 1265

389955

712 723 TGCTCACAGGCG 1-10-1 MOE 1158

389754

712 723 TGCTCACAGGCG 1-9-2 MOE 1158

397951

980 993 GGTGACAGGCGACT 2-10-2 MOE 1266

398025

981 992 GTGACAGGCGAC 1-10-1 MOE 1267

389985

984 995 ATGGTGACAGGC 1-10-1 MOE 1268

389956

1206 1217 AGAGGCCTGGCA 1-10-1 MOE 1269

389755

1206 1217 AGAGGCCTGGCA 1-9-2 MOE 1269

389987

1248 1259 CTGGATGGTTGC 1-10-1 MOE 1270

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

397952

1266 1279 AATGGCTGCTGCGG 2-10-2 MOE 1271

398026

1267 1278 ATGGCTGCTGCG 1-10-1 MOE 1160

389957

1274 1285 CCGGGTAATGGC 1-10-1 MOE 1272

389756

1274 1285 CCGGGTAATGGC 1-9-2 MOE 1272

397953

1282 1295 TGGACCGCAGCCGG 2-10-2 MOE 1273

398027

1283 1294 GGACCGCAGCCG  1-10-1 MOE 1155

397954

1313 1326 TGATGCCCCTCGCT 2-10-2 MOE 1274

398028

1314 1325 GATGCCCCTCGC 1-10-1 MOE 1275

397955

1330 1343 CTGGACTTGGCGGT 2-10-2 MOE 1276

398029

1331 1342 TGGACTTGGCGG 1-10-1 MOE 1186

397956

1340 1353 GGAAATGGCTCTGG 2-10-2 MOE 1277

389958

1341 1352 GAAATGGCTCTG 1-10-1 MOE 1278

389757

1341 1352 GAAATGGCTCTG 1-9-2 MOE 1278

389989

1353 1364 TTCTGCAGGATG 1-10-1 MOE 1170

397957

1375 1388 AGAAGCTGCTGGTG 2-10-2 MOE 1279

398030

1376 1387 GAAGCTGCTGGT 1-10-1 MOE 1143

389959

1383 1394 GATGGCAGAAGC 1-10-1 MOE 1280

389758

1383 1394 GATGGCAGAAGC 1-9-2 MOE 1280

397958

1386 1399 AGAGAGATGGCAGA 2-10-2 MOE 1281

398031

1387 1398 GAGAGATGGCAG 1-10-1 MOE 1282

397959

1406 1419 GTGGCTGAAGAAAA 2-10-2 MOE 1283

389990

1407 1418 TGGCTGAAGAAA 1-10-1 MOE 1284

397960

1420 1433 ATGTCTGGGAGCCT 2-10-2 MOE 1285

392058

1420 1433 ATGTCTGGGAGCCT 2-10-2 Methyloxy BNA 5-methylcytosine in the wing 1285

389991

1421 1432 TGTCTGGGAGCC 1-10-1 MOE 1286

336142

1432 1445 ATGATGGCTGTCAT 3-8-3 MOE 1287

389992

1436 1447 TGATGATGGCTG 1-10-1 MOE 1288

397961

1437 1450 CTTTGATGATGGCT 2-10-2 MOE 1289

398032

1438 1449 TTTGATGATGGC  1-10-1 MOE 1222

336143

1444 1457 ACGATCTCTTTGAT  3-8-3 MOE 1290

392059

1455 1468 TGTTTCTGCTAACG  2-10-2 Methyloxy BNA 5-methylcytosine in the wing 1291

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

389960

1456 1467 GTTTCTGCTAAC  1-10-1 MOE 1292

389759

1456 1467 GTTTCTGCTAAC  1-9-2 MOE 1292

336144

1457 1470 TTTGTTTCTGCTAA  3-8-3 MOE 1293

336145

1470 1483 CTTGATATCTCCTT 3-8-3 MOE 1294

397962

1476 1489 CATCCTCTTGATAT 2-10-2 MOE 1295

398033

1477 1488 ATCCTCTTGATA 1-10-1 MOE 1198

336146

1480 1493 AATCCATCCTCTTG 3-8-3 MOE 1296

389993

1483 1494 GAATCCATCCTC 1-10-1 MOE 1297

336147

1490 1503 GTCTAAGTCGAATC 3-8-3 MOE 1298

389994

1495 1506 CAAGTCTAAGTC 1-10-1 MOE 1299

398034

1499 1510 AGGTCAAGTCTA 1-10-1 MOE 1300

398010

1500 1513 TACAGGTCAAGTCT 2-10-2 MOE 1166

398077

1501 1512 ACAGGTCAAGTC 1-10-1 MOE 1167

398011

1512 1525 CGCAGAAATGGATA 2-10-2 MOE 1301

398078

1513 1524 GCAGAAATGGAT 1-10-1 MOE 1302

398012

1570 1583 TTCGCATCCGTCTA 2-10-2 MOE 1303

398079

1571 1582 TCGCATCCGTCT 1-10-1 MOE 1304

398013

1663 1676 CCCTAGGTTGAATA 2-10-2 MOE 1305

398080

1664 1675 CCTAGGTTGAAT 1-10-1 MOE 1306

398014

2025 2038 GTTATGCAAATCAG 2-10-2 MOE 1307

398081

2026 2037 TTATGCAAATCA 1-10-1 MOE 1308

398015

2620 2633 TGACTCAGTAAATT 2-10-2 MOE 1309

398082

2621 2632 GACTCAGTAAAT 1-10-1 MOE 1310

398016

2655 2668 TTAAAATTCTTGGG 2-10-2 MOE 1311

398083

2656 2667 TAAAATTCTTGG 1-10-1 MOE 1312

398017

2687 2700 CCTAACTTTTAGAC  2-10-2 MOE 1313

398084

2688 2699 CTAACTTTTAGA  1-10-1 MOE 1314

398018

2745 2758 ACCTGAAACTGCAA 2-10-2 MOE 1315

398085

2746 2757 CCTGAAACTGCA 1-10-1 MOE 1157

398019

13166 13179 GTGTCAAAACCACT 2-10-2 MOE 1316

398086

13167 13178 TGTCAAAACCAC 1-10-1 MOE 1204

398020

14675 14688 CCTATTCCCACTGA 2-10-2 MOE 1317

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398087

14676 14687 CTATTCCCACTG 1-10-1 MOE 1318

390033

15351 15362 AGCCAACTGCAA 1-10-1 MOE 1483

398021

30985 30998 TTGGATAAATATCT 2-10-2 MOE 1168

398088

30986 30997 TGGATAAATATC 1-10-1 MOE 1169

397964

31001 31014 CCCATAGCAATAAT 2-10-2 MOE 1319

336150

31001 31014 CCCATAGCAATAAT 3-8-3 MOE 1319

398035

31002 31013 CCATAGCAATAA 1-10-1 MOE 1320

389961

31005 31016 ATCCCATAGCAA 1-10-1 MOE 1321

389760

31005 31016 ATCCCATAGCAA 1-9-2 MOE 1321

397965

31013 31026 TCTGCAGGAAATCC 2-10-2 MOE 1322

398036

31014 31025 CTGCAGGAAATC 1-10-1 MOE 1323

336151

31014 31027 TTCTGCAGGAAATC 3-8-3 MOE 1324

389996

31017 31028 TTTCTGCAGGAA  1-10-1 MOE 1165

336152

31025 31038 CCTTCAAGTCTTTC  3-8-3 MOE 1325

336153

31040 31053 TTGTTCCTGTATAC 3-8-3 MOE 1326

397966

31045 31058 CAATATTGTTCCTG 2-10-2 MOE 1327

398037

31046 31057 AATATTGTTCCT 1-10-1 MOE 1202

389962

31047 31058 CAATATTGTTCC 1-10-1 MOE 1328

389761

31047 31058 CAATATTGTTCC 1-9-2 MOE 1328

336154

31052 31065 ACATCATCAATATT 3-8-3 MOE 1329

389977

31480 31491 CTTAAAATTTGG 1-10-1 MOE 1421

389776

31480 31491 CTTAAAATTTGG 1-9-2 MOE 1421

397967

62446 62459 CTTTGAATCCAAAA 2-10-2 MOE 1330

389998

62447 62458 TTTGAATCCAAA 1-10-1 MOE 1331

336156

62450 62463 TATGCTTTGAATCC  3-8-3 MOE 1332

336157

62463 62476 TTGTAATGGTTTTT 3-8-3 MOE 1333

389963

62468 62479 ATCTTGTAATGG 1-10-1 MOE 1334

389762

62468 62479 ATCTTGTAATGG 1-9-2 MOE 1334

336158

62475 62488 AGATTGTATATCTT 3-8-3 MOE 1335

390000

67987 67998 GTCATAATGTCT 1-10-1 MOE 1194

397968

67987 68000 GTGTCATAATGTCT 2-10-2 MOE 1195

398038

67988 67999 TGTCATAATGTC 1-10-1 MOE 1200

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336159

67989 68002 CGGTGTCATAATGT 3-8-3 MOE 1336

336160

67997 68010 AAATTTGGCGGTGT  3-8-3 MOE 1337

397969

67999 68012 TTAAATTTGGCGGT  2-10-2 MOE 1338

398039

68000 68011 TAAATTTGGCGG 1-10-1 MOE 1339

397971

69952 69965 TCTTCAAAAGGATA 2-10-2 MOE 1340

336162

69952 69965 TCTTCAAAAGGATA 3-8-3 MOE 1340

398041

69953 69964 CTTCAAAAGGAT 1-10-1 MOE 1196

389964

69955 69966 GTCTTCAAAAGG 1-10-1 MOE 1197

389763

69955 69966 GTCTTCAAAAGG 1-9-2 MOE 1197

398089

69957 69968 TGGTCTTCAAAA 1-10-1 MOE 1341

397972

69963 69976 GTGGGTTATGGTCT 2-10-2 MOE 1342

336163

69963 69976 GTGGGTTATGGTCT 3-8-3 MOE 1342

398042

69964 69975 TGGGTTATGGTC 1-10-1 MOE 1214

336164

69977 69990 AAGTTCTAGCTGTG 3-8-3 MOE 1343

390002

69981 69992 ATAAGTTCTAGC 1-10-1 MOE 1344

336165

69988 70001 AAGGGTTTGATAAG  3-8-3 MOE 1345

390003

70003 70014 AAGATCTTCACA 1-10-1 MOE 1243

397973

70003 70016 TCAAGATCTTCACA 2-10-2 MOE 1346

336166

70003 70016 TCAAGATCTTCACA 3-8-3 MOE 1346

398043

70004 70015 CAAGATCTTCAC 1-10-1 MOE 1244

336167

70012 70025 AGCCATTGGTCAAG 3-8-3 MOE 1347

390004

70021 70032 TTCACTTAGCCA 1-10-1 MOE 1208

336168

70021 70034 TCTTCACTTAGCCA 3-8-3 MOE 1348

389965

70040 70051 CTGCAACATGAT 1-10-1 MOE 1018

389764

70040 70051 CTGCAACATGAT 1-9-2 MOE 1018

397974

70040 70053 TGCTGCAACATGAT 2-10-2 MOE 1349

336169

70040 70053 TGCTGCAACATGAT 3-8-3 MOE 1349

398044

70041 70052 GCTGCAACATGA 1-10-1 MOE 1350

336170

70051 70064 TTACAGTGAATTGC 3-8-3 MOE 1351

390005

70059 70070 CCAGCTTTACAG  1-10-1 MOE 1352

389966

70081 70092 CATTACACCAGT 1-10-1 MOE 1353

389765

70081 70092 CATTACACCAGT 1-9-2 MOE 1353

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

397975

70081 70094 ATCATTACACCAGT 2-10-2 MOE 1354

336171

70081 70094 ATCATTACACCAGT 3-8-3 MOE 1354

398045

70082 70093 TCATTACACCAG 1-10-1 MOE 1355

336172

70096 70109 AATAAATATGCACA 3-8-3 MOE 1356

389967

70123 70134 TGCCTTTAAAAA 1-10-1 MOE 1217

389766

70123 70134 TGCCTTTAAAAA 1-9-2 MOE 1217

397976

70123 70136 TGTGCCTTTAAAAA 2-10-2 MOE 1357

398046

70124 70135 GTGCCTTTAAAA 1-10-1 MOE 1199

336173

70124 70137 TTGTGCCTTTAAAA 3-8-3 MOE 1358

336174

70131 70144 GGGCCTCTTGTGCC 3-8-3 MOE 1359

336175

70154 70167 CCTTACTTCCCCAT 3-8-3 MOE 1360

335345

70161 70176 GTCTCTGGTCCTTACT 3-10-3 MOE 1362

335356

70161 70176 GTCTCTGGTCCTTACT 3-10-3 MOE Phosphodiester link on the wings 1362

335414

70161 70176 GTCTCTGGTCCTTACT 3-10-3 MOE C in the 3 ’wing is 9 (aminoethoxy) phenoxazine 1362

335415

70161 70176 GTCTCTGGTCCTTACT 3-10-3 MOE C in the 5 ’wing is 9 (aminoethoxy) phenoxazine 1362

335416

70161 70176 GTCTCTGGTCCTTACT 3-10-3 MOE The C in the wings are 9 (aminoethoxy) phenoxazine 1362

336176

70161 70174 CTCTGGTCCTTACT 3-8-3 MOE 1361

335371

70161 70176 GTCTCTGGTCCTTACT 3-10-3 Menyloxy BNA Phosphodiester bond on the wings 1362

335382

70161 70176 GTCTCTGGTCCTTACT 3-10-3 Methylene BNA 1362

335344

70162 70175 TCTCTGGTCCTTAC 2-10-2 MOE 1363

335355

70162 70175 TCTCTGGTCCTTAC 2-10-2 MOE Phosphodiester link on the wings 1363

335411

70162 70175 TCTCTGGTCCTTAC 2-10-2 MOE 3’ C is 9 (aminoethoxy) phenoxazine 1363

335412

70162 70175 TCTCTGGTCCTTAC 2-10-2 MOE 2º C is 9 (aminoethoxy) phenoxazine 1363

335413

70162 70175 TCTCTGGTCCTTAC 2-10-2 MOE 21 and 3 ’terminal C are 9 (aminoethoxy) phenoxazine 1363

335370

70162 70175 TCTCTGGTCCTTAC 2-10-2 Menyloxy BNA Phosphodiester bond on the wings 1363

335381

70162 70175 TCTCTGGTCCTTAC 2-10-2 Methylene BNA 1363

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398068

79799 79810 ACAGCTACACAA 1-10-1 MOE 1472

389968

89056 89067 TCTGACTGGGAA 1-10-1 MOE 1151

389767

89056 89067 TCTGACTGGGAA 1-9-2 MOE 1151

336177

89056 89069 CCTCTGACTGGGAA 3-8-3 MOE 1364

336178

89063 89076 CATAGCGCCTCTGA 3-8-3 MOE 1365

336179

89083 89096 CAGGTAGCTATAAT 3-8-3 MOE 1366

390007

89085 89096 CAGGTAGCTATA 1-10-1 MOE 1367

390009

89135 89146 ATCTTGTGAAAC 1-10-1 MOE 1175

397977

89135 89148 TCATCTTGTGAAAC 2-10-2 MOE 1368

336180

89135 89148 TCATCTTGTGAAAC 3-8-3 MOE 1368

398047

89136 89147 CATCTTGTGAAA 1-10-1 MOE 1369

336181

89145 89158 GTTTCAAACATCAT 3-8-3 MOE 1370

397978

89147 89160 TAGTTTCAAACATC  2-10-2 MOE 1371

398048

89148 89159 AGTTTCAAACAT 1-10-1 MOE 1372

389969

89152 89163 GAATAGTTTCAA  1-10-1 MOE 1373

389768

89152 89163 GAATAGTTTCAA  1-9-2 MOE 1373

336182

89155 89168 CATTGGAATAGTTT 3-8-3 MOE 1374

397979

89162 89175 CACTGAACATTGGA 2-10-2 MOE 1375

398049

89163 89174 ACTGAACATTGG 1-10-1 MOE 1376

390010

89165 89176 CCACTGAACATT 1-10-1 MOE 1240

336183

89166 89179 CCGCCACTGAACAT 3-8-3 MOE 1377

397980

94786 94799 CAGACCACAAACTG 2-10-2 MOE 1378

398050

94787 94798 AGACCACAAACT 1-10-1 MOE 1379

392060

94790 94803 CTGGCAGACCACAA 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1380

389970

94791 94802 TGGCAGACCACA 1-10-1 MOE 1249

389769

94791 94802 TGGCAGACCACA 1-9-2 MOE 1249

336185

94792 94805 AGCTGGCAGACCAC 3-8-3 MOE 1381

397981

94798 94811 ACCTTTAGCTGGCA  2-10-2 MOE 1382

398051

94799 94810 CCTTTAGCTGGC  1-10-1 MOE 1220

336186

94803 94816 TCTTCACCTTTAGC  3-8-3 MOE 1383

390012

94860 94871 TCAAAGTACATG 1-10-1 MOE 1384

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

336187

94862 94875 GAACTCAAAGTACA 3-8-3 MOE 1385

389971

94865 94876 GGAACTCAAAGT 1-10-1 MOE 1386

389770

94865 94876 GGAACTCAAAGT 1-9-2 MOE 1386

397982

94865 94878 AGGGAACTCAAAGT 2-10-2 MOE 1387

398052

94866 94877 GGGAACTCAAAG 1-10-1 MOE 1388

336188

94869 94882 GCTGAGGGAACTCA 3-8-3 MOE 1389

336189

94888 94901 TCACCACACACAGG 3-8-3 MOE 1390

336190

94904 94917 GAACTCTACTTTGA  3-8-3 MOE 1391

389972

94909 94920 GAAGAACTCTAC 1-10-1 MOE 1392

389771

94909 94920 GAAGAACTCTAC 1-9-2 MOE 1392

397983

94910 94923 GTGGAAGAACTCTA 2-10-2 MOE 1393

398053

94911 94922 TGGAAGAACTCT 1-10-1 MOE 1394

336191

94915 94928 TGTTTGTGGAAGAA  3-8-3 MOE 1395

336192

94925 94938 CATCTTGTTCTGTT 3-8-3 MOE 1396

397984

97824 97837 AGTGAAACATTTTG  2-10-2 MOE 1397

398054

97825 97836 GTGAAACATTTT 1-10-1 MOE 1144

336194

97827 97840 AAAAGTGAAACATT 3-8-3 MOE 1145

389973

97835 97846 TTACCCAAAAGT 1-10-1 MOE 1398

389772

97835 97846 TTACCCAAAAGT 1-9-2 MOE 1398

336195

97836 97849 TATTTACCCAAAAG 3-8-3 MOE 1399

397985

97837 97850 GTATTTACCCAAAA 2-10-2 MOE 1400

398055

97838 97849 TATTTACCCAAA 1-10-1 MOE 1401

397986

97853 97866 TCCTGGTATGAAGA 2-10-2 MOE 1402

336196

97853 97866 TCCTGGTATGAAGA 3-8-3 MOE 1402

398056

97854 97865 CCTGGTATGAAG 1-10-1 MOE 1403

390015

97857 97868 GGTCCTGGTATG 1-10-1 MOE 1404

336197

97862 97875 TTCCTCTGGTCCTG 3-8-3 MOE 1405

397987

97866 97879 AGGTTTCCTCTGGT  2-10-2 MOE 1406

398057

97867 97878 GGTTTCCTCTGG 1-10-1 MOE 1407

336198

97873 97886 TTTTCTGAGGTTTC  3-8-3 MOE 1408

336199

97891 97904 AGACTTCCATTTTC  3-8-3 MOE 1409

389974

97893 97904 AGACTTCCATTT 1-10-1 MOE 1410

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

389773

97893 97904 AGACTTCCATTT 1-9-2 MOE 1410

336200

97918 97931 CAAATGCTATCGAT 3-8-3 MOE 1411

336201

97933 97946 GCACGCTCTATACT 3-8-3 MOE 1412

389975

97934 97945 CACGCTCTATAC 1-10-1 MOE 1413

389774

97934 97945 CACGCTCTATAC 1-9-2 MOE 1413

336202

97948 97961 TCCTTGTCATTATC 3-8-3 MOE 1414

397988

97990 98003 GCTTTGTCAAGATC  2-10-2 MOE 1415

389976

97991 98002 CTTTGTCAAGAT  1-10-1 MOE 1177

389775

97991 98002 CTTTGTCAAGAT  1-9-2 MOE 1177

336203

97991 98004 TGCTTTGTCAAGAT  3-8-3 MOE 1416

397989

98017 98030 AAGTATCGGTTGGC 2-10-2 MOE 1417

336204

98017 98030 AAGTATCGGTTGGC 3-8-3 MOE 1417

398058

98018 98029 AGTATCGGTTGG 1-10-1 MOE 1418

336205

98032 98045 TTAAAATTTGGAGA 3-8-3 MOE 1419

397990

98034 98047 CCTTAAAATTTGGA 2-10-2 MOE 1420

389977

98035 98046 CTTAAAATTTGG 1-10-1 MOE 1421

389776

98035 98046 CTTAAAATTTGG 1-9-2 MOE 1421

336207

102230 102243 TCTACTGTTTTTGT 3-8-3 MOE 1422

336208

102236 102249 GGCTCCTCTACTGT 3-8-3 MOE 1423

335330

102251 102265 AGCCTCTGGATTTGA  1-10-4 MOE 1424

335331

102252 102266 TAGCCTCTGGATTTG  1-10-4 MOE 1426

336209

102252 102265 AGCCTCTGGATTTG  3-8-3 MOE 1425

335377

102252 102266 TAGCCTCTGGATTTG  1-10-4 Methylene BNA Phosphodiester on the 3 ’wing 1426

335376

102252 102266 TAGCCTCTGGATTTG  1-10-4 Menyloxy BNA 1426

390577

102253 102266 TAGCCTCTGGATTT 1-10-3 MOE Unmodified cytosines T on the wings are 2-thiothymines 1427

335332

102253 102267 CTAGCCTCTGGATTT 1-10-4 MOE 1429

386770

102253 102266 TAGCCTCTGGATTT 1-11-2 MOE 1427

375560

102253 102267 CTAGCCTCTGGATTT 2-10-3 MOE 1429

391449

102253 102267 CTAGCCTCTGGATTT 2-10-3 MOE Unmodified cytosines 1429

392055

102253 102267 CTAGCCTCTGGATTT 2-10-3 MOE Unmodified cytosines in the hollow 1429

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

362977

102253 102268 GCTAGCCTCTGGATTT 2-12-2 MOE 1428

371975

102253 102267 CTAGCCTCTGGATTT 3-10-2 MOE 1429

386556

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

335341

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

335350

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

383739

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 5-methylcytosine in the hollow 1428

390576

102253 102268 GCTAGCCTCTGGA 3-10-3 MOE 5-methylcytosine in the hollow T in the wings are 2-thiothymines 1428

390580

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE Pyrimidines in the wings are 5 thiazole Unmodified cytosines in the hollow 1428

390581

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE Unmodified cytosines in the hole 1428

391096

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

391098

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE 1428

391863

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE Unmodified cytosines 1428

384071

102253 102268 GCTAGCCTCTGGATTT 3-10-3 OMe 5-methylcytosine in the hollow 1428

385036

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 OMe / 2’-O-methyl-4’-uncle / 2’-O-methyl4’-uncle Unmodified cytosines in the wing 1428

335368

102253 102268 GCTAGCCTCTGGATTT 3-10-3 Menyloxy BNA Phosphodiester bond on the wings 1428

391864

102253 102268 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA Unmodified cytosines in the hole 1428

392054

102253 102267 CTAGCCTCTGGATTT 2-10-3 Methyloxy BNA Unmodified cytosines in the hole 1429

391172

102253 102267 CTAGCCTCTGGATTT 2-10-3 Methyloxy BNA Unmodified cytosines 1429

391865

102253 102268 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA Unmodified cytosines 1428

391868

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 (SR) -5’-methyl-Methylene oxy BNA / Methylene oxy BNA / (5’R) -5’-methyl-Methylene oxy BNA Unmodified cytosines 1428

391869

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 Methylene BNA / (5’S) -5’-methyl-Methylene BNA / (5’S) -5’-methyl-Methylene BNA Unmodified cytosines 1428

384073

102253 102268 GCTAGCCTCTGGATTT 3-10-3 Methyloxy BNA 5-methylcytosine in the hollow 1428

335379

102253 102268 GCTAGCCTCTGGATTT 3-10-3 Methylene BNA 1428

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

390579

102253 102268 GCTAGCCTCTGGATTT 1-1-1-10-3 MOE / 4'tio / 2'-O - [(2-methoxy) ethyl] 4'-thio / 2'-O - [(2-methoxy) etIl] -4'- Uncle Unmodified cytosines on the wings Phosphodiester bond on the wings 1428

390582

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 MOE / 4’tio / 2’-O - [(2-methoxy) ethyl] -4’thio Unmodified cytosines on the wings Phosphorodiester link on the wings 1428

390606

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines on the wings Phosphodiester link on the wings 1428

384072

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines in the wings 1428

385871

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 OMe / 2'-O - [(2-methoxy) ethyl] -4'-thio / 2'-O - [(2-methoxy) ethyl] -4'-thio Unmodified cytosines in the wing 1428

390607

102253 102268 GCTAGCCTCTGGATTT 3-10-3 MOE / pentaF Unmodified cytosines in the wing 1428

390608

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 MOE / pentaF / pentaF Unmodified cytosines in the wing 1428

390609

102253 102268 GCTAGCCTCTGGATTT 3-10-2-1 MOE / MOE / pentaF Unmodified cytosines in the wing 1428

386682

102253 102268 GCTAGCCTCTGGATTT 1-2-10-3 2 ’- (butylacetamide) -palmitamide / MOE / MOE 1428

391173

102253 102267 CTAGCCTCTGGATTT 2-10-3 (5’R) -S’-methyl-Methyloxy BNA Unmodified cytosines 1429

391174

102253 102267 CTAGCCTCTGGATTT 2-10-3 (5’S) -5’-methyl-Methyloxy BNA Unmodified cytosines 1429

386970

102254 102266 TAGCCTCTGGATT 1-10-2 MOE 1432

390578

102254 102266 TAGCCTCTGGATT 1-10-2 MOE Unmodified cytosines T on the wings are 2-thiothymines 1432

335333

102254 102268 GCTAGCCTCTGGATT 1-10-4 MOE 1430

331429

102254 102267 CTAGCCTCTGGATT 2-10-2 MOE 1431

335349

102254 102267 CTAGCCTCTGGATT 2-10-2 MOE 1431

335367

102254 102267 CTAGCCTCTGGATT 2-10-2 Menyloxy BNA Phosphodiester bonds on the wings 1431

392061

102254 102267 CTAGCCTCTGGATT 2-10-2 Methyloxy BNA Unmodified cytosines in the hole 1431

335378

102254 102267 CTAGCCTCTGGATT 2-10-2 Methylene BNA 1431

383991

102254 102266 TAGCCTCTGGATT 1-10-2 2 ’- (acetylamino-butyl-acetamido) cholesterol / MOE 1432

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

383992

102254 102266 TAGCCTCTGGATT 1-10-2 2 ’- (acetylamino-butyl-acetamido) colic acid / MOE 1432

386683

102254 102266 TAGCCTCTGGATT 1-10-2 5 ’terminal 2’ - (butylacetamide) palmitamide / MOE 1432

390614

102254 102266 TAGCCTCTGGATT 1-10-2 PentaF 1432

389954

102255 102266 TAGCCTCTGGAT 1-10-1 MOE 1434

335334

102255 102269 TGCTAGCCTCTGGAT 1-10-4 MOE 1433

389777

102255 102266 TAGCCTCTGGAT 1-9-2 MOE 1434

390430

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines 1163

390431

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines C in wing 9- (aminoethoxy) phenoxazine 1163

390432

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE 1163

390433

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 6 is 9- (aminoethoxy) phenoxazine 1163

390434

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 7 is 9- (aminoethoxy) phenoxazine 1163

390435

102256 102268 GCTAGCCTCTGGA 1-10-2 MOE Unmodified cytosines Nt 9 is 9- (aminoethoxy) phenoxazine 1163

335335

102256 102270 CTGCTAGCCTCTGGA 1-10-4 MOE 1435

335336

102257 102271 ACTGCTAGCCTCTGG 1-10-4 MOE 1436

335337

102258 102272 AACTGCTAGCCTCTG 1-10-4 MOE 1437

335338

102259 102273 GAACTGCTAGCCTCT 1-10-4 MOE 1438

335339

102260 102274 TGAACTGCTAGCCTC 1-10-4 MOE 1439

335340

102261 102275 TTGAACTGCTAGCCT 1-10-4 MOE 1440

336210

102261 102274 TGAACTGCTAGCCT 3-8-3 MOE 1441

397991

102264 102277 AGTTGAACTGCTAG 2-10-2 MOE 1442

398059

102265 102276 GTTGAACTGCTA 1-10-1 MOE 1443

390017

102268 102279 GAAGTTGAACTG 1-10-1 MOE 1444

336211

102269 102282 ACAGAAGTTGAACT 3-8-3 MOE 1445

397992

102293 102306 TCATTGTCACTAAC 2-10-2 MOE 1446

336212

102293 102306 TCATTGTCACTAAC 3-8-3 MOE 1446

398060

102294 102305 CATTGTCACTAA 1-10-1 MOE 1447

389978

102301 102312 TCAGGTTCATTG 1-10-1 MOE 1448

389778

102301 102312 TCAGGTTCATTG 1-9-2 MOE 1448

336213

102303 102316 ATGATCAGGTTCAT 3-8-3 MOE 1449

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

397993

102307 102320 TATAATGATCAGGT 2-10-2 MOE 1450

398061

102308 102319 ATAATGATCAGG 1-10-1 MOE 1451

336214

102314 102327 GAATATCTATAATG 3-8-3 MOE 1139

390019

102320 102331 GTCAGAATATCT 1-10-1 MOE 1173

397994

102322 102335 TGGTGTCAGAATAT 2-10-2 MOE 1452

398062

102323 102334 GGTGTCAGAATA 1-10-1 MOE 1255

336215

102326 102339 TCAGTGGTGTCAGA 3-8-3 MOE 1453

336216

102339 102352 CTCTGGATCAGAGT 3-8-3 MOE 1454

390020

102340 102351 TCTGGATCAGAG 1-10-1 MOE 1149

336217

102349 102362 AAGGTTCATTCTCT 3-8-3 MOE 1455

397995

102357 102370 TTCATCAAAAGGTT 2-10-2 MOE 1456

389979

102358 102369 TCATCAAAAGGT 1-10-1 MOE 1176

389779

102358 102369 TCATCAAAAGGT 1-9-2 MOE 1176

336218

102358 102371 CTTCATCAAAAGGT 3-8-3 MOE 1457

390021

102360 102371 CTTCATCAAAAG 1-10-1 MOE 1458

336219

102366 102379 ATGCTGATCITCAT 3-8-3 MOE 1459

336220

102381 102394 TTTTGTAATTTGTG  3-8-3 MOE 1460

336221

102387 102400 TCAGACTTTTGTAA  3-8-3 MOE 1461

390022

102443 102454 CAGTTTATTCAA  1-10-1 MOE 1142

397996

102477 102490 TGTCCTATTGCCAT 2-10-2 MOE 1462

398063

102478 102489 GTCCTATTGCCA 1-10-1 MOE 1205

397997

102487 102500 TCTGACACAATGTC 2-10-2 MOE 1463

398064

102488 102499 CTGACACAATGT 1-10-1 MOE 1464

397998

102505 102518 TGTTCCTATAACTG 2-10-2 MOE 1465

398065

102506 102517 GTTCCTATAACT 1-10-1 MOE 1466

397999

102528 102541 AAGATTGGTCAGGA 2-10-2 MOE 1467

398066

102529 102540 AGATTGGTCAGG 1-10-1 MOE 1468

398000

102561 102574 GTGTCAAAACCCTG 2-10-2 MOE 1469

398067

102562 102573 TGTCAAAACCCT 1-10-1 MOE 1210

390025

102563 102574 GTGTCAAAACCC 1-10-1 MOE 1211

390026

102595 102606 AGCTACACAACC 1-10-1 MOE 1470

398001

102596 102609 CACAGCTACACAAC 2-10-2 MOE 1471

ISIS Nº

Target site in 5 ’ Target site in 3 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

398068

102597 102608 ACAGCTACACAA 1-10-1 MOE 1472

398002

102607 102620 TATATACATGACAC 2-10-2 MOE 1473

398069

102608 102619 ATATACATGACA 1-10-1 MOE 1474

390027

102612 102623 AGGTATATACAT 1-10-1 MOE 1206

398003

102637 102650 AATTTTAAATGTCC  2-10-2 MOE 1475

398070

102638 102649 ATTTTAAATGTC  1-10-1 MOE 1476

390028

102648 102659 TCCTAATTGAAT 1-10-1 MOE 1477

390029

102667 102678 AAAGTGCCATCT 1-10-1 MOE 1478

398004

102689 102702 TTTATAAAACTGGA 2-10-2 MOE 1479

398071

102690 102701 TTATAAAACTGG 1-10-1 MOE 1480

390030

102691 102702 TTTATAAAACTG 1-10-1 MOE 1074

398005

102827 102840 TGCAAACTTATCTG 2-10-2 MOE 1481

398072

102828 102839 GCAAACTTATCT 1-10-1 MOE 1482

390033

102836 102847 AGCCAACTGCAA 1-10-1 MOE 1483

398006

102837 102850 CTTAGCCAACTGCA 2-10-2 MOE 1484

398073

102838 102849 TTAGCCAACTGC 1-10-1 MOE 1485

398007

103069 103082 AGCACCAATATGCT 2-10-2 MOE 1247

398074

103070 103081 GCACCAATATGC 1-10-1 MOE 1248

398008

103267 103280 TAAATCATTGTCAA 2-10-2 MOE 1486

398075

103268 103279 AAATCATTGTCA 1-10-1 MOE 1233

398009

103327 103340 GCACTGGCCTTGAT 2-10-2 MOE 1487

398076

103328 103339 CACTGGCCTTGA 1-10-1 MOE 1488

390041

103332 103343 TTAGCACTGGCC 1-10-1 MOE 1489

390047

103585 103596 TGTGTAAGGTCA 1-10-1 MOE 1490

390049

103636 103647 GTTAATGACATT 1-10-1 MOE 1491

390050

103660 103671 GTATTCAAGTAA 1-10-1 MOE 1140

390052

103780 103791 GACAATTTCTAC  1-10-1 MOE 1492

390054

103862 103873 AACACTGCACAT 1-10-1 MOE 1493

Salts, prodrugs and bioequivalents

The antisense compounds disclosed herein comprise any pharmaceutically acceptable salt, ester or salts of said esters, or any other functional equivalent that, upon administration to an animal, including a human being, can provide (directly or indirectly) the metabolite biologically. asset or a residue thereof. Accordingly, for example, the disclosure also extends to prodrugs and pharmaceutically acceptable salts of the antisense compounds, pharmaceutically acceptable salts of said prodrugs, and other bioequivalents.

The term "prodrug" indicates a therapeutic agent that is prepared in an inactive or less active form that is converted into an active form (ie, the drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals. and / or conditions. In particular, the prodrug versions of the oligonucleotides are prepared as SATE ((S-actyl-2-thioethyl) phosphate derivatives according to the procedures disclosed in WO 93/24510 or WO 94/26764. Prodrugs may also include antisense compounds in which one or both ends comprise nucleotide bases that are cleaved (e.g., incorporating phosphodiester bonds in the backbone at the ends) to produce the active compound.In certain embodiments, one or more moieties that are not drugs they are cleaved from a prodrug, giving the active form.In certain of said embodiments, said non-drug moieties are not a nucleotide or an oligonucleotide.

The term "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of the compounds described herein, that is, salts that retain the desired biological activity of the parent compound and that do not produce unwanted toxicological effects therein. The sodium salts of the antisense oligonucleotides are useful and well accepted for therapeutic administration to humans.

In certain embodiments, salts, including but not limited to, salts of double stranded nucleic acids (including, but not limited to, double stranded ARD compounds) are disclosed.

G. Certain pharmaceutical compositions

In certain embodiments, the pharmaceutical compositions of the present disclosure comprise one or more short antisense compounds and one or more excipients. In certain of said embodiments, water excipients, saline solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscose paraffin, hydroxymethylcellulose and polyvinylpyrrolidone are selected.

In certain embodiments, a pharmaceutical composition of the present disclosure is prepared using known techniques, including, inter alia, mixing, dissolution, granulation, tablet formation, crushing, emulsion, encapsulation, entrapment or tabletting.

In certain embodiments, a pharmaceutical composition of the present disclosure is a liquid (eg, a suspension, elixir and / or solution). In certain of said embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including but not limited to water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents.

In certain embodiments, a pharmaceutical composition of the present disclosure is a solid (eg, a polco, tablet and / or capsule). In certain of said embodiments, a solid pharmaceutical composition comprising one or more oligonucleotides is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders and disintegrating agents.

In certain embodiments, a pharmaceutical composition of the present disclosure is formulated as a depot preparation. Certain depot preparations are usually longer-acting than non-depot preparations. In certain embodiments, said preparations are administered by implantation (eg subcutaneous or intramuscular) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or in the form of sparingly soluble derivatives, for example in the form of a sparingly soluble salt.

In certain embodiments, a pharmaceutical composition of the present disclosure comprises a release system. Examples of release systems include, among others, liposomes and emulsions. Certain release systems are useful for preparing certain pharmaceutical compositions, including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents, such as dimethylsulfoxide, are used.

In certain embodiments, a pharmaceutical composition of the present disclosure comprises one or more tissue specific release molecules designed to release the one or more pharmaceutical agents of the present disclosure into specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue specific antibody.

In certain embodiments, a pharmaceutical composition of the present disclosure comprises a co-solvent system. Certain of said co-solvent systems comprise, for example, benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. In certain embodiments, said co-solvent systems are used for hydrophobic compounds. A non-limiting example of said co-solvent system is the VPD co-solvent system, which is an absolute ethanol solution comprising 3% w / v benzyl alcohol, 8% w / v of the apolar surfactant, polysorbate 80.TN and 65% w / v polyethylene glycol 300. The proportions of said co-solvent systems can be varied considerably without significantly altering their solubility and toxicity characteristics. In addition, the identity of the components of the co-solvent can be varied: for example, other surfactants can be used instead of Polysorbate 80.TM; The size of the polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example polyvinylpyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, a pharmaceutical composition of the present disclosure comprises a sustained release system. A non-limiting example of such a sustained release system is a semipermeable matrix of solid hydrophobic polymers. In certain embodiments, sustained release systems may, depending on their chemical nature, release pharmaceutical agents for a period of hours, days, weeks or months.

In certain embodiments, a pharmaceutical composition of the present disclosure is prepared for oral administration. In certain of said embodiments, a pharmaceutical composition is formulated by combining one or more oligonucleotides with one or more pharmaceutically acceptable carriers. Certain of said carriers allow the pharmaceutical compositions to be formulated in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, thick suspensions, suspensions and the like, for ingestion by a subject. In certain embodiments, pharmaceutical compositions for oral use are obtained by mixing oligonucleotides and one or more solid excipients. Suitable excipients include, among others, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). In certain embodiments, said mixture is optionally crushed and optionally adjuvants are added. In certain embodiments, the pharmaceutical compositions are formed to obtain tablets or tablet cores. In certain embodiments, disintegrating agents are added (eg, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate).

In certain embodiments, the tablet cores are provided with coatings. In certain of said embodiments, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coatings of tablets or tablets.

In certain embodiments, pharmaceutical compositions for oral administration are hard capsules made of gelatin. Certain of said hard capsules comprise one or more pharmaceutical agents of the present invention mixed with one or more fillers, such as lactose, binders, such as starches and / or lubricants, such as talc.

or magnesium stearate, and, optionally, stabilizers. In certain embodiments, pharmaceutical compositions for oral administration are sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more pharmaceutical agents of the present disclosure are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added.

In certain embodiments, the pharmaceutical compositions are prepared for oral administration. Certain of said pharmaceutical compositions are tablets or pills formulated in a conventional manner.

In certain embodiments, a pharmaceutical composition for administration by injection (eg, intravenous, subcutaneous, intramuscular, etc.) is prepared. In certain of said embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers, such as Hank's solution, Ringer's solution or physiologically buffered saline. In certain embodiments, other ingredients are included (eg, ingredients that aid solubility or serve as preservatives). In certain embodiments injectable suspensions are prepared using suitable liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in single-dose form, for example in ampoules, or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Certain solvents for use in pharmaceutical compositions for injection include, but are not limited to lipophilic solvents and fatty oils such as sesame oil, or esters of synthetic fatty acids, such as ethyl oleate or triglycerides, and liposomes. Aqueous injectable suspensions may comprise substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, said suspensions may also comprise suitable stabilizers or agents that increase the solubility of pharmaceutical agents to allow the preparation of highly concentrated solutions.

In certain embodiments, a pharmaceutical composition for transmucosal administration is prepared. In certain of said embodiments suitable penetrants are used to cross the barrier. Such penetrants are generally known in the art.

In certain embodiments, a pharmaceutical composition is prepared for administration by inhalation. Certain of said pharmaceutical compositions are prepared in the form of an aerosol nebulizer in a pressurized container or nebulizer. Certain of said pharmaceutical compositions comprise a propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit can be determined by providing a valve that releases a measured amount. In certain embodiments, capsules and cartridges can be formulated for use in an inhaler or insufflator. Certain of these formulations comprise a powder mixture of a pharmaceutical agent of the disclosure and a suitable powder base, such as lactose or starch.

In certain embodiments, a pharmaceutical composition for rectal administration, such as suppositories or retention enema, is prepared. Certain of said pharmaceutical compositions comprise known ingredients, such as cocoa butter and / or other glycerides.

In certain embodiments, a pharmaceutical composition is prepared for topical administration. Certain of said pharmaceutical compositions comprise soft hydration bases, such as ointments or creams. Examples of suitable bases for ointments include, among others, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions, such as Eucerin. TM., Available in Beiersdorf (Cincinnati, Ohio). Examples of suitable cream bases include, among others, Nivea.TM. Cream, available in Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream.TM, available in Johnson & Johnson (New Brunswick, NJ), hydrophilic ointment (USP) and Lubriderm.TM., Available in Pfizer (Morris Plains, NJ.).

In certain embodiments, a pharmaceutical composition of the present disclosure comprises an oligonucleotide in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or improve the symptoms of a disease or to prolong the survival of the subject being treated. The determination of a therapeutically effective amount falls well within the ability of those skilled in the art.

In certain embodiments, one or more short antisense compounds of the present disclosure are formulated as a prodrug. In certain embodiments, after in vivo administration, a prodrug is chemically converted into the biologically, pharmaceutically or therapeutically more active form of the short antisense compound. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain cases, a prodrug may be more bioavailable (eg, by oral administration) than its corresponding active form. In certain cases, a prodrug may fear better solubility compared to the corresponding active form. In certain embodiments, the prodrugs are less water soluble than the corresponding active form. In certain cases, said prodrugs have superior transmission through cell membranes, in which water solubility is detrimental to mobility. In certain embodiments, a prodrug is an ester. In certain of said embodiments, the ester is metabolically hydrolyzed into carboxylic acid after administration. In certain cases, the compound containing carboxylic acid is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyamino acid) attached to an acid group. In certain of said embodiments, the peptide is cleaved after administration to form the corresponding active form.

In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound so that the active compound will regenerate after in vivo administration. The prodrug can be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of a drug or to alter other characteristics or properties of a drug. Based on knowledge of pharmacodynamic processes and metabolism of drugs in vivo, those skilled in the art, once the pharmaceutically active compound is known, can design prodrugs of the compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388392).

In certain embodiments, a pharmaceutical composition comprising one or more pharmaceutical agents of the present disclosure is useful for treating conditions or disorders in a mammal, and, particularly, in a human subject. Suitable routes of administration include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, by inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary and subcutaneous). In certain embodiments intrathecal pharmaceutical agents are administered to achieve local rather than systemic exposures. For example, pharmaceutical compositions may be injected directly into the area of the desired effect (eg, in the renal or cardiac area).

In certain embodiments, the short antisense compounds, compared to their parental oligonucleotides, are not particularly suitable for oral administration. In certain embodiments, short antisense compounds are better adapted for oral administration than their parental oligonucleotides, because they have greater potency compared to said parental oligonucleotides. In certain embodiments, short antisense compounds are better adapted for oral administration than their parental oligonucleotides, because they have better stability, availability or solubility properties compared to parental oligonucleotides.

In a further aspect, a pharmaceutical agent is a sterile lyophilized oligonucleotide that is reconstituted with a suitable diluent, for example sterile water for injections. The reconstituted product is administered as a subcutaneous injection or as an intravenous infusion after dilution in saline. The lyophilized drug product consists of an oligonucleotide that has been prepared in water for injections, adjusted to pH 7.0-9.0 with acid or base during the preparation and then lyophilized. The lyophilized oligonucleotide may be 25-800 mg of the oligonucleotide. It is understood that this covers 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 425, 450, 475, 500, 525, 550, 575, 600 , 625, 650, 675, 700, 725, 750, 775 and 800 mg of lyophilized oligonucleotide. The lyophilized drug product can be packaged in a 2 ml type 1 transparent glass vial (treated with ammonium sulfate), capped with a bromobutyl rubber closure and sealed with a FLIP-OFF® aluminum OVERSEAL.

The compositions of the present disclosure may additionally comprise other adjuvant components conventionally found in pharmaceutical compositions at their levels of use established in the art. Thus, for example, the compositions may comprise additional, pharmaceutically compatible compatible materials, such as, for example, antipruritic, astringent, local anesthetics or anti-inflammatory agents, or may comprise additional materials useful in the physical formulation of various dosage forms of the Compositions of the present disclosure, such as colorants, flavoring agents, preservatives, antioxidants, opacifiers, thickening and stabilizing agents. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present disclosure. The formulations can be sterilized and, if desired, mixed with adjuvant agents, for example lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts influencing osmotic pressure, buffers, dyes, flavorings and / or aromatic substances and the like, that do not interact detrimentally with the oligonucleotides of the formulation.

The antisense compounds disclosed herein may be mixed, encapsulated, conjugated or otherwise associated with other molecules, molecular structures or mixtures of compounds.

Pharmaceutical compositions and formulations that include the antisense compounds disclosed herein are also described herein. The pharmaceutical compositions can be administered in various ways depending on whether local or systemic treatment is desired and the area to be treated. In a preferred embodiment, administration is topical on the surface of the respiratory tract, particularly pulmonary, for example by nebulization, inhalation or insufflation of powders or aerosols, by mouth and / or nose.

The pharmaceutical formulations described in the present invention, which can be conveniently presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of contacting the active ingredients with the pharmaceutical carrier (s) or excipient (s). In general, the formulations are prepared by uniformly and closely contacting the active ingredients with liquid carriers or finely divided solid carriers or with both, and then, if necessary, shaping the product in the desired formulation (e.g. , in a specific particle size for release). In a preferred embodiment, the pharmaceutical formulations are prepared for pulmonary administration in a suitable solvent, for example water or normal saline, possibly in a sterile formulation, with carriers or other agents to allow the formation of drops of the desired diameter for release using inhalers. , nasal release devices, nebulizers and other devices for lung release. Alternatively, pharmaceutical formulations can be formulated as dry powders for use in dry powder inhalers.

A "pharmaceutical carrier" or "excipient" may be a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert carrier to release one or more nucleic acids to an individual and are known in the art. The excipient can be liquid or solid and is selected, with the intended mode of administration in mind, so as to provide volume and consistency etc. desired when combined with a nucleic acid and the other components of a given pharmaceutical composition.

H. Certain therapeutic uses

In certain embodiments, antisense compounds are used to modulate the expression of a target gene in an animal, such as a human being. In certain embodiments, said compounds can be used to treat metabolic disorders or modulate one or more disease indications. For example, the methods comprise the step of administering to said animal that needs therapy for a disease or condition associated with a target gene an effective amount of an antisense compound that modulates the expression of the gene. The antisense compounds disclosed herein that effectively modulate the expression of a target RNA or expression protein products are considered active antisense compounds. Active antisense compounds may also include compounds that effectively modulate one or more of a series of disease indications, including indications of metabolic and cardiovascular disease, examples of which are described below.

The modulation of the expression of a target gene can be measured in a body fluid, which may or may not contain cells, tissue or organ of the animal. Procedures for obtaining samples for analysis, such as body fluids (e.g., sputum, serum, urine), tissues (e.g., biopsy) or organs and sample preparation procedures to allow analysis are well known for Those skilled in the art. Procedures for RNA analysis and protein levels are discussed above and are well known to those skilled in the art. The effects of the treatment can be evaluated by measuring biomarkers, or indications of disease, associated with the expression of the target gene in the fluids, tissues or organs mentioned above, collected from an animal in contact with one or more compounds described herein, by Routine clinical procedures known in the art. These biomarkers include, among others: hepatic transaminases, albumin bilirubin, blood urea nitrogen, creatinine and other markers of renal and hepatic function; interleukins, tumor necrosis factors, intracellular adhesion molecules, C-reactive protein, chemokines, cytokines and other markers of inflammation. The antisense compounds disclosed herein can be used in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier. Acceptable transporters and diluents are well known to those skilled in the art. The selection of a diluent or carrier is based on a number of factors, including but not limited to the solubility of the compound and the route of administration. Such considerations are well known pores skilled in the art. In one aspect, the antisense compounds described herein inhibit the expression of a target gene. The compounds can also be used in the manufacture of a medicament for the treatment of diseases and disorders related to a target gene.

Methods are also contemplated by which body fluids, organs or tissues are contacted with an effective amount of one or more of the antisense compounds or compositions disclosed herein. Body fluids, organs or tissues can be contacted with one or more of the compounds, resulting in modulation of the expression of a target gene in the cells of body fluids, organs or tissues. An effective amount can be determined by monitoring the modulating effect of the antisense compound or compounds or compositions on the target nucleic acids or their products by routine procedures for those skilled in the art.

In certain embodiments, two or more antisense compounds are co-administered. In certain embodiments, the pharmaceutical compositions include one or more antisense compounds, particularly oligonucleotides, directed to a first nucleic acid and one or more antisense compounds directed to a second target nucleic acid. One or more of said antisense compounds may be a short antisense compound. In certain embodiments, the pharmaceutical compositions include two or more antisense compounds targeting different regions of the same target nucleic acid. One or more of said antisense compounds may be a short antisense compound. Two or more compounds combined can be used together or sequentially.

Joint Administration

In certain embodiments, one or more pharmaceutical compositions are co-administered with one or more other pharmaceutical agents. In certain embodiments, said one or more other pharmaceutical agents are designed to treat the same disease or condition different from that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one or more other pharmaceutical agents are designed to treat another disease or condition other than that of the one or more pharmaceutical compositions of the present disclosure. In certain embodiments, said one plus distinct pharmaceutical agents are designed to treat an unwanted effect of the

or more pharmaceutical compositions of the present disclosure. In certain embodiments, one or more pharmaceutical compositions of the present disclosure are co-administered with another pharmaceutical agent to treat an unwanted effect of said other pharmaceutical agent. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are administered at different times. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions of the present disclosure and one or more other pharmaceutical agents are prepared separately.

In certain embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include lipid lowering agents. In certain of said embodiments, pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, atorvastatin, simvastatin, rosuvastatin and ezetimibe. In certain of said embodiments, the lipid lowering agent is administered prior to the administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered after administration of a pharmaceutical composition of the present disclosure. In certain of said embodiments, the lipid lowering agent is administered at the same time as the pharmaceutical composition of the present disclosure. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is the same as the dose that would be administered if the lipid-lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid lowering agent is less than the dose that would be administered if the lipid lowering agent was administered alone. In certain of said embodiments, the dose of a co-administered lipid-lowering agent is greater than the dose that would be administered if the lipid-lowering agent was administered alone.

In certain embodiments, a coadministered lipid lowering agent is an HMG-CoA reductase inhibitor. In certain of said embodiments, the HMG-CoA reductase inhibitor is a statin. In certain of said embodiments, the statin is selected from atorvastatin, simvastatin, pravastatin, fluvastatin and rosuvastatin. In certain embodiments, a coadministered lipid lowering agent is a cholesterol absorption inhibitor. In certain of said embodiments, the cholesterol absorption inhibitor is ezetimibe. In certain embodiments, a coadministered lipid-lowering agent is an HMG-CoA reductase inhibitor formulated in conjunction with a cholesterol absorption inhibitor. In certain of said embodiments, the jointly formulated lipid lowering agent is ezetimibe / simvastatin. In certain embodiments, a co-administered lipid-lowering agent is a microsomal triglyceride transfer protein inhibitor.

In certain embodiments, a co-administered pharmaceutical agent is a bile acid sequestrant. In certain of said embodiments, the bile acid sequestrant is selected from cholestyramine, colestipol and colesevelam.

In certain embodiments, a co-administered pharmaceutical agent is a nicotinic acid. In certain of said embodiments, nicotinic acid is selected from nicotinic acid immediate release, nicotinic acid extended release and nicotinic acid sustained release.

In certain embodiments, a co-administered pharmaceutical agent is a fibric acid. In certain of said embodiments, the fibric acid is selected from gemfibrozil, fenofibrate, clofibrate, bezafibrate and ciprofibrate.

Other examples of pharmaceutical agents that can be co-administered with a pharmaceutical composition of the present disclosure include, among others, corticosteroids, including, but not limited to, prednisone; immunoglobulins, including, inter alia intravenous immunoglobulin (IVIG); analgesics (eg, acetaminophen); anti-inflammatory agents, including but not limited to non-steroidal anti-inflammatory drugs (eg, ibuprofen, COX-1 inhibitors and COX-2 inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (eg, biguanides, glucosidase inhibitors, insulins, sulfonylureas and thiazolidendiones); adrenergic modifiers; diuretics; hormones (eg, anabolic steroids, androgens, estrogens, calcitonin, progestin, somatostatin and thyroid hormones); immunomodulators; muscle relaxants; antihistamines, antiosteoporosis agents (eg, bisphosphonates, calcitonin and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; products of poisonous Atlantic oak or poison sumac; antibodies; and vaccines.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be co-administered with a lipid lowering therapy. In certain of these embodiments, a lipid lowering therapy is a therapeutic lifestyle change. In certain of these embodiments, a lipid-lowering therapy is LDL apheresis.

I. Kit, research reagents and diagnostics

The antisense compounds disclosed herein can be used for diagnosis and as reagents and research kit. In addition, antisense compounds that can inhibit gene expression or modulate gene expression with specificity are often used by those skilled in the art to clarify the function of specific genes.

or distinguish between functions of several members of a biological pathway.

For use in kit and diagnosis, the antisense compounds described herein, either alone or in combination with other compounds or therapeutics, can be used as tools in differential and / or combination analysis to clarify the expression patterns of a portion or the whole complement of genes expressed within cells or tissues. Methods of analysis of gene expression are well known to those skilled in the art.

J. Certain advantages of short antisense compounds

In certain embodiments, short antisense compounds have advantages when compared to their parental oligonucleotide. For example, in certain embodiments, short antisense compounds have greater affinity for a target nucleic acid than their parental oligonucleotide. In certain embodiments, short antisense compounds have greater potency in vitro than their parental oligonucleotide. In certain of said embodiments, the greater in vitro potency is not fully explained by its greater affinity. In certain of said embodiments, said greater in vitro potency can be attributed to an increase in the ability of short antisense compounds to penetrate cells and / or the greater ability to access target nucleic acids in a cell. In certain embodiments, short antisense compounds have greater potency in vivo than their parental oligonucleotides. In certain embodiments, said greater potency in vivo cannot be attributed to the increase in potency in vitro or to the increase in affinity. In certain embodiments, short antisense compounds have even greater potency in vivo compared to their parental oligonucleotides than would be predicted based on their potencies in vitro or in affinities. In certain embodiments, said increase in potency in vivo can be attributed to the increase in bioavailability, less penetration into the cell, better access to the target nucleic acid once it is in the cell or to other factors.

In certain embodiments, short antisense compounds would be expected to be less specific to their target nucleic acid compared to their parental oligonucleotides. In certain of these embodiments, an increase in side effects, including the potential for toxic effects, of short antisense compounds could be expected. In certain embodiments, said additional side effects are not observed. In certain embodiments, non-target nucleic acids to which a short antisense compound can be attached are not available for the short antisense compound. In such embodiments, the side effects, including toxicity, are less problematic than one would expect.

In certain embodiments, because they are smaller, short antisense compounds are less likely to bind to proteins. In certain of said embodiments, said lower protein binding results in less toxicity, since protein binding may have undesirable consequences. In certain of said embodiments, said lower protein binding results in greater potency, since it leaves more antisense compound available for the therapeutic effect. In certain embodiments, lower protein binding results in lower toxicity by drug interaction.

Example 1: Cell culture and treatment with short antisense compounds

The effect of short antisense compounds on the expression of the target nucleic acid can be analyzed in any one of a series of cultured or primary cell lines. Cell lines can be obtained from publicly available sources, such as the American Type Culture Collection ((Manassas, VA). Cells are grown according to procedures well known to those skilled in the art.

When the cells reached adequate confluence, they were treated with oligonucleotide using LIPOFECTIN®, as described. When the cells reached a confluence of 65-75% they were treated with oligonucleotide. The oligonucleotide was mixed with LIPOFECTIN® Invitrogen Life Technologies, Carlsbad, CA) in Opti-MEM® medium with serum reduction (Invitrogen Life Technologies, Carlsbad, CA) to achieve the desired oligonucleotide concentration and a LIPOFECTIN® concentration of 2, 5 or 3 µg / ml per 100 nM oligonucleotide. This transfection mixture was incubated at room temperature for approximately 0.5 hours. For cells grown in 96-well plates, the cells were washed once with 100 µl of OPTI-MEM®-1 and then treated with 130 µl of the transfection mixture. Cells grown in 24-well plates or other standard tissue culture plates were treated similarly, using suitable volumes of medium and oligonucleotide. The cells were treated and the data were obtained in duplicate or in triplicate. After approximately 4-7 hours of treatment at 37 ° C, the medium containing the transfection mixture was replaced with fresh culture medium. Cells were collected 16-24 hours after oligonucleotide treatment.

Control oligonucleotides are used to determine the optimal concentration of the oligomeric compound for a particular cell line. In addition, when oligomeric compounds are analyzed in experiments for selective detection of oligomeric compounds or phenotypic assays, control oligonucleotides are analyzed in parallel.

The concentration of the oligonucleotide used varies from one cell line to another cell line. To determine the optimal oligonucleotide concentration for a particular cell line, cells are treated with a positive control oligonucleotide with a series of concentrations. The concentration of the positive control oligonucleotide that results in 80% inhibition of the target mRNA is then used as a selective detection concentration for new oligonucleotides in subsequent experiments for said cell line. If 80% inhibition is not reached, the lower concentration of the positive control oligonucleotide that results in 60% inhibition of the target mRNA is then used as a selective oligonucleotide detection concentration in subsequent experiments for said cell line. If 60% inhibition is not achieved, it is estimated that said specific cell line is inadequate for oligonucleotide transfection experiments. The concentrations of the antisense oligonucleotides used herein are 50 nM to 300 nM when the antisense oligonucleotide is transfected using a liposome reagent and 1 nM to 40 nM when the antisense oligonucleotide is transfected by electroporation.

Example 2: Real-time quantitative PCR analysis of target mRNA levels

Quantification of target mRNA levels was performed by quantitative real-time PCR using the ABI PRISM® 7600, 7700, or 7900 sequence detection system (PE-Applied Biosystems, Foster City, CA) according to the manufacturer's instructions .

Prior to quantitative PCR analysis, the specific probe-priming equipment of the target gene being measured was evaluated according to its ability to "multiplex" with a GAPDH amplification reaction. After isolation, the RNA is subjected to transcriptase sequence reaction inverse (TI) and real-time PCR, both performed in the same well.Reagents for IT and PCR were obtained from Invitrogen Life Technologies (Carlsbad, CA). Real-time IT PCR was carried out therein by adding 20 µl of PCR cocktail (2.5 X PCR buffer minus MgCl2, 6.6 mM MgCl2, 375 µM each of dATP, dCTP, dCTP and dGTP, 375 nM of each direct primer and reverse primer, 125 nM probe, 4 Units of RNase inhibitor, 1.25 units of PLATINUM® Taq, 5 Units of MuLV reverse transcriptase and 2.5 x Rox pigment) to 96-well plates containing 30 µl of RNA solution total (20-200 ng) The IT reaction was carried out by incubation last 30 minutes at 48 ° C. After a 10 minute incubation at 95 ° C to activate the PLATINUM® Taq, 40 cycles of a two-stage PCR protocol were carried out: 95 ° C for 15 seconds (denaturation), followed by 60 ºC for 1.5 minutes (hybridization / extension)

5 The amounts of the target gene obtained by real-time PCR with TI were normalized using the expression level of GAPDH, a gene whose expression is constant, or by quantifying the total RNA using RiboGreen® (Molecular Probes, Inc. Eugene, OR). GAPDH expression was quantified by real-time PCR with TI performed simultaneously with the target, multiplexing or separately. Total RNA was quantified using RiboGreen® quantification reagent (Molecular Probes, Inc. Eugene, OR)

10 In a 96-well plate containing 30 µl of purified cellular RNA 170 µl of RiboGreen® working reagent (RiboGreen® reagent diluted at 1: 350 in 10 mM Tris-Hcl, 1 mM EDTA, pH 7, was pipetted 5). The plate was read on a CytoFluor® 4000 (PE Applied Biosystems) reader with 485 nm excitation and 530 nm emission.

GAPDH PCR probes have JOE covalently attached at the 5 ’end and TAMRA or MGB covalently attached to the 3’ end, where JOE is the fluorescent indicator dye and TAMRA or MGB is the dye

15 inactivator. In some cell types, primers and probes designed for a GAPDH sequence of a different species are used to measure GAPDH expression costs. For example, a probe and primer kit for GAPDH is used to measure GAPDH expression in mono-derived cells and cell lines.

The probes and primers for use in real-time PCR were designed to hybridize with the target nucleic acids through routine procedures. For example, PrimerExpress® software (Applied Biosystems, Foster City, CA) is used

20 routinely to design probes and primers for use in real-time PCR. Examples of sequences of primers and probes and of the nucleic acids with which they hybridize are presented in Table 24. Target specific PCR probes have FAM covalently attached to the 5 'end and TAMRA or MGB covalently linked to the 3' end, where FAM is the fluorescent dye and TAMRA or MGB is the inactivating dye.

Table 24

Primers and target specific probes for use in real-time PCR

Diana's Name

Species Sequence description Sequence (5 ’to 3’) SEQ ID NO.

ApoB

Mouse Direct primer CGTGGGCTCCAGCATTCTA 1524

ApoB

Mouse Reverse primer AGTCATTTCTGCCTTTGCGTC 1525

ApoB

Mouse Probe CCAATGGTCGGGCACTGCTCAA 1526

ApoB

Mouse Direct primer GAAAATAGACTTCCTGAATAACTATGCATT  1527

ApoB

Mouse Reverse primer ACTCGCTTGCCAGCTTGC 1528

ApoB

Mouse Probe TTTCTGAGTCCCCGTGCCCAACA 1529

GCGR

Mouse Direct primer TGAGCCTTGCCACCTTCTCT 1530

GCGR

Mouse Reverse primer GCGCACCCCAGCCAA 1531

GCGR

Mouse Probe AGAGGAGCTTCTTTTCCCTCTACCTGGGC 1532

GCGR

Mouse Direct primer ATTTCCTGCCCCTGGTACCT  1533

GCGR

Mouse Reverse primer CGGGCCCACACCTCTTG 1534

GCGR

Mouse Probe CCACAAAGTGCAGCACCGCCTAGTGT 1535

PTEN

Mouse Direct primer GCCACAGGCTCCCAGACAT 1536

PTEN

Mouse Reverse primer TCCATCCTCTTGATATCTCCTTTTG 1537

PTEN

Mouse Probe ACAGCCATCATCAAAGAGATCGTTAGCAGAA 1538

PTEN

Mouse Direct primer ATGACAATCATGTTGCAGCAATTC 1539

Primers and target specific probes for use in real-time PCR

Diana's Name

Species Sequence description Sequence (5 ’to 3’) SEQ ID NO.

PTEN

Mouse Reverse primer CGATGCAATAAATATGCACAAATCA 1540

PTEN

Mouse Probe CTGTAAAGCTGGAAAGGGACGGACTGGT 1541

Example 3: Short antisense compounds targeting an ApoB nucleic acid and having 2’MOE or methylene (4’-CH2O-2 ’) BNA modifications

In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME) it was injected via

5 intraperitoneal (i.p.) antisense compounds targeting ApoB at a frequency of twice a week for three weeks. Doses of antisense compounds included 2.4, 1.2, 0.6, 0.3 and 0.15 mol / kg. For antisense compounds 14 nucleotides in length, these doses correspond to approximately 12, 6, 3, 1.5 or 0.75 mg / kg, respectively. Table 25 shows the sequences and motifs of the antisense compounds used in this study. The antisense compounds have a length of 20 or 14 nucleotides and have a central "hollow" region that

10 consists of ten 2'-deoxynucleotides flanked by wings having "wings" modified with 2'-O-methoxyethyl (2'-MOE) or BNA. For example, the motif of GEM 2-10-2 MOE indicates an antisense compound with a ten nucleotide gap flanked by 2 nucleotide wings with 2’-MOE modifications. Bold residues indicate 2’-O-methoxyethyl moieties and italicized residues indicate methyloxy (4’-CH2O-2 ’) BNA. The internucleoside bonds of each compound are, in all, phosphorothioate. All cytosine residues of ISIS 147764 and ISIS 372938 are replaced with 5-methylcytosines.

For ISIS 387462, only the cytosine residue in the compound's wing is substituted by 5-methylcytosines. The antisense compounds for ApoB are directed to the available ApoB-100 sequences, including the Genbank registration number XM_137955.5 (SEQ ID NO: 2).

Table 25: Antisense compounds targeting an ApoB nucleic acid

ISIS Nº

SEQ ID No. of the target Target site in 5 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

147764

2 8865 GTCCCTGAAGATGTCAATG C 5-10-5 MOE 1561

372938

2 8235 GGTACATGGAAGTC 2-10-2 MOE 190

387462

2 8235 GGTACATGGAAGTC 2-10-2 methylene (4’-CH2-O-2 ’) BNA 190

20 Forty-eight hours after the final injection, mice were sacrificed to evaluate transaminases (Table 26); the weight of the liver and kidneys (Table 27); triglyceride levels, LDL, HDL and free fatty acids (Table 28); levels of target mRNA in the liver (Table 29); plasma target protein levels; and concentration of oligonucleotides in tissue (Table 30). These assessment criteria were determined using procedures described herein and well known to those skilled in the art.

25 Table 26: ALT and AST levels (IU / l)

ISIS Nº

mol / kg dose ALT AST

Saline solution

N / A 27.8 46.3

147764

2.4 29.5 64.0

372938

2.4 26.0 49.0

372938

1.2 24.8 49.5

372938

0.6 28.0 79.3

ISIS Nº

mol / kg dose ALT AST

372938

0.3 28.3 60.0

372938

0.15 28.3 50.3

387462

2.4 41.3 84.0

387462

1.2 35.3 63.5

387462

0.6 32.0 77.3

387462

0.3 27.8 55.0

387462

0.15 29.3 68.3

Table 27: Liver and kidney weight (% control saline)

ISIS Nº

mol / kg dose Liver Kidney

Saline solution

N / A 100 100

147764

2.4 102 105

372938

2.4 100 100

372938

1.2 90 101

372938

0.6 96 112

372938

0.3 91 107

372938

0.15 96 98

387462

2.4 116 90

387462

1.2 113 90

387462

0.6 106 97

387462

0.3 101 126

387462

0.15 95 100

Table 28: Triglyceride levels (TRIG), total cholesterol (COL), HDL, LDL and free fatty acids (AGL)

Total body weight and food consumption did not differ significantly between animals treated with saline or oligonucleotides. Glucose levels were similar in all treatment groups.

ISIS Nº

mol / kg dose TRIG (mg / dl) COL (mg / dl) HDL (mg / dl) LDL (mg / dl) AGL (mg / dl)

Saline solution

N / A 167 107 81.8 11.0 1.76

147764

2.4 167 107 81.3 10.3 1.29

372938

2.4 153 104 79 10.3 1.28

372938

1.2 136 101 77.8 9.5 1.7

372938

0.6 184 110 83.3 10.8 1.66

ISIS Nº

mol / kg dose TRIG (mg / dl) COL (mg / dl) HDL (mg / dl) LDL (mg / dl) AGL (mg / dl)

372938

0.3 138 109 84.3 11.0 1.53

372938

0.15 151 106 82.8 10.8 1.57

387462

2.4 49 14 9.0 1.5 0.74

387462

1.2 71 2. 3 16.5 2.0 0.76

387462

0.6 150 55 39.3 3.7 1.43

387462

0.3 136 92 72.8 7.5 1.14

387462

0.15 163 104 81.5 9.3 1.47

Table 29:% ApoB mRNA levels (with respect to control saline)

ISIS Nº

2.4 μmol / kg 1.2 μmol / kg  0.6 μmol / kg  0.3 μmol / kg  0.15 μmol / kg

147764

57.7 ND ND ND ND

372938

77 90.0 87.3 92.6 93.1

387462

1.5 8.5 27.4 58.9 75.8

Treatment with ISIS 387462 resulted in a significant dose-dependent reduction of levels of

5 triglycerides, total cholesterol, HDL, LDL and free fatty acids. In accordance with these phenotypic findings, treatment with ISIS 387462 also led to a dose-dependent reduction of ApoB mRNA levels (Table 29) and of proteins (not shown) in mouse plasma. To determine whether the observed increase in efficiency with the methylene methoxy (4'-CH2O-2 ') BNA is due to an increase in the accumulation of oligonucleotides, the concentration of full-length and total oligonucleotides in the liver and kidney was determined. .

10 Table 30: Tissue concentration of full-length and full-length antisense compounds (M) relative to ApoB mRNA level (% control saline)

ISIS Nº

mol / kg dose Full length in kidney Full length in liver Total in kidneys Total in liver ApoB mRNA

147764

2.4 28.6 22.9 33.5 31.3 58

372938

2.4 32 5.49 3. 4 7.76 77

387462

2.4 37.2 5.69 38.9 7.31 1.5

387462

1.2 29.8 3.71 31.3 4.91 8.5

387462

0.6 18.9 1.97 twenty 2.57 27

387462

0.3 9.11 0.73 9.49 0.78 59

387462

0.15 6.97 0.19 7.43 0.24 76

The levels of the -10-2 methylene methoxy (4'-CH2-O-2 ') BNA were similar to those of 5-10-5 and 2-10-2 MOE in the kidneys but were significantly reduced in the liver. The EC50 for ISIS 387462 in the liver was determined

15 comparing the concentration of the oligonucleotide in the liver with the inhibition of ApoB mRNA. The approximate EC50 for ISIS 387462 is 1 M. In contrast to this, an effective 5-10-5 MOE capsule compound typically has an EC50 of approximately 15 µM in the liver.

Together, these results demonstrate that the short ApoB cap that has methyloxy (4'-CH2-O-2 ') on the wings is a potent inhibitor of target mRNA expression and can effectively reduce triglyceride levels, cholesterol and free fatty acids. The potency of the short antisense compound does not appear to be the result of increased accumulation in tissue, since similar levels of the compound have been observed in the kidney and in the liver were found.

5 reduced levels in relation to 5-10-5 MOE. In addition, the GNA (4’-CH2-O-2 ’) BNA exhibited few or no adverse side effects.

Example 4: Short antisense compounds targeting a GCGR nucleic acid and having 2’MOE modifications

One dose was administered in male C57 / BL6 eight-week-old mice (Jackson Laboratory, Bar Harbor, ME).

10 single GCGR oligonucleotide by intraperitoneal injection at a concentration of 6.25, 12.5, 25 or 50 mg. Each dose group consisted of four animals. Table 31 shows the sequences, motifs and conjugates of the GCGR antisense compounds used in this study. Residues in bold indicate 2’-O-methoxyethyl (2’-MOE) moieties. All compounds comprise phosphorothioate internucleoside bonds and each cytosine is substituted by 5-methylcytosine. The compounds ISIS 386626, ISIS 386627 and ISIS 386628 further comprise a conjugated C16 group

15 joined in the 2'-O position of the sugar by a diamide bond (2’-OCH2C (= O) N (H) (CH2) 4N (H) C (= O) - (CH2) 15CH3). The antisense compounds for GCGR are directed to the published GCGR sequences, including the Genbank registration number BC031885.1 (SEQ ID NO: 7).

Table 31: Short antisense compounds targeting a GCGR nucleic acid

ISIS Nº

SEQ ID No. of the target Target site in 5 ’ Sequence (5’-3 ’) Gápmero motive Conjugate SEQ ID NO.

148364

7 393 TGCACTTTGTGGTACCAAGG 5-10-5 MOE None 1562

386626

7 1768 GC16CTTCTCCATCATA  2-10-2 MOE C16 1563

386627

7 1244 GC16GGCATGCTCGTCA  2-10-2 MOE C16 653

386593

7 1244 GGGCATGCTCGTCA  2-10-2 MOE None 649

386628

7 1680 TC16GTCTTGCTGCTTT  2-10-2 MOE C16 1564

386594

7 1680 TGTCTTGCTGCTTT  2-10-2 MOE None 1565

20 Mice were sacrificed 48 hours after injection to determine transaminase levels (Table 32); the weight of the liver, white adipose tissue (TAB), spleen and kidney (Table 33); cholesterol, triglyceride and glucose levels (Table 34); GCGR mRNA levels (Tables 35-41) and the concentration of full length and total oligonucleotides in liver and kidney (Table 42). The assessment criteria were evaluated using procedures described herein and well known to those skilled in the art. Data from a blood draw are included

25 pre-treatment (pre-extraction) and post-treatment blood extraction (post-extraction)

Table 32: ALT and AST levels (IU / l)

ISIS Nº

Dose (mg / kg) ALT Pre-extraction ALT Post-extraction AST Pre-extraction AST Post-extraction

Saline solution

N / A 36 51 55 85

ISIS Nº

Dose (mg / kg) ALT Pre-extraction ALT Post-extraction AST Pre-extraction AST Post-extraction

148364

fifty 24 40 40 115

148364

25 26 35 42 87

148364

12.5 2. 3 32 44 69

148364

6.25 28 3. 4 47 76

386626

fifty 28 40 48 120

386626

25 30 36 44 92

386626

12.5 28 3. 4 44 90

386626

6.25 26 42 46 69

386627

fifty 27 457 42 451

386627

25 29 97 Four. Five 142

386627

12.5 29 62 46 81

386627

6.25 2. 3 87 38 96

386593

fifty 2. 3 33 46 58

386593

25 25 32 41 95

386593

12.5 26 33 43 74

386593

6.25 28 31 43 53

386628

fifty 28 68 44 76

386628

25 24 32 40 57

386628

12.5 28 35 42 75

386628

6.25 22 29 40 59

386594

fifty 29 3. 4 46 92

386594

25 27 31 47 82

386594

12.5 28 33 Four. Five 74

386594

6.25 2. 3 48 42 67

Table 33: Organ weights (% control saline)

ISIS Nº

Dose (mg / kg) Liver TAB Kidney Spleen

Saline solution

N / A 100 100 100 100

148364

fifty 103 80 108 123

148364

25 103 75 112 115

148364

12.5 100 84 108 96

148364

6.25 101 89 104 113

ISIS Nº

Dose (mg / kg) Liver TAB Kidney Spleen

386626

fifty 112 77 104 130

386626

25 109 97 103 120

386626

12.5 96 73 97 114

386626

6.25 100 90 100 95

386627

fifty 90 113 102 165

386627

25 99 87 99 143

386627

12.5 109 93 102 136

386627

6.25 103 96 102 131

386593

fifty 96 98 102 118

386593

25 83 94 100 104

386593

12.5 99 82 101 129

386593

6.25 96 77 98 144

386628

fifty 104 100 99 126

386628

25 102 97 109 113

386628

12.5 101 111 99 114

386628

6.25 98 106 102 151

386594

fifty 90 80 99 131

386594

25 93 76 99 128

386594

12.5 94 98 100 113

386594

6.25 102 85 101 119

Table 34: Triglyceride levels (TRIG), cholesterol (COL) and glucose (IU / l)

In general, the antisense compounds for GCGR exhibited little or no adverse side effects.

ISIS Nº

Dose (mg / kg) TRIG Pre-extraction TRIG Post-extraction COL Pre-extraction COL Post-extraction

Saline solution

N / A 132 181 91 96

148364

fifty 110 177 81 94

148364

25 115 200 83 96

148364

12.5 106 179 85 89

148364

6.25 86 162 86 89

386626

fifty 87 163 79 57

386626

25 100 187 87 72

386626

12.5 100 148 82 76

386626

6.25 86 162 85 90

ISIS Nº

Dose (mg / kg) TRIG Pre-extraction TRIG Post-extraction COL Pre-extraction COL Post-extraction

386627

fifty 106 120 83 126

386627

25 101 148 90 115

386627

12.5 99 203 86 98

386627

6.25 111 165 88 104

386593

fifty 130 128 100 95

386593

25 119 135 83 77

386593

12.5 122 128 83 79

386593

6.25 120 138 84 78

386628

fifty 102 98 88 95

386628

25 102 129 84 85

386628

12.5 90 123 90 94

386628

6.25 117 121 83 85

386594

fifty 93 99 84 85

386594

25 106 94 90 86

386594

12.5 118 133 85 95

386594

6.25 112 146 78 94

The GCGR 2-10-2 MOE cathamers exhibited a tendency towards lower levels of post-extraction triglycerides compared to the 5-10-5 MOE catheter, with the compounds ISIS 386628 and ISIS 386594 having the greatest dose-dependent effect. Glucose levels also decreased in a dose-dependent manner after treatment with ISIS.

5 386626 and ISIS 386627. Treatment with ISIS 386628, ISIS 386593 and ISIS 386594 also led, in general, to a decrease in post-extraction glucose levels. Cholesterol levels did not appear to differ significantly between treatment groups.

To determine whether the phenotypic changes shown above correlated with a decrease in GCGR mRNA, treated animals were evaluated to determine levels of liver target mRNA by PCR in

10 real time according to the procedures described in this document. Tables 35 to 41 show the results of direct comparisons of the antisense compounds directed to the GCGR nucleic acid in terms of their effect on target expression. The results are expressed as a percentage of the control saline solution.

Table 35: GCGR mRNA levels after treatment with ISIS 148364 and ISIS 386626

ISIS NO

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

148364

36 79 87 62

386626

0 8 3 7

Table 36: GCGR mRNA levels after treatment with ISIS 148364 and ISIS 386627

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

148364

63 87 105 86

386627

3 30 57 74

Table 37: GCGR mRNA levels after treatment with ISIS 148364 and ISIS 386593

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

148364

56 74 105 86

386593

9 38 74 90

Table 38: GCGR mRNA levels after treatment with ISIS 148364 and ISIS 386628

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

148364

42 77 98 101

386628

2 18 53 77

Table 39: GCGR mRNA levels after treatment with ISIS 148364 and ISIS 386594

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

148364

59 98 102 96

386594

25 47 fifty 96

Table 40: GCGR mRNA levels after treatment with ISIS 386627 and ISIS 386593

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

386627

5 40 58 42

386593

10 29 3. 4 71

Table 41: GCGR mRNA levels after treatment with ISIS 386628 and ISIS 386594

ISIS Nº

50 mg / kg 25 mg / kg 12.5 mg / kg 6.25 mg / kg

386628

4 13 38 97

386594

19 fifty 56 99

10

Treatment with 2-10-2 MOE gammers led to a significant dose-dependent decrease in GCGR mRNA expression. The compound ISIS 386626 exhibited the greatest decrease in levels of target mRNA. To determine whether the observed increase in efficiency with short antisense compounds is due to an increase in the accumulation of the antisense compound, the concentration of the total antisense compound was determined.

15 in liver and kidney.

Table 42: Total and full length antisense compound concentrations in liver and kidney (g / g)

ISIS Nº

Total in kidneys Total in liver Full-length kidney Full length liver

148364

90 54 58 46

386626

757 274 355 125

386593

91 12 77 12

ISIS Nº

Total in kidneys Total in liver Full-length kidney Full length liver

386628

496 286 305 202

The results shown in Table 42 demonstrate that short antisense compounds comprising a C16 conjugate exhibit a significant increase in the accumulation of antisense compound in both liver and kidneys. However, compound ISIS 386593, which was effective in reducing levels of target mRNA,

5 triglycerides and glucose, accumulates at a level similar to 5-10-5 MOE in liver and at a lower level in kidneys. These results suggest that, although conjugation with C16 may increase the concentration of the antisense compound in liver and kidney, it does not fully justify the efficacy of short antisense compounds.

Together, these results demonstrate that GCGR short antisense compounds are able to significantly inhibit the expression of the target mRNA while reducing triglyceride and glucose levels. Also, with the

10 Except for ISIS 386627, the MOE short cathams exhibited little or no toxic effect.

Example 5: Short antisense compounds targeting a GCGR nucleic acid and having 2’-MOE or methylene (4’-CH2O-2 ’) BNA modifications

A single dose of GCGR antisense compound was administered in intraperitoneal (ip) injection at a concentration of 10, 3.2, 1, and 15 0 in male C57 / BL6 mice eight weeks old (Jackson Laboratory, Bar Harbor, ME). , 32 mmol / kg. Each dose group consisted of four animals. Table 43 shows the sequences, motifs and conjugates of the GCGR antisense compounds used in this study. Bold residues indicate 2’-O-methoxyethyl (2’-MOE) modifications and italicized residues indicate methyloxy (4’-CH2O-2 ’) BNA modifications. All antisense compounds comprise phosphorothioate internucleoside bonds and each cytosine is replaced by 5-methylcytosine. The antisense compounds for GCGR are directed to the published GCGR nucleic acids,

20 including the registration number in Genbank BC031885.1 (SEQ ID NO: 7).

Table 43: Antisense compounds directed to a GCGR nucleic acid

ISIS Nº

SEQ ID No. of the target Target site in 5 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

148364

7 393 TGCACTTTGTGGTACCAAGG 5-10-5 MOE 1562

396144

7 1768 GCTTCTCCATCATA 2-10-2 MOE 1566

396148

7 1768 GCTTCTCCATCATA 2-10-2 Methylene methoxy (4’CH2-O-2 ’) BNA 1567

396145

7 1765 ATGGCTTCTCCATCATATCC 5-10-5 MOE 1568

396146

7 1244 GGGCATGCTCGTCA 2-10-2 MOE 650

396149

7 1244 GGGCATGCTCGTCA 2-10-2 Methylene oxide (4’-CH2-O-2 ’) BNA 652

396147

7 1241 CTTGGGCATGCTCGTCAGTC  5-10-5 MOE 1569

To determine whether the phenotypic changes shown above correlated with a decrease in GCGR mRNA, treated animals were evaluated to determine levels of liver target mRNA by PCR in

25 real time with IT in accordance with the procedures described in this document. Table 44 shows the results of direct comparisons of the antisense compounds directed to the GCGR nucleic acid in terms of their effect on target expression. The results are expressed as a percentage of the control saline solution.

TABLE 44: GCGR mRNA levels

ISIS Nº

0.32 μmol / kg 1 μmol / kg  3.2 μmol / kg 10 μmol / kg

148364

105 106 73 38

396144

122 117 40 35

396148

twenty 6 2 one

396145

nd Nd 33 8

396146

98 135 95 35

396149

91 41 30 7

396147

nd Nd 68 28

As shown in Table 44, each short antisense compound that has methylene alkoxy modifications (4’-CH2-O-2 ’) BNA demonstrated a dose-dependent reduction of GCGR mRNA levels. In addition, the compounds

5 short antisense were more effective in reducing the target than 5-10-5 MOE. Each short antisense compound comprising methyloxy 4'-CH2-O-2 ') BNA in the wings resulted in a significant reduction of the CGCGR protein with respect to both the control saline solution and the treatment with ISIS 148364. Then, the DE50 concentrations Estimates for each antisense were calculated using Graphpad Prism; ED50 is the dose at which a 50% reduction in mRNA is observed. The results are shown below in table 45.

10 Table 45: Estimated DE50 concentration

Gápmero motive

ISIS Nº DE50 (μmol / kg) ED50 (mg / kg)

5-10-5 MOE

148364 7 50.6

2-10-2 MOE

396144 4 18.1

2-10-2 methyloxy BNA

396148 0.1 0.4

5-10-5 MOE

396145 2.1 9.3

2-10-2 MOE

396146 8.3 40

2-10-2 methyloxy BNA

396149 1.1 5

5-10-5 MOE

396147 5.2 37.5

Example 6: Short antisense compounds targeting a PTEN nucleic acid and having modifications (4’-CH2-O-2 ’) BNA

In male Balb / c mice of six weeks of age (Jackson Laboratory, Bar Harbor, ME) a single one was administered

15 injection i.p. of the antisense PETN compound at a dose of 8 mol / kg. Each dose group consisted of four animals. Table 46 shows the sequences and motifs of the PTEN antisense compounds used in this study. Bold residues indicate 2’-O-methoxyethyl (2’-MOE) moieties and italic residues indicate methyloxy BNA nucleotides. Each antisense compound comprises phosphorothioate bonds. In addition, cytosine residues in the hollow of ISIS 384073 and in the wings of ISIS 392056, ISIS 392057, ISIS 392061 and ISIS 392063 are replaced by 5

20 methylcytosines. Antisense compounds are directed to published PTEN nucleic acids, including Genbank registration number U92437.1 (SEQ ID NO: 13).

Table 46: Antisense compounds directed to a PTEN nucleic acid

ISIS Nº

SEQ ID No. of the target Target site in 5 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

141923

Control N / A CCTTCCCTGAAGGTTCCTCC  5-10-5 MOE 1570

116847

29 2011 TCAAATCCAGAGGCTAGCAG  5-10-5 MOE 1571

384073

29 2013 AAATCCAGAGGCTAGC 3-10-3 methyloxy (4 -CH2O-2 ’) BNA 1428

391172

29 2013 AAATCCAGAGGCTAG 2-10-3 methylene oxy (4’-CH2-O-2 ’) BNA 1429

392056

29 140 AGCTGCAGCCATGA 2-10-2 methyloxy (4-CH2O-2 ’) BNA 1263

392057

29 807 GGTCCAGGGCCAAG 2-10-2 methyloxy (BNA 1162

392061

29 2014 AATCCAGAGGCTAG 2-10-2 methylene (4’-CH2-O-2 ’) BNA 1431

392063

29 3099 AGGCCAGTGCTAAG 2-10-2 methylene oxide (4’-CH2O-2 ’) BNA 1226

Mice were sacrificed 72 hours after injection to determine serum transaminase levels (Table 47); liver and spleen weights (Table 47); and the levels of PTEN mRNA in liver, kidney and fat (Table 48), according to the procedures described herein and well known to those skilled in the art.

Table 47: Transaminase levels and organ weights

ISIS Nº

ALT (IU / l) ALT (IU / l) % saline solution in liver weight % saline solution in spleen weight

Saline solution

98.5 37.5 100 100

141923

89.5 34.8 101 108

116847

59.8 29.5 109 108

384073

57.8 29.3 115 111

391172

48.5 32.8 120 112

392056

516 892 125 167

392057

63.8 34.5 125 101

392061

189 42 123 111

392063

67.3 21.8 127 134

In general, short antisense compounds with methyloxy modifications (4’-CH2-O-2 ’) BNA exhibited few or no adverse side effects. In addition, total body weight did not differ significantly between treatment groups.

Table 48:% PTEN RNA levels in liver, kidney and fat

ISIS Nº

Liver Kidney Grease

Saline solution

100 100 100

141923

102 133 118

116847

37 96 85

384073

24 74 77

391172

18 63 101

392056

27 88 74

392057

33 79 96

392061

24 61 85

392063

6.5 52 72

As shown in Table 48, each antisense compound directed to a PTEN nucleic acid led to a significant reduction in levels of target mRNA in liver compared to animals treated with saline and treated with control. The antisense compounds produced several effects on the levels of target mRNA in

5 kidneys and fats.

Example 7: Short antisense compounds directed to a PTEN nucleic acid and having BNA modifications

In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME) a single intraperitoneal (ip) injection of the antisense compound directed to a PETN nucleic acid was administered at a dose of 8, 4, 2 or 1 10 mol / kg. Each dose group consisted of four animals. Table 49 shows the sequence, wing chemistry and motifs of each antisense compound used in this study. Residues in bold indicate the nucleotides modified with 2’-MOE, the italicized letters indicate the methylene methoxy modifications (4’-CH2O2 ’) BNA. All antisense compounds comprise phosphorothioate bonds in each position. Each cytosine of ISIS 116847 and the cytosine residues in the wings with methylene (4’-CH2-O-2 ’) BNA of ISIS 392063 are substituted with 5-methylcytosines,

15 while thymidine residues on the wings with methylene (4’-CH2-O-2 ’) BNA from ISIS 392745 are substituted with 5-methylthymidines. Antisense compounds are directed to published PTEN nucleic acids, including Genbank registration number U92437.1 (SEQ ID NO: 13).

Table 49: Antisense compounds directed to a PTEN nucleic acid

ISIS Nº

SEQ ID No. of the target Target site Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

116847

13 2011 TCAAATCCAGAGGCTAGCAG 5-10-5 MOE 1571

392063

13 3099 CTTAGCACTGGCCT 2-10-2 BNA Methyloxy BNA 1226

392745

13 3099 CTTAGCACTGGCCT 2-10-2 methyloxy BNA 1226

20 Mice were sacrificed 72 hours after injection to determine serum transaminase levels (Table 50); liver, kidney and spleen weights (Table 50); PTEN mRNA levels in the liver (Table 51), and the estimated oligonucleotide concentration DE50 (Table 52). These assessment criteria were measured using procedures described herein and well known to those skilled in the art.

Table 50: AST, ALT and bilirubin levels and organ weights

ISIS Nº

Dose ### mol / kg AST (IU / l) ALT (IU / l) Bilirubin (mg / dl) % saline solution in liver weight % saline solution in kidney weight % saline solution in spleen weight

Saline solution

N / A 64.0 31.8 0.15 100 100 100

116847

8 73.0 32.0 0.1 114 92 106

392063

8 50.3 17.3 0.1 115 98 115

392063

4 100.8 31.3 0.15 122 94 116

392063

2 60.5 32.8 0.1 112 99 106

392063

one 57.5 29.3 0.1 104 95 107

392745

8 75.5 23.5 0.13 125 99 100

392745

4 77.0 29.3 0.13 121 100 96

392745

2 69.0 32.0 0.13 110 98 103

392745

one 52.0 27.3 0.1 109 97 104

In general, PTEN antisense compounds showed no significant signs of toxicity. The weights of the kidneys, liver and spleen were all within normal limits. Total body weight did not differ significantly between treatment groups.

Table 51:% Levels of PTEN mRNA in liver (with respect to control saline)

ISIS Nº

8 μmol / kg 4 μmol / kg 2 μmol / kg 1 μmol / kg

116847

36 ND ND ND

392063

7.4 16 32 60

392745

5.2 eleven 31 60

As shown in Table 51, each short antisense compound having methylene modifications (4’-CH2-O-2 ’)

10 BNA demonstrated a dose-dependent reduction of PTEN mRNA levels. In addition, short antisense compounds were more effective in target reduction than 5-10-5 MOE. The levels of PTEN protein in the liver were also determined after administration of each antisense compound at a dose of 8 μmol / kg. Each short antisense compound comprising 4'-CH2-O-2 ’) BNA in the wings resulted in a significant reduction of PTEN protein with respect to both control saline and treatment with ISIS

116847. The estimated DE50 concentrations for each oligonucleotide were then calculated using Graphpad Prism. The results are shown below in table 52.

Table 52: Estimated DE50 concentration

Wing chemistry

ISIS Nº DE50 (μmol / kg) ED50 (mg / kg)

MOE (with 5-MeC)

116847 6.3 45.2

Methylene BNA (with 5-MeC)

392063 1.3 5.8

methyloxy BNA

392745 1.2 5.6

To further investigate different types of bicyclic nucleic acid compounds, an additional group of short antisense compounds targeting PTEN nucleic acid was designed and analyzed. In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME) a single intraperitoneal injection (i.p.) of the antisense compound was administered at a dose of 8, 4, 2 or 1 mol / kg. Each dose group consisted of four animals. In

5 Table 53 shows the sequence, wing chemistry and motifs of each antisense compound used in this study. All antisense compounds comprise phosphorothioate bonds in each position. The cytosine residues in the methyloxy (4’-CH2-O-2 ’) BNA of ISIS 392063 are substituted by 5-methylcytosines. The antisense compound was directed to published PTEN nucleic acids, including Genbank registration number U92437.1 (SEQ ID NO: 13).

10 Table 53: Antisense compounds directed to a PTEN nucleic acid

ISIS Nº

SEQ ID No. of the target Target site in 5 ’ Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

392063

29 3099 CTTAGCACTGGCC T 2-10-2 Methylene BNA 1226

396564

29 3099 CTTAGCACTGGCC T 2-10-2 (4’-CH2N (R) -O- 2 ’) (4’-CH2-N (R) -O-2’) BNA 1226

396006

29 3099 CTTAGCACTGGCC T 2-10-2 α-L-Methylene methoxy BNA 1226

Mice were sacrificed 72 hours after injection to determine serum transaminase levels (Table 54); liver and spleen weights (Table 54); and the levels of PTEN mRNA in liver, kidney and fat (Table 55), according to the procedures described herein and well known to those skilled in the art.

Table 54: AST and ALT levels and organ weights

ISIS Nº

mol / kg dose AST (IU / L) ALT (IU / L) Liver weight Spleen Weight

Saline solution

N / A 71 33 100 100

392063

8 97 38 118 103

392063

4 179 36 115 107

392063

2 67 32 109 116

392063

one 68 27 102 105

396564

8 67 25 100 104

396564

4 96 30 102 106

396564

2 68 27 100 119

396564

one 79 39 97 109

396006

8 56 28 110 104

396006

2 139 36 97 105

Table 55:% Levels of PTEN mRNA in liver (with respect to control saline)

ISIS Nº

8 μmol / kg 4 μmol / kg 2 μmol / kg 1 μmol / kg

392063

6.9 18 39 71

396564

86 97 100 96

396006

6.5 ND ND 70

As shown above, short antisense compounds that have -L-methyloxy (4’-CH2-O2 ’) BNA modifications led to a dose-dependent reduction of target mRNA levels. Treatment with the short antisense compound that has BNA oxyamino modifications led to a modest reduction in target expression.

Example 8. Study of dose response of single dose administration with antisense compounds

Shorts targeting ApoB and PTEN nucleic acids

In male Balb / c mice of six weeks of age (Jackson Laboratory, Bar Harbor, ME) a single one was administered

10 intraperitoneal injection (i.p.) of the antisense compound at a dose of 8, 4, 2 or 1 mol / kg. Each dose group consisted of four animals. Table 56 shows the sequence, wing chemistry and motifs of each antisense compound used in this study. The italicized residues indicate the methyloxy (4'-CH2-O-2 ') BNA modifications, the underlined residues indicate the N-methyl-oxyamino (4'-CH2-N (CH3) -O-2') BNA modifications and the residues in boxes indicate the modifications alpha-L-methyloxy (4'-CH2-O-2 ') BNA. All antisense compounds comprise

15 phosphorothioate bonds in each position. Each cytosine of ISIS 116847 and the cytosine residues in the wings with methylene (4'-CH2-O-2 ') BNA of ISIS 392063 are substituted with 5-methylcytosines, while thymidine residues in the wings with methyleneloxy (4 ISIS 392745 '-CH2-O-2') BNA are substituted with 5-methylthymidines. PTEN antisense compounds are directed to published PTEN nucleic acids, including Genbank registration number U92437.1 (SEQ ID NO: 13). ApoB antisense compounds are directed to published ApoB nucleic acids, including

20 the registration number in Genbank XM_137955.5 (SEQ ID NO: 2).

Table 56: Short antisense compounds targeting ApoB and PTEN nucleic acids

ISIS Nº

Diana SEQ ID of the target Target site in 5 ’ SEQUENCE Gamer SEQ ID NO.

387462

ApoB 19 8235 GGTACATGGAAGTC 2-10-2 Methylene BNA 193

392063

PTEN 29 3099 CTTAGCACTGGCCT 2-10-2 Methylene BNA 1226

396565

PTEN 29 3099 CUTAGCACTGGCC U 2-10-2 N-Me-oxyamino 1126

396006

PTEN 29 3099 2-10-2 -L-menyloxy BNA 1226

Table 57:% Reduction of ApoB and PTEN mRNA (with respect to control saline)

ISIS Nº

Dose (μmol / kg) % ApoB mRNA reduction (compared to saline solution) % Reduction of PTEN mRNA (compared to saline)

387462

8 0.62 92.8

4

6.55 103

2

18.6 105

one

42 98

392063

8 126 6.79

ISIS Nº

Dose (μmol / kg) % ApoB mRNA reduction (compared to saline solution) % Reduction of PTEN mRNA (compared to saline)

 4

111 18.1

2

112 42.4

one

114 62.3

396565

8 116 23.8

4

1.04 46.6

2

94.4 76.1

one

115 89.5

396006

8 94.3 62.9

4

101 18.2

2

79.7 52.4

one

111 82.4

As shown in Table 57, each short antisense compound that has methylene BNA modifications demonstrated a dependent reduction in the mRNA levels of the target. It should be noted that the short antisense compound with the N-methyl oxyamino BNA wings (ISIS 396565) also demonstrated a dose-dependent reduction of PTEN expression similar to that of the short antisense compounds with β-D-methylene oxy BNA and  -L-methyloxy BNA. The estimated DE50 concentrations for each antisense were then calculated using Graphpad Prism. The results are shown below in Table 58.

Table 58: Estimated DE50 concentrations

Wing chemistry

ISIS Nº DE50 (μmol / kg) ED50 (mg / kg)

Methylene BNA

387462 0.8 3.9

Methylene BNA

392063 1.5 7

N-Me-oxyamino BNA

396565 3.8 17.4

-L-methyloxy BNA

396006 2.1 9.3

10 EXAMPLE 9: Administration of a mixed skeleton parental and parental antisense compound targeting the SGLT-2 mRNA

In db / db mice (Charles River Laboratories, Wilmington, MA) ISIS 257016 was administered intraperitoneally at a dose of 1, 7.5, 14 or 17 mg / kg twice a week. The control groups included a group that received saline solution according to the same dosing schedule and a group that received ISIS 145733. Both ISIS 257016 and ISIS 145733 15 comprise the sequence GAAG-TAGCCACCAACTGTGC (SEQ ID No. 1572), which also comprises a region “ "central" hollow consisting of ten 2'-deoxynucleotides, which is flanked on both sides (directions 5 'and 3') by "wings" of five nucleotides. The wings are composed of 2’-methoxyethyl (2’-MOE) nucleotides. All citidine residues are 5-methylcytidines. The internucleoside bonds (skeleton) are phosphorothioate (P = S) along the oligonucleotide for ISIS 145733; however, ISIS 257016 has a mixed skeleton. The internucleoside bonds for

20 ISIS 257016 are phosphodiester (P = O) in the wings and phosphorothioate in the hollow. Forty-eight hours after administration of the last dose, mice were sacrificed and renal tissue was analyzed to determine the levels of SGLT-2 mRNA. The results are shown below in Table 59.

Table 59: Antisense inhibition of SGLT2 mRNA expression in vivo by 5-10-5 MOE

% Change in SGLT2 expression with respect to saline solution

Nmol / kg oligonucleotide dose

ISIS 145733 ISIS 257016

17

-37.5 -76

14

-31.25 -74

7.5

-12.5 -62.5

one

+3 -44

Both ISIS 257016 and ISIS 145733 markedly reduced SGLT-2 levels compared to control saline. (MRNA levels were determined using real-time PCR with IT, as described above.) However, ISIS 257016 has been shown to be approximately 20-50 times more potent in the reduction of SGLT-2 mRNA compared to ISIS 145733. An associated reduction in plasma glucose levels was observed in the treatment groups. (661  14 for the saline group compared to 470  23 for the group receiving ISIS 257016). The accumulation of ISIS 257016 and ISIS 145733 in the kidney was similar for the entire dose range, however little was detected of the full length 257016 antisense in the kidney, which supports the theory that a degradation product is responsible for the increase of activity. Also, the start of the action after

10 a single dose of 25 mg / kg was correlated with a time point where there was little 257016 antisense compound intact.

Similar studies were conducted with low-mass ob / ob mice and in ZDF rats ((Charles Rivers Laboratories) using ISIS 257016, ISIS 145733 or saline solution according to a similar dosing schedule as described above. for ISIS 145733 and ISIS 257016 it is conserved among mice and rats 15 (see Table 60). The reduction of SGLT-2 mRNA in the kidney was similar to that observed previously.In a study with rats, at a dose of 10 mg / kg administered twice a week for two weeks, it was shown that ISIS 145733 reduced levels of SGLT-2 mRNA by approximately 40%, while the reduction achieved with ISIS 257016 was greater than 80%. SGT2 expression maximally at a low dose of 12.5 mg / kg Additional studies with lower dose ranges show a significant reduction in mRNA levels

20 of SGLT2 with the mixed skeleton antisense compound at doses below 1 mg / kg / week.

EXAMPLE 10: Administration of a parental and short antisense compound targeting the SGLT-2 mRNA

Pharmacokinetic studies indicated that ISIS 257016 acted as a prodrug that was metabolized to a 12-nucleotide base pharmacophore. In a subsequent study, intraperitoneal doses of 1.5 mg / kg of ISIS 257016 or ISIS 370717 or saline solution were administered to rats twice a week according to a dosing schedule

25 similar. ISIS 370717 is an antisense compound of 12 nucleotide bases directed to the SGLT-2 nucleic acid, which comprises the sequence TAGCCACCAACT (SEQ ID No. 154) and which also comprises a central "hollow" region consisting of ten 2'-deoxynucleotides, which is flanked on both sides (directions 5 'and 3') by "wings" of a nucleotide. The wings are composed of 2’-methoxyethyl (2’-MOE) nucleotides. All citidine residues are 5 methyl cytidines. The internucleoside bonds (skeleton) are phosphorothioate (P = S) along the oligonucleotide.

30 After five weeks of dose administration the animals were sacrificed and the renal tissue was analyzed to determine the levels of SGLT-2 mRNA. The pharmacological activity of ISIS 257016 and ISIS 370717 was similar, however the 12 nucleotide antisense compound showed a faster onset of action. ISIS 370717 showed almost 80% inhibition of SGLT2 expression in kidneys on day two after a single dose of 2.8 umoles / kg, while ISIS 257016 showed only a 25% inhibition on day 2 after it single dose administration.

35 The data support that ISIS 257016 is a prodrug that has a 12 nucleotide pharmacophore.

EXAMPLE 11: Potency and bioavailability of a short antisense compound

The enhanced potency shown by ISIS 370717 and the best oral bioavailability for these short antisense compounds makes these compounds useful for oral administration. Normal rats received ISIS 370717, ISIS 145733 or saline solution at 100 mg / kg twice a week by intra-conjunctive administration. About 48

40 after the last dose, the animals were sacrificed and the renal tissue was analyzed to determine the concentration of the antisense compound and the levels of SGLT-2 mRNA. There was a significantly greater accumulation of ISIS 370717 in renal tissue (approximately 500 micrograms per gram of tissue) compared to controls. In addition, the SGLT-2 mRNA was reduced by more than 80% over controls.

EXAMPLE 12: Variations in the wing, the hollow and the total length around a short antisense compound of 12 nucleotides

ISIS 370717 1-10-1 MOE was used as a template to make oligos related to the sequence with various motifs. These variations are provided in Table 60. The antisense compounds were designed to direct them to different regions of the mouse or rat SGLT2 nucleic acid, using the published sequences (GenBank registration number U29881.1, which is incorporated herein document as SEQ ID No. 1575 and the GenBank registration number AJ292928.1, which is incorporated herein as SEQ ID No. 1576, respectively).

Table 60: Short antisense compounds targeting SGLT2 nucleic acids

ISIS Nº

Target site at 5 ’in SEQ ID No. 1575 in mouse Target site at 5 ’in SEQ ID No. 1576 in rat 1576 Gápmero motive Sequence (5’-3 ’) SEQ ID NO.

257016

2680 148 5-10-5 GAAGTAGCCACCAACTGTGC  1553

370717

2684 152 1-10-1 MOE TAGCCACCAACT  1554

386169

2684 152 2-8-2 MOE TAGCCACCAACT 1555

386176

2685 153 1-8-1 MOE AGCCACCAAC 1556

386196

2684 152 3-6-3 MOE TAGCCACCAACT 1557

Antisense compounds were analyzed according to their effect on the levels of SGLT22 mRNA. The data is

10 intervals taken from three experiments in which mice were administered doses twice a week for three weeks with 2.5, 0.5 or 0.1 umol / kg of the previous MOE gammers administered by intraperitoneal injection. Mice were sacrificed 48 hours after the last administration and SGLT2 levels in kidneys were evaluated.

SGLT2 mRNA levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The

15 results are shown below in Table 61.

Table 61: SGLT2 antisense inhibition in vivo by 1-10-1 and 1-10-2 MOE

% Change in SGLT2 expression with respect to saline solution

Oligonucleotide dose umol / kg

ISIS 370717 ISIS 386169 ISIS 386176 ISIS 386196 ISIS 386197

2.5

-82 -85 -80 -fifty -twenty

0.5

-70 -80 -68 -30 -fifteen

0.1

-55 -70 -65 -35 -twenty

These results illustrate that the various motifs analyzed inhibit the expression of SGLT2 in vivo in a dose-dependent manner. It was found that 1-10-1, 2-8-2 and 1-8-1 cathamers were particularly potent.

20 EXAMPLE 13: Rat SGLT2 antisense inhibition by 1-10-1 and 1-10-2 MOE

The antisense compounds of the 1-10-1 and 1-10-2 MOE gammers, provided in Table 62, were designed to target different regions of the mouse or rat SGLT2 RNA. All short antisense compounds of Table 62 were chimeric oligonucleotides ("gammers" 12 or 13 nucleotides in length, composed of a central "hollow" segment consisting of ten 2'-deoxynucleotides, which is flanked at the 5 'end by a "wing" of a

25 nucleoside and at the 3 'end by a "wing" of two or a nucleotide. The wings are composed of 2’methoxyethyl (2’-MOE) nucleotides. The internucleoside bonds (skeleton) are phosphorothioate (P = S) along the oligonucleotide. All citidine residues are 5-methylcytidines.

Table 62: Antisense compounds targeting SGLT2 nucleic acids

ISIS Nº

Target site at 5 ’in SEQ ID No. XXX (mouse) Target site at 5 ’in SEQ ID No. XXX (rat) Gápmero motive Sequence (5’-3 ’) SEQ ID NO.

370717

2684 152 1-10-1 MOE TAGCCACCAACT  1554

382675

2683 151 1-10-1 MOE TAGCCACCAACTG  1559

379692

508 1-10-1 MOE TGTTCCAGCCCA  246

382676

507 1-10-2 MOE TGTTCCAGCCCAG  246

379699

1112 1-10-2 MOE GGCATGAGCTTC  281

382677

1111 1-10-2 MOE GGCATGAGCTTCA  281

382677

958 1-10-2 MOE GGCATGAGCTTCA  281

Short antisense compounds were analyzed for their effect on the levels of SGLT2 mRNA in rats. The data are intervals taken from three experiments with male Male Sprague-Dawley rats (170-200 g) in which

5 administered the doses twice a week for three weeks with 450, 150 or 50 umol / kg of the 1-10-1 or 110-2 MOE screener administered by intraperitoneal injection. Rats were sacrificed 48 hours after the last administration and SGLT2 mRNA levels in kidneys were evaluated. The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown below in Table 63.

10 Table 63: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 and 1-10-2 MOE

% Change in SGLT2 expression with respect to saline solution

Nmol / kg oligonucleotide dose

ISIS 370717 1-10-1 ISIS 382675 1-10-2 ISIS 379692 1-10-1 ISIS 382676 1-10-2 ISIS 379699 1-10-1 ISIS 382677 1-10-2

450

-70 -80 -90 -85 -83 -75

150

-70 -65 -85 -80 -75 -60

fifty

-55 -fifty -80 -65 -60 -40

These results illustrate that both gammers, 1-10-1 and 1-10-2, reduce SGLT2 mRNA in vivo in a dose-dependent manner.

The total body weight, liver, spleen and kidney weight were then evaluated in the rats. Significant changes in the

The weight of the liver, spleen or body may indicate that a specific compound produces toxic effects. All changes were within the margin of error of the experiment. No significant changes in body weight were observed during treatment or at the end of the study. Nor were significant changes in liver or spleen weight observed.

The toxic effects of short antisense compounds administered in vivo can be assessed by measuring the levels of

20 enzymes and proteins associated with liver or kidney disease or injury. Often, elevations in serum transaminase levels, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are indicators of liver disease or injury. Total serum bilirubin is an indicator of liver and biliary function, and albumin and blood urea nitrogen (BUN) are indicators of renal function. Occasionally, glucose and triglyceride levels are altered due to the toxicity of a treatment. Serum glucose also depends in part on the activity of

25 SGLT2. The levels of ALT, AST, total bilirubin, albumin, BUN, glucose and triglycerides were measured in rats treated with short antisense compounds. The levels of routine clinical indicators of liver and kidney injury and disease were within normal ranges and did not change significantly compared to animals treated with saline, which shows that short antisense compounds do not significantly affect renal function or liver Triglyceride and glucose levels did not rise significantly compared to animals treated with saline.

EXAMPLE 14: Antisense inhibition of mouse and rat SGLT2 by 1-10-1 MOE

The antisense compounds with the 1-10-1 MOE cap designed to target different regions of the mouse SGLT2 mRNA are shown in Table 64.

Table 64: Composition of antisense compounds targeting the SLGT-2 mRNA

ISIS Nº

Target site at 5 ’in SEQ ID No. XXX (mouse) Target site at 5 ’in SEQ ID No. XXX (rat) Reason Sequence (5’-3 ’) SEQ ID NO.

370717

2684 152 1-10-1 MOE TAGCCACCAACT  1554

379692

508 1-10-1 MOE TGTTCCAGCCCA  246

379699

1112 1-10-1 MOE GGCATGAGCTTC  281

379702

1525 1-10-1 MOE GCACACAGCTGC  293

381408

3034 ** 1-10-1 MOE TACCGAACACCT  1560

** indicates 3 mismatches with a target sequence

Short antisense compounds were analyzed for their effect on mouse SGLT2 mRNA levels. The data are intervals taken from three experiments in which the week-old male Balb / c mice were administered doses twice a week for two weeks with 450, 150 or 50 nmol / kg of one of the catophers 1-10 -1 MOE

10 previous administered by intraperitoneal injection. Mice were sacrificed 48 hours after the last administration and the levels of SGLT2 mRNA in the kidneys were evaluated. The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown in Table 65 below.

15 Table 65: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 MOE

% Change in SGLT2 expression with respect to saline solution

Nmol / kg oligonucleotide dose

ISIS 370717 ISIS 379692 ISIS 379699 ISIS 379702 ISIS 381408

450

-65 -80 -80 -75 -

150

-55 -70 -62.5 -72.5 -

fifty

-47.5 -52.5 -42.5 -52.5 -

These results illustrate that all 1-10-1 MOE guinea pigs except ISIS 381408 inhibit the expression of SGLT2 in vivo in a dose-dependent manner. The activity of ISIS 381408 has been demonstrated in studies with rats (see Table 65).

20 Evaluation of catfish 1-10-1 in rats

The effect of previous 1-10-1 (see Table 64 above) cathamers on rat SGLT2 mRNA levels. Data are taken from four experiments in which male Sprague-Dawley male rats (170-200 g) were administered twice weekly for three weeks with 250 nmol / kg administered by intraperitoneal injection. Rats were sacrificed 48 hours after the last administration and SGLT2 mRNA levels were evaluated in

25 kidneys The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown in Table 66 below.

Table 66: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 MOE

% Change in SGLT2 expression with respect to saline solution

Nmol / kg oligonucleotide dose

ISIS 370717 ISIS 379692 ISIS 379699 ISIS 379702 ISIS 381408

250

-70 -85 -75 -25 -5

These results illustrate that all 1-10-1 MOE gammers inhibit SGLT2 expression in vivo in rat studies.

5 EXAMPLE 15: Antisense inhibition of mouse and rat SGLT2 expression by additional 1-10-1 and 2-8-2 MOE

The short antisense compounds of the 1-10-1 and 2-8-2 MOE captamers were designed to target different regions of the mouse SGLT2 RNA but have complementarity between species. Short antisense compounds are shown in Table 67. All short antisense compounds of Table 67 are 12 nucleotide gammers of

10 length, composed of a central “hollow” segment consisting of 2’-deoxynucleotides, which is on both sides (5 ’and 3’ directions) by wing segments that have 2 ’modifications. The wings are composed of 2’methoxyethyl (2’-MOE) nucleotides. The internucleoside bonds (skeleton) are phosphorothioate (P = S) along the oligonucleotide. All citidine residues are 5-methylcytidines.

Table 67: Short antisense compounds targeting SGLT2 nucleic acid

ISIS Nº

Target site in 5 ’(rat) SEC ID target (rat) Gápmero motive Sequence (5’-3 ’) SEQ ID NO.

379692

508 1-10-1 MOE TGTTCCAGCCCA  246

388625

508 1-10-1 MOE TGTTCCAGCCCA  246

379699

1112 1-10-1 more GGCATGAGCTTC  281

388626

1112 2-8-2 MOE GGCATGAGCTTC  281

379702

1525 2-8-2 MOE GCACACAGCTGC  293

388627

1525 2-8-2 MOE GCACACAGCTGC  293

fifteen

Short antisense compounds were analyzed for their effect on mouse SGLT2 mRNA levels in vivo. The data were taken from three experiments in which 6-week-old male Balb / c rats were administered twice weekly for three weeks with 0.5, 0.1 or 0.02 umol / kg of the catheter 1-10-1 or 2-8-2 MOE administered by intraperitoneal injection. Mice were sacrificed 48 hours after the last administration and evaluated

20 levels of SGLT2 in kidneys. The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown below in Table 68.

Table 68: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 and 2-8-2 MOE

% Change in SGLT2 expression with respect to saline solution

Oligonucleotide dose umol / kg

ISIS 379692 1-10-1 ISIS 388625 2-8-2 ISIS 379699 1-10-1 ISIS 388626 2-8-2 ISIS 379702 1-10-1 ISIS 388627 2-8-2

0.5

-85 -90 -75 -80 -70 -65

0.1

-75 -88 -60 -60 -65 -fifty

0.02

-55 -65 -30 -Four. Five -40 -38

5

10

fifteen

twenty

25

30

35

40

These results illustrate that both gammers, 1-10-1 and 2-8-2, inhibit the expression of SGLT2 in vivo in a dose-dependent manner.

The total body weight, liver, spleen and kidney weight were then evaluated in the mice. All changes were within the margin of error of the experiment. No significant changes in body weight were observed during treatment or at the end of the study. Nor were significant changes in liver or spleen weight observed.

The levels of ALT, AST, BUN, transaminases, plasma creatinine, glucose and triglycerides were measured in mice treated with short antisense compounds. The levels of routine clinical indicators of liver and kidney injury and disease were within normal ranges and did not change significantly compared to animals treated with saline, which shows that short antisense compounds do not significantly affect renal function or liver Triglyceride and glucose levels did not rise significantly compared to animals treated with saline.

Evaluation of ISIS 379692 1-10-1 MOE catheter, ISIS 3921701-101 Methylenehexy BNA, ISIS 388625 2-8-2 MOE, and ISIS 392173 2-8-2 Methylenexy BNA in mice

The effect of ISIS 379692 1-10-1 MOE and ISIS 388625 2-8-2 MOE are compared with the effect of ISIS 392170 1-10-1 Methylenehex BNA and ISIS 392173 2-8-2 Methyleneloxy BNA (see Table 69) on mouse SGLT2 mRNA levels in vivo. Data are taken from three experiments in which 6-week-old male Balb / c mice were administered twice weekly for three weeks with 5, 25 and 125 mmol / kg of ISIS 379692 1-10- 1 MOE or ISIS 388625 2-8-2 MOE screener administered by intraperitoneal injection. Mice were sacrificed 48 hours after the last administration and the levels of SGLT2 mRNA in the kidneys were evaluated. The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The data are expressed as a percentage change ("+" indicates an increase, "-" indicates a decrease) with respect to animals treated with saline solution and are illustrated in Table 69.

Table 69: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 and 2-8-2 MOE

Nmol / kg oligonucleotide dose

ISIS 379692 1-10-1 MOE ISIS 392170 1-10-1 Menyloxy BNA ISIS 388625 2-8-2 MOE ISIS 392173 2-8-2 Methylene BNA

125

-58 -69 -70 -75

25

-46 -54 -47 -57

5

-7 -2. 3 -18 -44

These results illustrate that both gammers, 1-10-1 and 2-8-2, inhibit the expression of SGLT2 in vivo at the three highest dosage intervals in a dose-dependent manner. The results also illustrate that the methylene BNA constructs are more potent than the MOE constructs. No significant changes in body weight were observed during treatment or at the end of the study. Nor were significant changes in liver or spleen weight observed. The toxicity parameters, including levels of ALT, AST, BUN and creatinine, were within normal limits and had not changed with respect to animals treated with saline, which shows that the compounds do not significantly affect function renal or hepatic

Evaluation of ISIS 3796921-10-1 MOE and ISIS 3886252-8-2 MOE in rats

The effect of ISIS 379692 1-10-1 MOE and ISIS 388625 MOE 2-8-2 (see Table 70) on the levels of rat SGLT2 mRNA in vivo. Data are taken from four experiments in which Sprague-Dawley male rats (170-200 g) were dosed twice a week for three weeks with 200, 50, 12.5 or 3,125 nmol / kg of the ISIS catheter 379692 1-10-1 MOE or ISIS 388625 2-8-2 MOE scintillator administered by intraperitoneal injection. Rats were sacrificed 48 hours after the last administration and SGLT2 levels in kidneys were evaluated. The target levels were determined by real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown below in Table 70.

Table 70: Antisense inhibition of SGLT2 mRNA in vivo by 1-10-1 and 2-8-2 MOE

% Change in SGLT2 expression with respect to saline solution

Oligonucleotide dose umol / kg

ISIS 379692 1-10-1 ISIS 388625 2-8-2

200

-80 -80

fifty

-65 -65

12.5

-fifteen -fifteen

3,125

+ 30 + 25

These results illustrate that both gammers, 1-10-1 and 2-8-2, inhibit the expression of SGLT2 in vivo at the three highest dosage intervals in a dose-dependent manner.

5 The total body weight, liver, spleen and kidney weight were then evaluated in the rats. All changes were within the margin of error of the experiment. No significant changes in body weight were observed during treatment or at the end of the study. Nor were significant changes in liver or spleen weight observed.

The levels of ALT, AST, BUN, cholesterol, plasma creatinine and triglycerides were measured in rats treated with short antisense compounds. The levels of routine clinical indicators of liver and kidney injury and disease

10 were within normal ranges and did not change significantly compared to animals treated with saline, which shows that short antisense compounds do not significantly affect renal or hepatic function.

EXAMPLE 16: Antisense inhibition of SGLT2 expression in ZDF rats

The effect of ISIS 388625, 388626 and the control oligo ISIS 388628 on plasma glucose levels in

15 rats ZDF and HbA1c. The diabetic rat Zucker (ZDF) deficient in leptin is a useful model for the investigation of type 2 diabetes. Diabetes develops spontaneously in these male rats at 8-10 weeks of age and is associated with hyperphagia, polyuria, Polydipsia and alteration of weight gain, symptoms that appear in parallel to the clinical symptoms of diabetes (Phillips MS, et al., 1996, Nat Genet 13, 18-19). In six-week-old ZDF rats, the short antisense compound was injected intraperitoneally at a dose of 40 OnM / kg once a week for

20 twelve weeks. The data are illustrated in tables 71 and 72.

Table 71: Plasma glucose

ISIS NO.

SEQ ID NO. Sequence (5’-3 ’) Reason Plasma glucose levels recorded on specific dates (mg / dl)

Day 10

Day 40 Day 55 Day 66

PBS

n / a n / a 450.7 478.5 392.8 526.2

388625

246 TGTTCCAGCCCA 2-8-2 MOE 435.5 278.7 213.8 325.5

388626

281 GGCATGAGCTTC 2-8-2 MOE 434.7 300.5 219.8 379.8

388628

226 TAGCCGCCCACA 2-8-2 MOE 436 502 411.2 668.8

Table 72: HbA1c Status

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Reason Percentage of HbA1c on specific dates (%) p <0.001

Day 40

Day 55 Day 68

PBS

n / a n / a 8 8.9 10

388625

246 TGTTCCAGCCCA 2-8-2 MOE 6.5 5.8 4.3

388626

281 GGCATGAGCTTC 2-8-2 MOE 6.6 5.9 4

388628

226 TAGCCGCCCACA 2-8-2 MOE 8 9.1 7.8

ISIS 388625 and 388626 significantly reduced plasma glucose and HbAIC levels compared to animals treated with PBS and control.

5 EXAMPLE 17: Antisense inhibition of SGLT2 expression in dog kidney (ISIS 388625)

ISIS 388625 is a 2-8-2 MOE catheter with the sequence TGTTCCAGCCCA (SEQ ID No. 246) (e.g., see Table 71). The effect of ISIS 388625 on mRNA levels of dog SGLT2. The data is taken from two dosage groups in which a total of nine male hound dogs received doses with one or ten mg / kg / week of ISIS 388625 or saline solution administered by subcutaneous injection twice a week. The 46th day of the study is

10 sacrificed all dogs and SGLT2 levels in kidneys were evaluated. The target levels were determined by quantitative real-time PCR with IT as described in other examples herein. The PCR results were normalized according to an internal ISIS control. The results are shown in Table 73 below.

Table 73: Antisense inhibition of SGLT2 mRNA in vivo by ISIS 388625

% Change in SGLT2 expression with respect to saline solution

Oligonucleotide dose mg / kg / week

ISIS 388625

one

-85

10

-95

fifteen

These results illustrate that a greater than 80% reduction in SGLT2 mRNA can be achieved at a dose of 1 mg / kg / week of ISIS 388625. An even greater reduction can be achieved at slightly larger doses. It was also shown that the administration of ISIS 388625 improved glucose tolerance. Maximum plasma glucose levels decreased by more than 50% on average and the subsequent decrease in glucose was reduced compared to

20 saline controls in a conventional glucose tolerance test. I also increase the excretion of glucose in urine.

EXAMPLE 18: In vivo analysis of short antisense compounds targeting SGLT2 nucleic acid

Twenty 1-10-1 MOE guinea pigs complementary to human / monkey / mouse / rat SGLT2 were designed, synthesized and analyzed in vivo to determine suppression of kidney SGLT2 mRNA levels. The target sites for mouse and rat are indicated in Table 74. The target sites for humans are indicated in Tables 4 and 5. The data are the means of two experiments in which 6-week-old male Baln7c mice received intraperitoneal injections of 350 nmol / kg of oligonucleotide, twice a week, for a period of two weeks (a total of four injections). Mice were sacrificed 48 hours after the last administration and the levels of SGLT2 mRNA in the kidneys were evaluated. SGLT2 mRNA levels were determined by quantitative real-time PCR analysis according to standard procedures, using two different primer-probe groups for PCR, the primer-probe group (PPS) 534 and PPS 553. The mRNA levels of SGLT2 were normalized to cyclophilin mRNA levels, which were also measured by quantitative real-time PCR. The results are shown below

in Table 74.

Table 74: SGLT22 antisense inhibition in vivo

ISIS Nº

Target site at 5 ’in SEQ ID No. XXX (mouse) Target site at 5 ’in SEQ ID No. XXX (rat) Sequence (5’-3 ’) Reason PPS 534% S. salina PPS 553% S. salina SEQ ID NO.

PBS

N / A - -

370717

2684 152 TAGCCACCAACT 1-10-1 MOE -84.4 -84.3 1554

379684

2070 64 TGTCAGCAGGAT 1-10-1 MOE -Four. Five -43.2 214

379685

2103 97 TGACCAGCAGGA 1-10-1 MOE -10.3 -20.5 219

379686

2121 * 115 ACCACAAGCCAA 1-10-1 MOE -71.9 -75.1 225

379687

2824 216 GATGTTGCTGGC 1-10-1 MOE -47.1 -52.1 230

379688

2876 268 CCAAGCCACTTG 1-10-1 MOE -62.6 -70.4 240

379689

298 AGAGCGCATTCC 1-10-1 MOE -17.5 -30.4 241

379690

415 ACAGGTAGAGGC 1-10-1 MOE -18.9 -22.5 242

379691

454 AGATCTTGGTGA 1-10-1 MOE -35 -48.6 243

379692

508 TGTTCCAGCCCA 1-10-1 MOE -88.1 -88.5 246

379693

546 CATGGTGATGCC 1-10-1 MOE -51.6 -59.9 254

379694

609 GACGAAGGTCTG 1-10-1 MOE -42.1 -54.4 264

379695

717 GGACACCGTCAG 1-10-1 MOE -52.5 -64.1 266

379696

954 CAGCTTCAGGTA 1-10-1 MOE -24.6 -36.2 267

ISIS Nº

Target site at 5 ’in SEQ ID No. XXX (mouse) Target site at 5 ’in SEQ ID No. XXX (rat) Sequence (5’-3 ’) Reason PPS 534% S. salina PPS 553% S. salina SEQ ID NO.

379697

982 CTGGCATGACCA 1-10-1 MOE -32 -46.3 272

379698

1071 GCAGCCCACCTC 1-10-1 MOE -11.8 -27 275

379699

1112 GGCATGAGCTTC 1-10-1 MOE -83.5 -85.8 281

379700

1138 CCAGCATGAGTC 1-10-1 MOE -2.8 -16.4 285

379701

1210 CCATGGTGAAGA 1-10-1 MOE -0.3 -11.9 288

379702

1525 GCACACAGCTGC 1-10-1 MOE -87.8 -89.5 293

379703

1681 GCCGGAGACTGA 1-10-1 MOE -44.2 -45.9 295

* indicates 1 or 2 mismatches with a target sequence

Example 19: Antisense inhibition of human PCSK9 in Hep3B cells

In short antisense compounds targeting a PCSK9 nucleic acid, their effects on PCSK9 mRNA were analyzed in vitro. The short antisense compounds are presented in Table 6. The Isis No., the motif of the gimer and SEQ ID 5 of each short antisense compound are shown again in Table 75. The cultured Hep3B cells were treated with 100 nM of compound. short antisense. 5-10-5 MOE cathamers targeting a PCSK9 nucleic acid were used as positive controls. After the treatment period, the RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The

10 results are presented in Table 75 in the form of the percent inhibition of PCSK9 (% Inhibit) with respect to the untreated control cells. In the "% Inhib" column, a "0" indicates that no reduction of PCSK9 mRNA was observed with said particular short antisense compound.

Table 75: PCSK9 antisense inhibition by short antisense compounds

ISIS Nº

SEQ ID NO. Target site at 5 ’in SEQ ID No. 4 Target site at 3 ’in SEQ ID No. 4 Gápmero motive % Inhibition interval % Inhibit

400297

329 695 708 2-10-2 MOE 0

400298

330 696 709 2-10-2 MOE 0

400299

331 697 710 2-10-2 MOE 0

400300

332 742 755 2-10-2 MOE 9

400301

333 757 770 2-10-2 MOE 20-30% 27

400302

334 828 841 2-10-2 MOE 0

ISIS Nº

SEQ ID NO. Target site at 5 ’in SEQ ID No. 4 Target site at 3 ’in SEQ ID No. 4 Gápmero motive % Inhibition interval % Inhibit

400303

335 829 842 2-10-2 MOE 0

400304

336 830 843 2-10-2 MOE 10-20% eleven

400305

337 937 950 2-10-2 MOE 30-40% 38

400306

338 952 965 2-10-2 MOE 40-50% 40

400307

339 988 1001 2-10-2 MOE 70-80% 76

400308

340 989 1002 2-10-2 MOE 50-60% 55

400309

341 990 1003 2-10-2 MOE 40-50% 44

400310

342 991 1004 2-10-2 MOE 8

400311

343 992 1005 2-10-2 MOE 10-20% 18

400312

344 993 1006 2-10-2 MOE 20-30% 28

400313

3. 4. 5 994 1007 2-10-2 MOE 10-20% 10

400314

346 1057 1070 2-10-2 MOE 20-30% 26

400315

347 1075 1088 2-10-2 MOE 0

400316

348 1076 1089 2-10-2 MOE 8

400317

349 1077 1090 2-10-2 MOE 7

400318

350 1078 1091 2-10-2 MOE 20-30% 26

400319

351 1093 1106 2-10-2 MOE 0

400320

352 1094 1107 2-10-2 MOE 0

400321

353 1095 1108 2-10-2 MOE 0

400322

354 1096 1109 2-10-2 MOE 0

400323

355 1147 1160 2-10-2 MOE 0

400324

356 1255 1268 2-10-2 MOE 7

400325

357 1334 1347 2-10-2 MOE 4

400326

358 1335 1348 2-10-2 MOE 0

400327

359 1336 1349 2-10-2 MOE 30-40% 36

400328

360 1453 1466 2-10-2 MOE 10-20% 13

400329

361 1454 1467 2-10-2 MOE 10-20% 14

400330

362 1455 1468 2-10-2 MOE 40-50% 43

400331

363 1456 1469 2-10-2 MOE 30-40% 35

400332

364 1569 1582 2-10-2 MOE 0

400333

365 1570 1583 2-10-2 MOE 0

400334

366 1571 1584 2-10-2 MOE 0

ISIS Nº

SEQ ID NO. Target site at 5 ’in SEQ ID No. 4 Target site at 3 ’in SEQ ID No. 4 Gápmero motive % Inhibition interval % Inhibit

400335

367 1572 1585 2-10-2 more 0

400336

368 1573 1586 2-10-2 MOE 4

400337

369 1574 1587 2-10-2 MOE 0

400338

370 1575 1588 2-10-2 MOE 9

400339

371 1576 1589 2-10-2 MOE 0

400340

372 1577 1590 2-10-2 MOE 0

400341

373 1578 1591 2-10-2 MOE 0

400342

374 1621 1634 2-10-2 MOE 0

400343

375 1622 1635 2-10-2 MOE 0

400344

376 1623 1636 2-10-2 MOE 0

400345

377 1624 1637 2-10-2 MOE 0

400346

378 1738 1751 2-10-2 MOE 5

400347

379 1739 1752 2-10-2 MOE 0

400348

380 1740 1753 2-10-2 MOE 0

400349

381 1741 1754 2-10-2 MOE 10-20% 13

400350

382 1834 1847 2-10-2 MOE 10-20% fifteen

400351

383 1835 1848 2-10-2 MOE 10-20% 14

400352

384 1836 1849 2-10-2 MOE 20-30% 29

400353

385 1837 1850 2-10-2 MOE 10-20% 19

400354

386 1838 1851 2-10-2 MOE 10-20% 19

400355

387 1839 1852 2-10-2 MOE 0

400356

388 1840 1853 2-10-2 MOE 0

400357

389 2083 2096 2-10-2 MOE 0

400358

390 2084 2097 2-10-2 MOE 10-20% 12

400359

391 2085 2098 2-10-2 MOE 0

400360

392 2086 2099 2-10-2 MOE 30-40% 38

400361

393 2316 2329 2-10-2 MOE 2

400362

394 2317 2330 2-10-2 MOE 10-20% 16

400363

395 2318 2331 2-10-2 MOE 8

400364

396 2319 2332 2-10-2 MOE 0

400365

397 2320 2333 2-10-2 MOE 20-30% 25

400366

398 2321 2334 2-10-2 MOE 10-20% fifteen

ISIS Nº

SEQ ID NO. Target site at 5 ’in SEQ ID No. 4 Target site at 3 ’in SEQ ID No. 4 Gápmero motive % Inhibition interval % Inhibit

400367

399 2322 2335 2-10-2 MOE 10-20% 12

400368

400 2323 2336 2-10-2 MOE 10-20% eleven

400369

401 2324 2337 2-10-2 MOE 0

400370

402 2325 2338 2-10-2 MOE 10-20% 13

400371

403 3543 3556 2-10-2 MOE 0

As illustrated in Table 75, short antisense compounds targeting a PCSK9 nucleic acid having a 2-10-2 motif motif reduced PCSK9 mRNA levels in cultured cells.

Short antisense compounds targeting a PCSK9 nucleic acid were analyzed in a response experiment.

5 at the dose in Hep3B cells. Cells were treated as described herein with nM concentrations of the short antisense compound as indicated in Table 76. After the treatment period the RNA was isolated from the cells and PCSK9 mRNA levels were measured by Quantitative real-time PCR, as described herein. PCSK9 mRNA levels were normalized with cyclophilin mRNA levels, measured by real-time PCR using a cyclophilin-specific primer-probe group. The results are presented

10 in the form of the percent inhibition of PCSK9 with respect to untreated control cells. EC50 is also shown (concentration at which a 50% reduction in mRNA is observed) for each short antisense compound analyzed in the dose response experiment, calculated using Graphpad Prism. As illustrated in the following table, mRNA levels were reduced in a dose dependent manner.

Table 76: Dose-dependent antisense inhibition of PCSK9 by short antisense compounds

% inhibition

160 nM

80 nM 40 nM 20 nM 10 nM 5 nM

5-10-5

95 96 85 78 58 38

400307

93 92 56 Four. Five 39 35

400308

86 77 40 26 10 31

400309

78 72 12 38 2. 3 49

400327

55 43 49 2. 3 37 5

400330

71 82 69 40 32 8

400331

82 75 63 47 40 29

400352

64 63 44 40 16 7

400353

48 54 43 2. 3 27 fifteen

Example 20: Antisense inhibition of PCSK9 by short antisense compounds comprising BNA

fifteen

Short antisense compounds targeting a PCSK9 nucleic acid were analyzed in dose response experiments in both human and mouse cultured cells. The compounds analyzed included ISIS 403739 and ISIS 403740. ISIS 403739 is a short antisense compound consisting of the nucleotide sequence SEQ ID No. 404 and

20 which has a 2-10-2 motif motif, in which the nucleotides of the wings comprise 6'5) -6'methyl BNA. ISIS 403740 is a short antisense compound targeting the nucleotide sequence SEQ ID No. 405 and having a 2-10-2 catheter motif, in which the nucleotides on the wings comprise 6’S) -6’methyl BNA. Also, 5-10-5 MOE scimer directed to a PCSK9 nucleic acid was analyzed.

Mouse hepatocytes were seeded and treated as described herein with nM concentrations of the short antisense compound as indicated in Table 77. After the treatment period the RNA was isolated from the cells and the levels of PCSK9 mRNA by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were normalized with cyclophilin mRNA levels, measured by real-time PCR using a cyclophilin-specific primer-probe group. The results are presented in the form of the percentage inhibition of PCSK9 with respect to the untreated control cells. When it is, "0" indicates that no reduction was observed in the mRNA of PCSK9. ISIS 403739 exhibited a dose-dependent reduction of mouse PCSK9 mRNA at doses of 30 nM and greater. ISIS 403740 exhibited a reduction in mouse PCSK9 mRNA at the two highest doses of the short antisense compound.

Table 77: Antisense inhibition of mouse PCSK9 by short antisense compounds comprising BNA

% inhibition

3.75 nM

7.5 nM 15 nM 30 nM 60 nM 120 nM 240 nM

5-10-5

10 fifteen twenty-one 18 44 43 77

403739

40 19 29 29 32 49 57

403740

3 0 29 13 0 40 33

10

Human Hep3B cells were treated with nM concentrations of the short antisense compound as described herein. After the treatment period, the RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. PCSK9 mRNA levels were normalized with cyclophilin mRNA levels, measured by real-time PCR using

15 a cyclophilin specific primer-probe group. The results are presented in the form of the percentage inhibition of PCSK9 with respect to the untreated control cells. The data are shown in Table 78 and demonstrate a dose-dependent reduction of human PCSK9 mRNA after treatment with ISIS 403740. ISIS 403739 exhibited a dose-dependent reduction at higher doses.

Table 78: Mouse PCSK9 antisense inhibition by short antisense compounds comprising BNA

% inhibition

2.5 nM

5 nM 10 nM 20 nM 40 nM 80 nM 160 nM

5-10-5

7 2 twenty-one 33 30 59 71

4037399

10 5 7 6 25 52 65

403740

6 12 16 29 Four. Five 48 59

Example 21: GCGR antisense inhibition in HepG2 cells

twenty

In short antisense compounds targeting a GCGR nucleic acid their effects on GCGR mRNA in vitro were analyzed.

HepG2 cells

25 HepG2 cells grown at a density of 10,000 cells per well in a 96-well plate were treated as described herein with 25, 50, 100 or 200 nM antisense oligonucleotide. After the treatment period, the RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. GCGR mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The results are presented in the form of the percentage of

30 inhibition of GCGR mRNA with respect to untreated control cells.

Table 79 presents data after treatment with the indicated doses of ISIS 327161, a 3-10-3 MOE scintillator. ISIS 327161 reduced GCGR mRNA levels in a dose dependent manner.

Table 79: GCGR antisense inhibition in HepG2 cells by a short antisense compound

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive 25 nM 50 nM 100 nM 200 nM

327161

520 AGCTGCTGTACATC 3-8-3 MOE -36 -30 -33 -64

Monkey hepatocytes

In the additional short antisense compounds directed to a GCGR nucleic acid their effects on

5 the monkey GCGR mRNA in vitro. Mono cultured primary hepatocytes were treated as described herein with 25, 50, 100 or 200 nM of the short antisense compounds. After the treatment period, the RNA was isolated from the cells and PCSK9 mRNA levels were measured by quantitative real-time PCR, as described herein. GCGR RNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The results are presented in Table 80 form of percent inhibition of

10 GCGR mRNA relative to untreated control cells.

Table 80: GCGR antisense inhibition in primary monkey hepatocytes by short antisense compounds

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive 25 nM 50 nM 100 nM 200 nM

327131

489 ATGTTGGCCGTGGT 3-8-3 MOE 0 -8 -36 -36

327161

520 AGCTGCTGTACATC 3-8-3 MOE -19 -33 -55 -54

Example 22: DGAT2 antisense inhibition by short antisense compounds

In short antisense compounds targeting a DGAT2 nucleic acid, their effects on the mRNA of

15 DGAT2 in vitro. A10 cells cultured in a 96-well plate were treated with 75 nM of the short antisense compound. After a treatment period of approximately 24 hours, the RNA was isolated from the cells and the DGAT2 mRNA levels were measured by quantitative real-time PCR, as described herein. DGAT2 mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The results are presented in TABLE 81 in the form of the percentage of DGAT2 inhibition with respect to the control cells without

20 try.

Table 81: DGAT2 antisense inhibition in A10 cells

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive % Control

372491

795 ACATGAGGATGACACT 3-10-3 MOE 80

372500

702 GTGTGTCTTCACCAGC 3-10-3 MOE 16

372501

704 TTGTGTGTCTTCACCA 3-10-3 MOE 28

372503

708 GCAGGTTGTGTGTCTT 3-10-3 MOE 35

372508

719 AGTTCCTGGTGGTCAG 3-10-3 MOE 35

372516

805 TACAGAAGGCACCCAG 3-10-3 MOE 27

372524

738 GCCAGGCATGGAGCTC 3-10-3 MOE twenty-one

372530

746 TCGGCCCCAGGAGCCC 3-10-3 MOE 35

372546

825 TTGGTCTTGTGATTGT 3-10-3 MOE 3. 4

372563

691 AGCCAGGTGACAGA 2-10-2 MOE 48

372569

796 CATGAGGATGACAC 2-10-2 MOE 104

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive % Control

372578

703 TGTGTCTTCACCAG 2-10-2 MOE 59

372580

707 GGTTGTGTGTCTTC 2-10-2 MOE 48

372586

720 GTTCCTGGTGGTCA 2-10-2 MOE 40

372594

806 ACAGAAGGCACCCA 2-10-2 MOE 77

372602

739 CCAGGCATGGAGCT 2-10-2 MOE 39

372618

765 GTGGTACAGGTCGA 2-10-2 MOE 29

372624

826 TGGTCTTGTGATTG 2-10-2 MOE 56

Additional short antisense compounds targeting DGAT2 mRNA were analyzed in vitro in a dose response experiment. A10 cells were prepared as described above and treated with short 6.25, 12.5, 25.0, 50.0, 100.0 and 200.0 nM antisense compounds to determine if DGAT2 inhibition occurs in a manner dependent on the dose. The data demonstrate that each of the short antisense compounds in Table 82 reduces the rat DGAT2 mRNA in a dose-dependent manner. The results are presented in the form of the percentage of inhibition to the untreated control cells. A "0" indicates that DGAT2 mRNA had not been reduced.

Table 82: Dose-dependent inhibition of DGAT2 in A10 cells

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive 6.25 nM 12.5 nM 25.0 nM 50.0 nM 100.0 nM 200.0 nM

372,562

784 GTCTTGGAGGGCCG 2-10-2 MOE 0 0 0 36 48 75

372568

794 GACACTGCAGGCCA 2-10-2 MOE 0 0 fifteen 26 72 69

372586

720 GTTCCTGGTGGTCA 2-10-2 MOE 19 0 7 22 Four. Five 77

372602

739 CCAGGCATGGAGCT 2-10-2 MOE 0 0 0 18 47 76

372618

765 GTGGTACAGGTCGA 2-10-2 MOE 0 5 0 27 65 80

10 Additional short antisense compounds targeting DGAT2 mRNA were analyzed in vitro. A10 cells were prepared as described above and treated with short 0.62, 1.85, 5.56, 50.0, 16.67, 50.0 and 150.0 nM antisense compounds to determine if it occurs DGAT2 inhibition in a dose dependent manner. DGAT2 mRNA was measured using real-time quantitative PCR, as described herein. The data demonstrate that each of the short antisense compounds in Table 83 below inhibits the

15 rat DGAT2 mRNA in a dose dependent manner. The results are presented in the form of the percentage of DGAT2 inhibition with respect to the untreated control cells. When it is, "0" indicates that no reduction in DGAT2 mRNA was observed.

Table 83: Dose-dependent inhibition of DGAT2 in A10 cells

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive 0.62 nM 1.85 nM 5.56 nM 16.67 nM 50 nM 150 nM

372500

702 GTGTGTCTTCACCAGC 310-3 MOE 0 0 0 18 64 88

372501

704 TTGTGTGTCTTCACCA 3-10-3 MOE one 5 10 eleven 25 68

372503

708 GCAGGTTGTGTGTCTT 3-10-3 MOE 7 10 4 25 54 80

372508

719 AGTTCCTGGTGGTCAG 3-10-3 MOE 0 0 6 14 39 71

372516

805 TACAGAAGGCACCCAG 3-10-3 MOE one 10 0 4 35 81

372524

738 GCCAGGCATGGAGCTC 3-10-3 MOE 7 0 5 30 68 91

372530

746 TCGGCCCCAGGAGCCC 3-10-3 MOE 0 2 0 10 38 78

372546

825 TTGGTCTTGTGATTGT 3-10-3 MOE 0 2 eleven 4 48 78

372563

691 AGCCAGGTGACAGA 2-10-2 MOE 0 0 0 one 4 46

372578

703 TGTGTCTTCACCAG 2-10-2 MOE 0 0 0 2 7 42

372580

707 GGTTGTGTGTCTTC 2-10-2 MOE 0 5 5 3 16 42

372586

720 GTTCCTGGTGGTCA 2-10-2 MOE 0 0 0 0 7 55

372594

806 ACAGAAGGCACCCA 2-10-2 MOE 0 0 0 0 2 fifteen

372602

739 CCAGGCATGGAGCT 2-10-2 MOE 0 0 10 0 19 51

372618

765 GTGGTACAGGTCGA 2-10-2 MOE 0 0 0 0 30 60

372624

826 TGGTCTTGTGATTG 2-10-2 0 0 0 one 16 38

ISIS Nº

SEQ ID NO. Sequence (5’-3 ’) Gápmero motive 0.62 nM 1.85 nM 5.56 nM 16.67 nM 50 nM 150 nM

MOE

Example 23: Antisense inhibition of human PTPIB in HuVEC cells

In short antisense compounds targeting a PTP1B nucleic acid, their effects on PTP1B mRNA in vitro were analyzed. HuVEC cells cultured at a density of 5000 cells per well in a 96-well plate were treated as described herein with 3 nM of the short antisense compound. After the period of treatment, the RNA was isolated from the cells and the levels of PTPIB mRNA were measured by quantitative real-time PCR, as described herein. PTP1B mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The results are presented in the form of the percent inhibition of PTP1B (% Inhib) with respect to the untreated control cells. The data demonstrated that short antisense compounds targeting a PTP1H nucleic acid having a 2-10-2 motif motif can reduce the

10 levels of PTP1B in HuVEC cells in Table 84.

Table 84: Antisense inhibition of PTP1B in HuVEC cells by short antisense compounds

ISIS Nº

SEQ ID NO. Gápmero motive % Inhibit

399301

1542 2-10-2 OMe 55

404137

1053 2-10-2 MOE 76

404138

1054 2-10-2 MOE 76

404139

1052 2-10-2 MOE 80

404140

1051 2-10-2 MOE 73

Example 24: Antisense inhibition of human PTP1B in HepG2 cells

In short antisense compounds targeting a PTP1B nucleic acid, their effects on the mRNA of

15 PTP1B in vitro. HepG2 cells cultured at a density of 10,000 cells per well in a 96-well plate were treated with 25 nM of the antisense oligonucleotide. After the treatment period the RNA was isolated from the cells and the levels of PTP1B mRNA were measured by quantitative real-time PCR, as described herein. PTP1B mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. The results are presented in the form of the percentage of inhibition of PTP1B (% Inhib) with respect to

20 untreated control cells. The data demonstrated that short antisense compounds targeting a PTP1B nucleic acid having a 2-10-2 motif motif can reduce PTP1B levels in HepG2 cells in Table 85.

Table 85: Antisense inhibition of PTP1B in HepG2 cells by short antisense compounds

ISIS Nº

SEQ ID NO. Gápmero motive % Inhibit

399301

1542 2-10-2 OMe 43

404137

1053 2-10-2 MOE 71

404138

1054 2-10-2 MOE 86

404139

1052 2-10-2 MOE Four. Five

404140

1051 2-10-2 MOE 93

Example 25: Antisense inhibition of PTP1B in HuVEC cells: Dose response experiment

25 Human vascular endothelial cells (HuVEC) were seeded at a density of 5,000 cells per well and treated as described herein with nM concentrations of the short antisense compound as indicated in Table 86. After the treatment period RNA was isolated from cells and levels of PTP1B mRNA were measured by quantitative real-time PCR, as described herein. PTP1B mRNA levels were adjusted according to a total RNA content measured by RIBOGREEN®. Two different primer-probe groups for human PTP1B were used to measure mRNA levels. The results with the probe primer group (PPS) 198 are shown in Table 86 and the results with the probe primer group (PPS) 3000 are shown in Table 87. The results are presented as a percentage inhibition of the expression of the PTP1B mRNA with respect to untreated control cells. When it is, "0" indicates that no reduction in PTP1B mRNA was observed. As illustrated in Tables 86 and 87, PTP1B mRNA levels were reduced in a dose-dependent manner.

Table 86: Dose response for human PTP1B in HuVEC cells using PPS 198

ISIS Nº

SEQ ID NO. Reason % inhibition

gamer

1.11 nM 3.33 nM 10.0 nM 30.0 nM

398105

1066 2-10-2 MOE 0 25 79 90

398112

1072 2-10-2 MOE one 10 73 93

398120

1086 2-10-2 MOE 0 31 80 96

399096

1544 2-10-2 MOE 3 30 78 96

399102

1545 2-10-2 MOE 0 fifteen 62 88

399113

1547 2-10-2 MOE 0 31 72 90

399132

1548 2-10-2 MOE 0 32 75 95

399173

1549 2-10-2 MOE 0 24 63 89

399208

1550 2-10-2 MOE 0 37 86 93

399276

1551 2-10-2 MOE 0 8 61 89

399301

1542 2-10-2 MOE 8 63 91 97

399315

1552 2-10-2 MOE 0 twenty 68 88

398173

1543 1-10-1 MOE 0 4 80 97

Table 87: Dose response for human PTP1B in HuVEC cells using PPS 3000

ISIS Nº

SEQ ID NO. Reason % inhibition

gamer

1.11 nM 3.33 nM 10.0 nM 30.0 nM

398105

1066 2-10-2 MOE 0 35 79 93

398112

1072 2-10-2 MOE 0 26 77 94

398120

1086 2-10-2 MOE 0 35 79 93

399096

1544 2-10-2 MOE 0 2. 3 75 94

399102

1545 2-10-2 MOE 0 9 60 87

399113

1547 2-10-2 MOE 0 9 65 90

399132

1548 2-10-2 MOE 0 26 76 91

399173

1549 2-10-2 MOE 0 eleven 59 92

399208

1550 2-10-2 MOE 0 47 85 96

ISIS Nº

SEQ ID NO. Reason % inhibition

gamer

1.11 nM 3.33 nM 10.0 nM 30.0 nM

399276

1551 2-10-2 MOE 0 14 64 86

399301

1542 2-10-2 MOE 16 65 93 99

399315

1552 2-10-2 MOE 0 25 71 93

398173

1543 1-10-1 MOE 0 18 80 90

Example 26: ApoB antisense inhibition by short antisense compounds

In the short antisense compounds shown in Table88 their effects were analyzed in vivo. In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME), intraperitoneal doses of 3.2, 1, 0.32, or 5 0.1 umol / kg were administered twice a week for three weeks. A 5-10-5 MOE capsule was used as a control treatment. Mice were sacrificed approximately 48 hours after the last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. ApoB mRNA levels were measured using real-time quantitative PCR, as described herein. ApoB mRNA levels were normalized with the RNA levels determined by RIBOGREEN and are presented in Table 89 as the

10 percent inhibition with respect to ApoB mRNA levels in control animals treated with saline.

Table 88: Antisense compounds directed to an ApoB nucleic acid

ISIS Nº

Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

387462

GGTACATGGAAGTC 2-10-2 Methylene BNA 190

398296

GGTACATGGAAGTC 2-10-2 6 ’- (S) -methyl Methyloxy BNA 190

Table 89: ApoB antisense inhibition by short antisense compounds comprising BNA

ISIS Nº

Dose (μmol / kg) % Inhibit

379818

one 56

387462

0.1 33

0.32

57

one

93

3.2

99

398296

0.1 17

0.32

35

one

80

3.2

98

15 Table 89 shows that ApoB mRNA levels were reduced in a dose-dependent manner after treatment with short antisense compounds having a 2-10-2 motif motif and BNA modifications in the wings. At the dose of 1 umol / kg, the inhibition of ApoB by the short antisense compounds was greater than that observed with a 5-10-5 MOE scupper at an equivalent dose. Cholesterol was reduced at doses of 1 and 3.2 umol / kg of short antisense compound.

20 Short antisense compounds exhibited little or no adverse side effects, judged by organ and body weights, serum transaminase levels, bilirubin, blood urea nitrogen and creatinine.

Example 27: PTEN antisense inhibition by short antisense compounds

In the short antisense compounds shown in Table 90, their effects were analyzed in vivo. In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME), intraperitoneal doses of 3.2, 1, 0.32, or 0.1 umol / kg were administered twice a week for three weeks. A 5-10-5 MOE capsule was used as a control treatment. Mice were sacrificed approximately 48 hours after the last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. PTEN mRNA levels were measured using real-time PCR, as described herein. PTEN mRNA levels were normalized with the RNA levels determined by RIBOGREEN and presented in Table 91 as the percentage of inhibition with respect to PTEN mRNA levels in control animals treated with saline.

10 Table 90: Short antisense compounds targeting a PTEN nucleic acid

ISIS Nº

Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

392063

AGGCCAGTGCTAAG 2-10-2 Methylene BNA 1226

392749

AGGCCAGTGCTAAG 2-10-2 (6’S) -6’-methyl Methyloxy BNA 1226

396006

AGGCCAGTGCTAAG 2-10-2 alpha-L-Methylene methoxy BNA 1226

Table 91: PTEN antisense inhibition by short antisense compounds comprising modifications BNA

ISIS Nº

Dose (μmol / kg) % Inhibit

116847

one 47

392063

0.1 26

0.32

43

one

74

3.2

96

392749

0.1 17

0.32

3. 4

one

64

3.2

96

396006

0.1 twenty

0.32

32

one

67

3.2

88

15 Table 91 shows that the levels of PTEN mRNA were reduced in a dose-dependent manner after treatment with short antisense compounds having a 2-10-2 motif motif and BNA modifications in the wings. At the dose of 1 umol / kg, the inhibition of PTEN by the short antisense compounds was greater than that observed with a 5-10-5 MOE scintillator at an equivalent dose.

With the exception of the highest dose of ISIS 392063, no significant increases in the 20 serum transaminases were observed. In general, short antisense compounds exhibited little or no adverse side effects.

Example 28: Administration of a single dose of short antisense compounds comprising BNA modifications

In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME), a single intraperitoneal injection (i.p.) of the antisense compound was administered at a dose of 8, 4, 2 or 1 μmol / kg. The short antisense compounds analyzed were ISIS 387462 and ISIS 398296. Each dose group consisted of four animals. A 5-10-5 MOE capsule was used as a control treatment. Mice were sacrificed approximately 48 hours after

5 last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. ApoB mRNA levels were measured using real-time quantitative PCR, as described herein. ApoB mRNA levels were normalized with the RNA levels determined by RIBOGREEN and are presented in Table 92 as the percentage of inhibition with respect to ApoB mRNA levels in control animals treated with saline.

10 Table 92: Antisense inhibition of ApoB by short antisense compounds comprising BNA

ISIS Nº

Dose (μmol / kg) % Inhibit

379818

8 77

387462

8 99

4

93

2

81

one

58

398296

8 97

4

81

2

54

one

19

Table 92 shows that ApoB mRNA levels were reduced in a dose-dependent manner after a single administration of short antisense compounds having a 2-10-2 motif motif and BNA modifications in the wings. At the dose of 8 umol / kg, the inhibition of ApoB by short antisense compounds was greater than observed with

15 a 5-10-5 MOE capsule at an equivalent dose. The DE50 of ISIS 387462 was 3.9 mg / kg and the DE50 of ISIS 398296 was 8.7 mg / kg. Cholesterol was also reduced in a dose dependent manner. Triglycerides were reduced at the highest dose.

The short antisense compounds exhibited little or no adverse side effects, judged by organ and body weights, serum transaminase levels, bilirubin, blood urea nitrogen and creatinine.

20 In a similar study of single dose administration, ISIS 392748, which has SEQ ID No. 1226, a motif of 2-10-2, in which the nucleotides in the wings comprise modifications (6'R) -6 'Methyl methyloxy BNA, reduced PTEN mRNA in a dose dependent manner. Additionally, ISIS 392749, which has SEQ ID No. 1226, a 2-10-2 catheter motif, in which the nucleotides of the wings comprise modifications (6'S) -6'methyl methyloxy BNA, reduced the PTEN mRNA of a dose dependent mode. A short antisense compound that has motifs

25 of gamer 2-2-10, the sequence of SEQ ID No. 1226 and modifications 6- (S) -CH2-O-CH3-BNA also reduced PTEN mRNA in a similar in vivo study. A short antisense compound having 2-2-10 motif motifs, the sequence of SEQ ID No. 1226 and modifications 66- (R) -CH2-O-CH3-BNA also reduced PTEN mRNA in a similar in vivo study.

Example 29: Administration of a single dose of short antisense compounds comprising 30 BNA modifications

In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME) a single intraperitoneal injection of the antisense compound was administered at a dose of 8, 4, 2 or 1 mol / kg. Each dose group consisted of four animals. The compounds analyzed were ISIS 392063, ISIS 392749 and ISIS 366006. A 5-10-5 MOE gammer was used as a control treatment. Mice were sacrificed approximately 48 hours after the last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. ApoB mRNA levels were measured using real-time quantitative PCR, as described herein. ApoB mRNA levels were normalized with the RNA levels determined by RIBOGREEN and are presented in Table 93 as the percentage of inhibition with respect to ApoB mRNA levels in animals.

Control treated with saline solution.

Table 93: PTEN antisense inhibition by short antisense compounds comprising modifications BNA

ISIS Nº

Dose (μmol / kg) % Inhibit

116847

8 62

392063

8 92

4

82

2

58

one

38

396565

8 76

4

38

2

24

one

eleven

396006

8 94

4

82

2

48

one

18

5 Table 93 shows that PTEN mRNA levels were reduced in a dose-dependent manner after treatment with short antisense compounds having a 2-10-2 motif motif and BNA modifications in the wings. At the dose of 8 umol / kg, the inhibition of PTEN by the short antisense compounds was greater than that observed with a 5-10-5 MOE gammer at an equivalent dose. The estimated ED50 were 7 mg / kg for ISIS 392063, 17.4 mg / kg for ISIS 396565 and 9.3 mg / kg for ISIS 396006

10 With the exception of the higher dose of ISIS 392063, no significant increases in serum transaminase levels were observed. In general, short antisense compounds exhibited little or no adverse side effects.

Example 30: Antisense inhibition of ApoB by short antisense compounds comprising palmitic acid conjugates

15 In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME), a single intraperitoneal injection of the antisense compound was administered at a dose of 2.5, 1.0, 0.4 and 0.16 umol / kg Each dose group consisted of four animals. The compounds analyzed are shown in Table 94. A 5-105 MOE scupper was used as a control treatment. Mice were sacrificed approximately 48 hours after the last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. MRNA levels of

20 ApoB were measured using real-time quantitative PCR, as described herein. ApoB mRNA levels were normalized with the levels of RNA determined by RIBOGREEN and are presented in Table 95 as the percentage of inhibition with respect to ApoB mRNA levels in control animals treated with saline.

Table 94: Short antisense compounds comprising palmitic conjugates

ISIS Nº

Sequence (5’-3 ’) Gápmero motive SEQ ID NO.

387462

GGTACATGGAAGTC 2-10-2 Methylene BNA 190

391871

GGTACATGGAAGTC 1-1-10-2 2 '- (butylacetomide) -palmitamide / MOE / MOE Unmodified cytosines in the hole (i.e. 2-10-2 MOE with 2' - (butylacetomide) -palmitamide substituted in the nucleotide in 5 ' 190

391872

GGTACATGGAAGTC 1-1-10-2 2 '- (butylaceceptide) -palmitamide Methylene oxy BNA / Methylene oxy BNA GGTACATGGAAGTC Unmodified cytosines in the recess (i.e., 2-10-2 methylene oxy BNA with 2' - (butylacetomide) -palmitamide substituted in the 5 'nucleotide) 190

Table 95: Antisense inhibition by short antisense compounds comprising palmitic acid conjugates

ISIS Nº

Dose (μmol / kg) % Inhibit

5-10-5

2.5 54

387462

2.5 99

one

91

0.4

65

0.16

16

391871

2.5 49

one

18

0.4

5

0.16

0

391872

2.5 99

one

92

0.4

fifty

0.16

18

5

Table 95 shows that ApoB mRNA levels were reduced in a dose-dependent manner after treatment with short antisense compounds having a palmitic acid conjugate (C16). At the dose of 2.5 umol / kg, the inhibition of ApoB by the short antisense compounds was greater than that observed with a 5-10-5 MOE gimer at an equivalent dose. In this study, the estimated ED50 were 1.5 mg / kg for ISIS 387462, 13.1 mg / kg for ISIS 391871 and

10 1.9 mg / kg for ISIS 391872. The estimated ED50 for the 5-10-5 MOE catheter was 17.4 mg / kg. Triglycerides were reduced at doses of 2.5 and 1.0 mg / kg of ISIS 387462 and ISIS 391872. ISIS 387462 and ISIS 391872 markedly reduced total cholesterol, HDL-C and LDL-C in a dose-dependent manner ; the LDL-C reduction was so marked that it was below the detection limit. In general, short antisense compounds exhibited little or no adverse side effects.

fifteen

Example 31: Antisense inhibition of PCSK9 in vivo by short antisense compounds comprising BNA modifications

In six-week-old male Balb / c mice (Jackson Laboratory, Bar Harbor, ME) a single intraperitoneal injection of the antisense compound was administered at a dose of 15, 4.7, 1.5 and 0.47 mol / kg of ISIS 403739 or 403740. Each dose group consisted of four animals. A 5-10-5 MOE capsule was used as a control treatment. Mice were sacrificed approximately 72 hours after the last dose. Liver tissue was collected to isolate the RNA and blood was taken for serum chemistry analysis. PCSK9 mRNA levels were measured using real-time quantitative PCR, as described herein. PCSK9 mRNA levels were normalized with cyclophilin mRNA levels determined by real-time PCR. ISIS 403739 reduced PCSK9 mRNA by approximately 70% compared to saline controls. ISIS 403740 reduced PCSK9 by approximately 13% compared to saline controls, however the reduction was not statistically significant. The lower doses did not significantly reduce the mRNA of PCSK9. In general, short antisense compounds exhibited little or no adverse side effects.

SEQUENCE LIST

<110> Isis Pharmaceuticals, Inc. Sanjay Bhanot Richard S. Geary Robert McKay Brett P. Monia Punit P. Seth Andrew M. Siwkowski Eric E. Swayze Edward Wancewitz

<120> COMPOUNDS AND PROCEDURES TO MODULATE GENE EXPRESSION

<130> CORE0061US7

<150> PCT / US2007 / 061183

<151> 2007-01-27

<150> 60 / 746,631

<151> 2006-05-05

<150> 60 / 747,059

<151> 2006-05-11

<150> 60 / 805,660

<151> 2006-06-23

<150> 60 / 864,554

<151> 2006-11-06

<160> 1576

<170> FastSEQ for Windows Version 4.0

<210> 1

<211> 14121

<212> DNA

<213> H. sapiens

<400> 1

image 1

image 1

image 1

image 1

image 1

<210> 2

<211> 13928

<212> DNA

<213> Mus musculus

<400> 2

image 1

image 1

image 1

image 1

<210> 3

<211> 2273

<212> DNA

<213> H. sapiens

<400> 3

image 1

image 1

<210> 4

<211> 3636

<212> DNA

<213> H. sapiens

<400> 4

image 1

<210> 5

<211> 874

<212> DNA

<213> H. sapiens

<400> 5

image 1

5 <210> 6

<211> 1631

<212> DNA

<213> H. sapiens

10 <400> 6

image 1

15 <210> 7

<211> 1898

<212> DNA

<213> Mus musculus

ggtcaaccac agagtc

16

<210> 83 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 83 gtcaaccaca gagt

14

<210> 84 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 84 cagccacatg cagc

14

<210> 85 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 85 ccagccacat gcag

14

<210> 86 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 86 accagccaca tgca

14

<210> 87 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 87 taccagccac atgc

14

<210> 88 <211> 14 <212> ADN <213> Secuencia Artificial

<220>
<223> Oligonucleótido Sintético
<400> 88 ttaccagcca catg
<210> 89
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 89 gttaccagcc acat
<210> 90
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 90 ggttaccagc caca
<210> 91
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 91 aggttaccag ccac
<210> 92
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 92 taggttacca gcca
<210> 93
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 93 aggttctgct ttcaac
<210> 94
14
14
14
14
14
16
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 94 ggttctgctt tcaa
<210> 95
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 95 tactgatcaa attgta
<210> 96
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 96 actgatcaaa ttgt
<210> 97
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 97 tttttcttgt atctgg
<210> 98
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 98 ttttcttgta tctg
<210> 99
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
16
14
16
14
<400> 99 atccattaaa acctgg
<210> 100
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 100 tccattaaaa cctg
<210> 101
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 101 atattgctct gcaaag
<210> 102
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 102 tattgctctg caaa
<210> 103
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 103 actg
<210> 104
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 104 atattgctct gcaa
<210> 105
<211> 14
<212> ADN
<213> Secuencia Artificial
16
14
16
14
4
14
<220>
<223> Oligonucleótido Sintético
<400> 105 aatattgctc tgca
<210> 106
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 106 gaatattgct ctgc
<210> 107
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 107 agaatattgc tctg
<210> 108
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 108 tagaatattg ctct
<210> 109
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 109 atagaatatt gctc
<210> 110
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 110 gatagaatat tgct
14
14
14
14
14
14
<210> 111
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 111 ggatagaata ttgc
<210> 112
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 112 atggaatcct caaatc
<210> 113
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 113 tggaatcctc aaat
<210> 114
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 114 gaattctggt atgtga
<210> 115
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 115 aattctggta tgtg
<210> 116
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
16
14
16
14
<400> 116 agctggaatt ctggta
<210> 117
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 117 gctggaattc tggt
<210> 118
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 118 tgaaaatcaa aattga
<210> 119
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 119 gaaaatcaaa attg
<210> 120
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 120 aaacagtgca tagtta
<210> 121
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 121 aacagtgcat agtt
<210> 122
<211> 16
<212> ADN
16
14
16
14
16 20 <400> 7 image 1
<210> 8
<211> 106000
<212> DNA
<213> H. sapiens
<400> 8 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1
<210> 9
<211> 2034
<212> DNA
<213> H. sapiens
<400> 9 image 1 image 1
<210> 10
<211> 2439
<212> DNA
<213> H. sapiens
<400> 10 <210> 11 image 1 image 1
<211> 3318
<212> DNA
<213> H. sapiens
<400> 11 <210> 12 image 1
<211> 78001
<212> DNA
<213> H. sapiens
<400> 12 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1
<210> 13
<211> 2160
<212> DNA
<213> Mus musculus image2
<210> 14
<211> 5572
<212> DNA
<213> H. sapiens
<400> 14 <210> 15 image 1 image 1
<211> 103886
<212> DNA
<213> H. sapiens
<400> 15 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1 image 1
<210> 16
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 16 ccggaggtgc ttgaat
<210> 17
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 17 cggaggtgct tgaa
<210> 18
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 18 gaagccatac acctct
<210> 19
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 19 aagccataca cctc
<210> 20
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 20
16
14
16
14
gttgaagcca tacacc
<210> 21
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 21 ttgaagccat acac
<210> 22
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 22 cctcagggtt gaagcc
<210> 23
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 23 ctcagggttg aagc
<210> 24
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 24 tttgccctca gggttg
<210> 25
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 25 ttgccctcag ggtt
<210> 26
<211> 16
<212> DNA
<213> Artificial Sequence
16
14
16
14
16
14
<220>
<223> Synthetic Oligonucleotide
<400> 26 agttcttggt tttctt
<210> 27
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 27 gttcttggtt ttct
<210> 28
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 28 cctcttgatg ttcagg
<210> 29
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 29 ctcttgatgt tcag
<210> 30
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 30 atgcccctct tgatgt
<210> 31
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 31 tgcccctctt gatg
<210> 32
16
14
16
14
16
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 32 tgccacattg ccct
<210> 33
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 33 ttgccacatt gccc
<210> 34
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 34 gttgccacat tgcc
<210> 35
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 35 tgttgccaca ttgc
<210> 36
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 36 ctgttgccac attg
<210> 37
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 37 tctgttgcca catt
<210> 38
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 38 ttctgttgcc acat
<210> 39
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 39 tttctgttgc poop
<210> 40
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 40 atttctgttg ccac
<210> 41
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 41 gtaggagaaa ggcagg
<210> 42
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 42 taggagaaag gcag
<210> 43
<211> 16
<212> DNA
<213> Artificial Sequence
14
14
14
14
16
14
<220>
<223> Synthetic Oligonucleotide
<400> 43 ggcttgtaaa gtgatg
<210> 44
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 44 gcttgtaaag tgat
<210> 45
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 45 ccactggagg atgtga
<210> 46
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 46 cactggagga tgtg
<210> 47
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 47 tttcagcatg ctttct
<210> 48
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 48 ttcagcatgc tttc
16
14
16
14
16
14
<210> 49
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 49 catatttgtc acaaac
<210> 50
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 50 atatttgtca caaa
<210> 51
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 51 atgcccatat ttgtca
<210> 52
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 52 tgcccatatt tgtc
<210> 53
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 53 ttttggtggt agagac
<210> 54
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
16
14
16
14
16
<400> 54 tttggtggta gaga
<210> 55
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 55 tctgcttcgc acct
<210> 56
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 56 gtctgcttcg cacc
<210> 57
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 57 agtctgcttc gcac
<210> 58
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 58 cagtctgctt cgca
<210> 59
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 59 tcagtctgct tcgc
<210> 60
<211> 14
<212> DNA
14
14
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 60 ctcagtctgc ttcg
<210> 61
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 61 cctcagtctg cttc
<210> 62
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 62 gcctcagtct gctt
<210> 63
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 63 agcctcagtc tgct
<210> 64
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 64 aactctgagg attgtt
<210> 65
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 65 actctgagga ttgt
14
14
14
14
16
14
<210> 66
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 66 tcattaactc tgagga
<210> 67
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 67 cattaactct gagg
<210> 68
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 68 attcatcatt aactct
<210> 69
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 69 ttcatcatta actc
<210> 70
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 70 ttgttctgaa tgtcca
<210> 71
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
16
14
16
14
16
<223> Synthetic Oligonucleotide
<400> 71 actg
<210> 72
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 72 actg
<210> 73
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 73 tgttctgaat gtcc
<210> 74
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 74 cagatgagtc catttg
<210> 75
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 75 agatgagtcc attt
<210> 76
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 76 atccacaggg aaattg
<210> 77
<211> 14
4
4
14
16
14
16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 77 tccacaggga aatt
<210> 78
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 78 cagttgtaca agttgc
<210> 79
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 79 agttgtacaa gttg
<210> 80
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 80 cacagagtca gccttc
<210> 81
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 81 acagagtcag cctt
<210> 82
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 82
14
16
14
16
14

ggtcaaccac agagtc

16

<210> 83 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 83 gtcaaccaca gagt

14

<210> 84 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 84 cagccacatg cagc

14

<210> 85 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 85 ccagccacat gcag

14

<210> 86 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 86 accagccaca tgca

14

<210> 87 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 87 taccagccac atgc

14

<210> 88 <211> 14 <212> DNA <213> Artificial Sequence

<220>
<223> Synthetic Oligonucleotide
<400> 88 ttaccagcca catg
<210> 89
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 89 gttaccagcc acat
<210> 90
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 90 ggttaccagc poop
<210> 91
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 91 aggttaccag ccac
<210> 92
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 92 taggttacca gcca
<210> 93
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 93 aggttctgct ttcaac
<210> 94
14
14
14
14
14
16
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 94 ggttctgctt tcaa
<210> 95
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 95 tactgatcaa attgta
<210> 96
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 96 actgatcaaa ttgt
<210> 97
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 97 tttttcttgt atctgg
<210> 98
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 98 ttttcttgta tctg
<210> 99
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
16
14
16
14
<400> 99 atccattaaa acctgg
<210> 100
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 100 tccattaaaa cctg
<210> 101
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 101 atattgctct gcaaag
<210> 102
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 102 tattgctctg caaa
<210> 103
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 103 actg
<210> 104
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 104 atattgctct gcaa
<210> 105
<211> 14
<212> DNA
<213> Artificial Sequence
16
14
16
14
4
14
<220>
<223> Synthetic Oligonucleotide
<400> 105 aatattgctc tgca
<210> 106
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 106 gaatattgct ctgc
<210> 107
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 107 agaatattgc tctg
<210> 108
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 108 tagaatattg ctct
<210> 109
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 109 atagaatatt gctc
<210> 110
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 110 gatagaatat tgct
14
14
14
14
14
14
<210> 111
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 111 ggatagaata ttgc
<210> 112
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 112 atggaatcct caaatc
<210> 113
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 113 tggaatcctc aaat
<210> 114
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 114 gaattctggt atgtga
<210> 115
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 115 aattctggta tgtg
<210> 116
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
16
14
16
14
<400> 116 agctggaatt ctggta
<210> 117
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 117 gctggaattc tggt
<210> 118
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 118 tgaaaatcaa aattga
<210> 119
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 119 gaaaatcaaa attg
<210> 120
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 120 aaacagtgca tagtta
<210> 121
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 121 aacagtgcat agtt
<210> 122
<211> 16
<212> DNA
16
14
16
14
16

14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 122 ttcaggaatt gttaaa
<210> 123
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 123 tcaggaattg ttaa
<210> 124
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 124 ttttgtttca ttatag
<210> 125
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 125 tttgtttcat tata
<210> 126
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 126 gatgacactt gattta
<210> 127
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 127 atgacacttg attt
16
14
16
14
16
14
<210> 128
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 128 gtgtgatgac acttga
<210> 129
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 129 tgtgatgaca cttg
<210> 130
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 130 tattcagtgt gatgac
<210> 131
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 131 attcagtgtg atga
<210> 132
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 132 attggtattc agtgtg
<210> 133
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
16
14
16
14
16
<223> Synthetic Oligonucleotide
<400> 133 ttggtattca gtgt
<210> 134
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 134 cctctagctg taag
<210> 135
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 135 ccctctagct gtaa
<210> 136
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 136 gccctctagc tgta
<210> 137
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 137 ggccctctag ctgt
<210> 138
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 138 aggccctcta gctg
<210> 139
<211> 14
14
14
14
14
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 139 gaggccctct agct
<210> 140
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 140 agaggccctc tagc
<210> 141
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 141 aagaggccct ctag
<210> 142
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 142 aaagaggccc tcta
<210> 143
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 143 gaatggacag gtcaat
<210> 144
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 144
14
14
14
14
16
aatggacagg tcaa
<210> 145
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 145 gttttgaatg gacagg
<210> 146
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 146 ttttgaatgg acag
<210> 147
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 147 tggtagtttt gaatgg
<210> 148
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 148 ggtagttttg aatg
<210> 149
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 149 tcactgtatg gttt
<210> 150
<211> 14
<212> DNA
<213> Artificial Sequence
14
16
14
16
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 150 ctcactgtat ggtt
<210> 151
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 151 gctcactgta tggt
<210> 152
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 152 ggctcactgt atgg
<210> 153
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 153 tggctcactg tatg
<210> 154
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 154 ctggctcact gtat
<210> 155
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 155 gctggctcac tgta
<210> 156
14
14
14
14
14
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 156 ggctggctca ctgt
<210> 157
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 157 aggctggctc actg
<210> 158
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 158 caggtccagt tcat
<210> 159
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 159 gcaggtccag ttca
<210> 160
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 160 tgcaggtcca gttc
<210> 161
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 161 gtgcaggtcc agtt
<210> 162
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 162 ggtgcaggtc cagt
<210> 163
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 163 tggtgcaggt ccag
<210> 164
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 164 ttggtgcagg tcca
<210> 165
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 165 tttggtgcag gtcc
<210> 166
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 166 ctttggtgca ggtc
<210> 167
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 167 taactcagat cctg
<210> 168
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 168 ataactcaga tcct
<210> 169
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 169 aataactcag atcc
<210> 170
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 170 aaataactca gatc
<210> 171
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 171 aaaataactc agat
<210> 172
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 172 caaaataact caga
14
14
14
14
14
14
<210> 173
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 173 gcaaaataac tcag
<210> 174
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 174 agcaaaataa ctca
<210> 175
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 175 tagcaaaata actc
<210> 176
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 176 cagggcctgg agag
<210> 177
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 177 tctgaagtcc atgatc
<210> 178
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
16
<400> 178 ctgaagtcca tgat
<210> 179
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 179 tgggcatgat tccatt
<210> 180
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 180 gggcatgatt ccat
<210> 181
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 181 tggagcccac gtgc
<210> 182
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 182 ttgaagttga gggctg
<210> 183
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 183 tgaagttgag ggct
<210> 184
<211> 16
<212> DNA
14
16
14
14
16
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 184 accagtatta attttg
<210> 185
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 185 ccagtattaa tttt
<210> 186
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 186 gtgttctttg aagcgg
<210> 187
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 187 tgttctttga agcg
<210> 188
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 188 agttactttg gtgt
<210> 189
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 189 tggtacatgg aagtct
16
14
16
14
14
16
<210> 190
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 190 ggtacatgga agtc
<210> 191
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 191 actg
<210> 192
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 192 actg
<210> 193
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 193 actg
<210> 194
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 194 actg
<210> 195
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
14
4
4
4
4 <223> Synthetic Oligonucleotide
<400> 195 actg
<210> 196
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 196 actg
<210> 197
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 197 actg
<210> 198
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 198 actg
<210> 199
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 199 actg
<210> 200
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 200 tccatgccat atgt
<210> 201
<211> 16
4
4
4
4
4 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 201 ccctgaagaa gtccat
<210> 202
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 202 cctgaagaag tcca
<210> 203
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 203 gcccagttcc atgacc
<210> 204
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 204 cccagttcca tgac
<210> 205
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 205 ttgaggaagc cagatt
<210> 206
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 206
16
14
16
14
16
tgaggaagcc agat
<210> 207
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 207 tggatgcagt aatctc
<210> 208
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 208 ggatgcagta atct
<210> 209
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 209 tataaagtcc agcatt
<210> 210
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 210 ataaagtcca gcat
<210> 211
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 211 aagttcctgc ttgaag
<210> 212
<211> 14
<212> DNA
<213> Artificial Sequence
14
16
14
16
14
16
<220>
<223> Synthetic Oligonucleotide
<400> 212 agttcctgct tgaa
<210> 213
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 213 aatggtgaag tact
<210> 214
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 214 tgtcagcagg at
<210> 215
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 215 cagcaggaaa ta
<210> 216
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 216 ccagcaggaa at
<210> 217
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 217 accagcagga aa
<210> 218
14
14
12
12
12
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 218 gaccagcagg aa
<210> 219
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 219 tgaccagcag ga
<210> 220
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 220 actg
<210> 221
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 221 atgaccagca gg
<210> 222
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 222 aatgaccagc ag
<210> 223
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
4
12
12
<400> 223 caatgaccag ca
<210> 224
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 224 ccaatgacca gc
<210> 225
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 225 accacaagcc aa
<210> 226
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 226 tagccgccca ca
<210> 227
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 227 actg
<210> 228
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 228 ccggccacca ca
<210> 229
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
4
12
<220>
<223> Synthetic Oligonucleotide
<400> 229 accggccacc ac
<210> 230
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 230 gatgttgctg gc
<210> 231
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 231 actg
<210> 232
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 232 cgatgttgct gg
<210> 233
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 233 ccgatgttgc tg
<210> 234
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 234 gccgatgttg ct
12
12
4
12
12
12
<210> 235
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 235 tgccgatgtt gc
<210> 236
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 236 ctgccgatgt tg
<210> 237
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 237 caggcccaca aa
<210> 238
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 238 ccaggcccac aa
<210> 239
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 239 gccaggccca ca
<210> 240
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12
12
<400> 240 ccaagccact tg
<210> 241
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 241 agagcgcatt cc
<210> 242
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 242 acaggtagag gc
<210> 243
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 243 agatcttggt ga
<210> 244
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 244 actg
<210> 245
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 245 tgttccagcc cag
<210> 246
<211> 12
<212> DNA
12
12
12
12
4
13
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 246 tgttccagcc ca
<210> 247
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 247 actg
<210> 248
<211> 4

<400> 364 cagggaacca ggcc

14

<210> 365 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 365 tcagggaacc aggc

14

<210> 366 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 366 ctcagggaac cagg

14

<210> 367 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 367 cctcagggaa ccag

14

<210> 368 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 368 tcctcaggga acca

14

<210> 369 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 369 gtcctcaggg aacc

14

<210> 370 <211> 14 <212> ADN

<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 370 ggtcctcagg gaac
<210> 371
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 371 tggtcctcag ggaa
<210> 372
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 372 ctggtcctca ggga
<210> 373
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 373 gctggtcctc aggg
<210> 374
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 374 gtgctggggg gcag
<210> 375
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 375 ggtgctgggg ggca
14
14
14
14
14
14

<210> 376 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 376 gggtgctggg gggc

14

<210> 377 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 377 tgggtgctgg gggg

14

<210> 378 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 378 gagcagctca gcag

14

<210> 379 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 379 ggagcagctc agca

14

<210> 380 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 380 tggagcagct cagc

14

<210> 381 <211> 14 <212> ADN <213> Secuencia Artificial

<220>

<223> Oligonucleótido Sintético

<400> 381 ctggagcagc tcag

14

<210> 382 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 382 ccctcacccc caaa

14

<210> 383 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 383 accctcaccc ccaa

14

<210> 384 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 384 caccctcacc ccca

14

<210> 385 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 385 acaccctcac cccc

14

<210> 386 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 386 gacaccctca cccc

14

<210> 387 <211> 14

<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 387 agacaccctc accc
<210> 388
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 388 tagacaccct cacc
<210> 389
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 389 tggcagcagg aagc
<210> 390
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 248 actg
<210> 249
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 249 actg
<210> 250
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 250 actg
<210> 251
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 251 atgttccagc cc
12
4
4
4
4 12
<210> 252
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 252 tggtgatgcc ca
<210> 253
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 253 atggtgatgc cc
<210> 254
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 254 catggtgatg cc
<210> 255
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 255 actg
<210> 256
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 256 tcatggtgat gc
<210> 257
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
12
12
12
4
12
<223> Synthetic Oligonucleotide
<400> 257 atcatggtga tg
<210> 258
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 258 ccctcctgtc ac
<210> 259
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 259 gccctcctgt ca
<210> 260
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 260 agccctcctg tc
<210> 261
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 261 cagccctcct gt
<210> 262
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 262 ccagccctcc tg
<210> 263
<211> 12
12
12
12
12
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 263 gccagccctc ct
<210> 264
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 264 gacgaaggtc tg
<210> 265
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 265 gtatttgtcg aa
<210> 266
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 266 ggacaccgtc ag
<210> 267
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 267 cagcttcagg ta
<210> 268
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 268
12
12
12
12
12
catgaccatg ag
<210> 269
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 269 gcatgaccat ga
<210> 270
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 270 ggcatgacca tg
<210> 271
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 271 tggcatgacc at
<210> 272
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 272 ctggcatgac ca
<210> 273
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 273 actg
<210> 274
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
12
4
<220>
<223> Synthetic Oligonucleotide
<400> 274 cctggcatga cc
<210> 275
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 275 gcagcccacc tc
<210> 276
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 276 agcagcccac ct
<210> 277
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 277 gagcagccca cc
<210> 278
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 278 catgagcttc ac
<210> 279
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 279 gcatgagctt ca
<210> 280
12
12
12
12
12
12
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 280 ggcatgagct tca
<210> 281
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 281 ggcatgagct tc
<210> 282
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 282 actg
<210> 283
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 283 gggcatgagc tt
<210> 284
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 284 cagcatgagt cc
<210> 285
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
13
12
4
12
12
<400> 285 ccagcatgag tc
<210> 286
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 286 actg
<210> 287
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 287 gccagcatga gt
<210> 288
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 288 ccatggtgaa ga
<210> 289
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 289 cacagctgcc cg
<210> 290
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 290 acacagctgc cc
<210> 291
<211> 12
<212> DNA
<213> Artificial Sequence
12
4
12
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 291 cacacagctg cc
<210> 292
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 292 gcacacagct gcc
<210> 293
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 293 gcacacagct gc
<210> 294
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 294 actg
<210> 295
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 295 gccggagact ga
<210> 296
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 296 attgaggttg ac
12
13
12
4
12
12
<210> 297
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 297 cattgaggtt ga
<210> 298
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 298 gcattgaggt tg
<210> 299
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 299 ggcattgagg tt
<210> 300
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 300 gggcattgag gt
<210> 301
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 301 actg
<210> 302
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12
4 <400> 302 actg
<210> 303
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 303 actg
<210> 304
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 304 actg
<210> 305
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 305 actg
<210> 306
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 306 actg
<210> 307
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 307 actg
<210> 308
<211> 4
<212> DNA
4
4
4
4
4
4
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 308 actg
<210> 309
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 309 actg
<210> 310
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 310 actg
<210> 311
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 311 actg
<210> 312
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 312 actg
<210> 313
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 313 actg
4
4
4
4
4
4
<210> 314
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 314 actg
<210> 315
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 315 actg
<210> 316
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 316 actg
<210> 317
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 317 actg
<210> 318
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 318 actg
<210> 319
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
4
4
4
4
4
<223> Synthetic Oligonucleotide
<400> 319 actg
<210> 320
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 320 actg
<210> 321
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 321 actg
<210> 322
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 322 actg
<210> 323
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 323 actg
<210> 324
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 324 actg
<210> 325
<211> 4
4
4
4
4
4
4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 325 actg
<210> 326
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 326 actg
<210> 327
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 327 actg
<210> 328
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 328 actg
<210> 329
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 329 atggggcaac ttca
<210> 330
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 330 4
4
4
4
14
catggggcaa cttc
<210> 331
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 331 acatggggca actt
<210> 332
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 332 gggatgctct gggc
<210> 333
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 333 cgctccaggt tcca
<210> 334
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 334 gatacacctc cacc
<210> 335
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 335 agatacacct ccac
<210> 336
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 336 gagatacacc tcca
<210> 337
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 337 gcctgtctgt ggaa
<210> 338
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 338 ctgtcacact tgct
<210> 339
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 339 cggccgctga ccac
<210> 340
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 340 ccggccgctg acca
<210> 341
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 341 cccggccgct gacc
<210> 342
14
14
14
14
14
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 342 tcccggccgc tgac
<210> 343
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 343 atcccggccg ctga
<210> 344
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 344 catcccggcc gctg
<210> 345
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 345 gcatcccggc cgct
<210> 346
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 346 gtgcccttcc cttg
<210> 347
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 347 atgagggtgc cgct
<210> 348
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 348 tatgagggtg ccgc
<210> 349
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 349 ctatgagggt gccg
<210> 350
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 350 cctatgaggg tgcc
<210> 351
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 351 cgaataaact ccag
<210> 352
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 352 ccgaataaac tcca
<210> 353
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 353 tccgaataaa ctcc
<210> 354
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 354 ttccgaataa actc
<210> 355
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 355 gccaggggca gcag
<210> 356
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 356 gagtagaggc aggc
<210> 357
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 357 ccccaaagtc ccca
<210> 358
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 358 tccccaaagt cccc
14
14
14
14
14
14
<210> 359
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 359 gtccccaaag tccc
<210> 360
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 360 acgtgggcag cagc
<210> 361
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 361 cacgtgggca gcag
<210> 362
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 362 ccacgtgggc agca
<210> 363
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 363 gccacgtggg cagc
<210> 364
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14

<400> 364 cagggaacca ggcc

14

<210> 365 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 365 tcagggaacc aggc

14

<210> 366 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 366 ctcagggaac cagg

14

<210> 367 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 367 cctcagggaa ccag

14

<210> 368 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 368 tcctcaggga acca

14

<210> 369 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 369 gtcctcaggg aacc

14

<210> 370 <211> 14 <212> DNA

<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 370 ggtcctcagg gaac
<210> 371
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 371 tggtcctcag ggaa
<210> 372
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 372 ctggtcctca ggga
<210> 373
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 373 gctggtcctc aggg
<210> 374
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 374 gtgctggggg gcag
<210> 375
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 375 ggtgctgggg ggca
14
14
14
14
14
14

<210> 376 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 376 gggtgctggg gggc

14

<210> 377 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 377 tgggtgctgg gggg

14

<210> 378 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 378 gagcagctca gcag

14

<210> 379 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 379 ggagcagctc agca

14

<210> 380 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 380 tggagcagct cagc

14

<210> 381 <211> 14 <212> DNA <213> Artificial Sequence

<220>

<223> Synthetic Oligonucleotide

<400> 381 ctggagcagc tcag

14

<210> 382 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 382 ccctcacccc caaa

14

<210> 383 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 383 accctcaccc ccaa

14

<210> 384 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 384 caccctcacc ccca

14

<210> 385 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 385 acaccctcac cccc

14

<210> 386 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 386 gacaccctca cccc

14

<210> 387 <211> 14

<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 387 agacaccctc accc
<210> 388
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 388 tagacaccct cacc
<210> 389
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 389 tggcagcagg aagc
<210> 390
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide

gcatggcagc agga

14

<210> 393 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 393 ggcagcagat ggca

14

<210> 394 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 394 cggcagcaga tggc

14

<210> 395 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 395 ccggcagcag atgg

14

<210> 396 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 396 tccggcagca gatg

14

<210> 397 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 397 ctccggcagc agat

14

<210> 398 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 398 gctccggcag caga

14

<210> 399 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 399 ggctccggca gcag

14

<210> 400 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 400 cggctccggc agca

14

<210> 401 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 401 ccggctccgg cagc

14

<210> 402 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 402 gccggctccg gcag

14

<210> 403 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 403 agttacaaaa gcaa

14

<210> 404

<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 404 actg
<210> 405
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 405 actg
<210> 406
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 406 gtcgcccttc agcacg
<210> 407
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 407 tcgcccttca gcac
<210> 408
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 408 cgcccttcag ca
<210> 409
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético 4
4
16
14
12
<400> 409 actctggacc caaacc
<210> 410
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 410 ctctggaccc aaac
<210> 411
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 411 ccatttcagg agacct
<210> 412
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 412 catttcagga gacc
<210> 413
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 413 tttgggaggt ggtc
<210> 414
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 414 cacaccaggc agag
<210> 415
<211> 14
<212> ADN
<213> Secuencia Artificial
16
14
16
14
14 14
<220>
<223> Oligonucleótido Sintético
<400> 415 ctttacagct tcca
<210> 416
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 416 cactaccttc cact
<210> 417
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 417 aacacacact acct
<210> 418
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 418 ctcttcaaaa caca
<210> 419
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 419 gtaattgtgc tgtc
<210> 420
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 420 tttttcttcg aatt
14
14
14
14
14
14
<210> 421
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 421 cattttcgat agcg
<210> 422
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 422 accttccagg ttca
<210> 423
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 423 ataggaagca taaa
<210> 424
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 424 tcttttaaag aaga
<210> 425
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 425 aaggatattt taaa
<210> 426
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
14
14
14
14
<400> 426 actg
<210> 427
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 427 gaacaaaaat taaa
<210> 428
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 428 ttccacagat ctgt
<210> 429
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 429 tttataaagt aaag
<210> 430
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 430 actg
<210> 431
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 431 actg
<210> 432
<211> 4
<212> ADN
4
14
14
14
4
4
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 432 actg
<210> 433
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 433 tactgtgaga aata
<210> 434
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 434 actg
<210> 435
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 435 ttccagcttg aaga
<210> 436
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 436 gatcagttct catg
<210> 437
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 437 actg
4
14
4
14
14
4
<210> 438
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 438 actg
<210> 439
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 439 ttatcaatga tgca
<210> 440
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 440 gcatgctgga cagt
<210> 441
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 441 actg
<210> 442
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 442 actg
<210> 443
<211> 14
<212> ADN
<213> Secuencia Artificial
<220> 4
14
14
4
4 <223> Oligonucleótido Sintético
<400> 443 ttgcacctga acta
<210> 444
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 444 cagaatatat ttct
<210> 445
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 445 actg
<210> 446
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 446 actg
<210> 447
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 447 actg
<210> 448
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 448 actg
<210> 449
<211> 4
14
14
4
4
4
4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 449 actg
<210> 450
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 450 ataagagatt aaaa
<210> 451
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 451 tcccccttct catt
<210> 452
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 452 gggcattgtt aaaa
<210> 453
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 453 actg
<210> 454
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 454 4
14
14
14
4 actg
<210> 455
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 455 agaactcaca tctg
<210> 456
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 456 gagctggacg gagg
<210> 457
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 457 aagcttcatc ggag
<210> 458
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 458 ataatggcat cccg
<210> 459
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 459 actg
<210> 460
<211> 14
<212> ADN
<213> Secuencia Artificial
4
4 14
14
14
14
<220>
<223> Oligonucleótido Sintético
<400> 460 tgctgtccta taag
<210> 461
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 461 cacaaaggta attg
<210> 462
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 462 atcatttctt ccag
<210> 463
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 463 actg
<210> 464
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 464 actg
<210> 465
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 465 actg
<210> 466
14
14
14
4
4
4
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 466 ccattacctt ccag
<210> 467
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 467 gcataaacag ggtt
<210> 468
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 468 actg
<210> 469
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 469 actg
<210> 470
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 470 actg
<210> 471
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
14
4
4
4 <400> 471 actg
<210> 472
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 472 tatgaaagga atgt
<210> 473
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 473 actg
<210> 474
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 474 ttccttaagc ttcc
<210> 475
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 475 actg
<210> 476
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 476 actg
<210> 477
<211> 4
<212> ADN
<213> Secuencia Artificial
4
14
4
14
4
4
<220>
<223> Oligonucleótido Sintético
<400> 477 actg
<210> 478
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 478 actg
<210> 479
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 479 actg
<210> 480
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 480 actg
<210> 481
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 481 actg
<210> 482
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 482 actg
4
4
4
4
4
4
<210> 483
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 483 actg
<210> 484
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 484 actg
<210> 485
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 485 gaacagttaa acat
<210> 486
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 486 tagagcttcc acttct
<210> 487
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 487 gagcttccac ttct
<210> 488
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético 4
4
14
16
14
<400> 488 tgttggccgt ggta
<210> 489
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 489 atgttggccg tggt
<210> 490
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 490 gatgttggcc gtgg
<210> 491
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 491 agatgttggc cgtg
<210> 492
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 492 gagatgttgg ccgt
<210> 493
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 493 ggagatgttg gccg
<210> 494
<211> 14
<212> ADN
14
14
14
14
14
14
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 494 aggagatgtt ggcc
<210> 495
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 495 caggagatgt tggc
<210> 496
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 496 gcaggagatg ttgg
<210> 497
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 497 ggcaggagat gttg
<210> 498
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 498 gtggtgccaa ggca
<210> 499
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 499 tgtggtgcca aggc
14
14
14
14
14
14
<210> 500
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 500 ttgtggtgcc aagg
<210> 501
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 501 tttgtggtgc caag
<210> 502
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 502 ctttgtggtg ccaa
<210> 503
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 503 actttgtggt gcca
<210> 504
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 504 cactttgtgg tgcc
<210> 505
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
14
14
14
14
14
<223> Oligonucleótido Sintético
<400> 505 gcactttgtg gtgc
<210> 506
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 506 tgcactttgt ggtg
<210> 507
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 507 ttgcactttg tggt
<210> 508
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 508 cggtgttgca cttt
<210> 509
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 509 gcggtgttgc actt
<210> 510
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 510 agcggtgttg cact
<210> 511
<211> 14
14
14
14
14
14
14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 511 aagcggtgtt gcac
<210> 512
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 512 gaagcggtgt tgca
<210> 513
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 513 cgaagcggtg ttgc
<210> 514
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 514 acgaagcggt gttg
<210> 515
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 515 cacgaagcgg tgtt
<210> 516
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 516
14
14
14
14
14
acacgaagcg gtgt
<210> 517
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 517 aacacgaagc ggtg
<210> 518
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 518 gctgctgtac atct
<210> 519
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 519 actg
<210> 520
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 520 agctgctgta catc
<210> 521
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 521 aagctgctgt acat
<210> 522
<211> 14
<212> ADN
<213> Secuencia Artificial
14
14
14
4
14
14
<220>
<223> Oligonucleótido Sintético
<400> 522 gaagctgctg taca
<210> 523
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 523 ggaagctgct gtac
<210> 524
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 524 tggaagctgc tgta
<210> 525
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 525 ctggaagctg ctgt
<210> 526
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 526 cctggaagct gctg
<210> 527
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 527 acctggaagc tgct
<210> 528
14
14
14
14
14
<400> 390 atggcagcag gaag
<210> 391
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 391 catggcagca ggaa
<210> 392
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 392
14
14
14
14
14

gcatggcagc agga

14

<210> 393 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 393 ggcagcagat ggca

14

<210> 394 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 394 cggcagcaga tggc

14

<210> 395 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 395 ccggcagcag atgg

14

<210> 396 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 396 tccggcagca gatg

14

<210> 397 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 397 ctccggcagc agat

14

<210> 398 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 398 gctccggcag caga

14

<210> 399 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 399 ggctccggca gcag

14

<210> 400 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 400 cggctccggc agca

14

<210> 401 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 401 ccggctccgg cagc

14

<210> 402 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 402 gccggctccg gcag

14

<210> 403 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 403 agttacaaaa gcaa

14

<210> 404

<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 404 actg
<210> 405
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 405 actg
<210> 406
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 406 gtcgcccttc agcacg
<210> 407
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 407 tcgcccttca gcac
<210> 408
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 408 cgcccttcag ca
<210> 409
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide 4
4
16
14
12
<400> 409 actctggacc caaacc
<210> 410
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 410 ctctggaccc aaac
<210> 411
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 411 ccatttcagg agacct
<210> 412
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 412 catttcagga gacc
<210> 413
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 413 tttgggaggt ggtc
<210> 414
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 414 cacaccaggc agag
<210> 415
<211> 14
<212> DNA
<213> Artificial Sequence
16
14
16
14
14 14
<220>
<223> Synthetic Oligonucleotide
<400> 415 ctttacagct tcca
<210> 416
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 416 cactaccttc cact
<210> 417
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 417 aacacacact acct
<210> 418
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 418 ctcttcaaaa poop
<210> 419
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 419 gtaattgtgc tgtc
<210> 420
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 420 tttttcttcg aatt
14
14
14
14
14
14
<210> 421
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 421 cattttcgat agcg
<210> 422
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 422 accttccagg ttca
<210> 423
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 423 ataggaagca taaa
<210> 424
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 424 tcttttaaag aaga
<210> 425
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 425 aaggatattt taaa
<210> 426
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 426 actg
<210> 427
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 427 gaacaaaaat taaa
<210> 428
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 428 ttccacagat ctgt
<210> 429
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 429 tttataaagt aaag
<210> 430
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 430 actg
<210> 431
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 431 actg
<210> 432
<211> 4
<212> DNA
4
14
14
14
4
4
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 432 actg
<210> 433
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 433 tactgtgaga aata
<210> 434
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 434 actg
<210> 435
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 435 ttccagcttg aaga
<210> 436
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 436 gatcagttct catg
<210> 437
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 437 actg
4
14
4
14
14
4
<210> 438
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 438 actg
<210> 439
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 439 ttatcaatga tgca
<210> 440
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 440 gcatgctgga cagt
<210> 441
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 441 actg
<210> 442
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 442 actg
<210> 443
<211> 14
<212> DNA
<213> Artificial Sequence
<220> 4
14
14
4
4 <223> Synthetic Oligonucleotide
<400> 443 ttgcacctga act
<210> 444
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 444 cagaatatat ttct
<210> 445
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 445 actg
<210> 446
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 446 actg
<210> 447
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 447 actg
<210> 448
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 448 actg
<210> 449
<211> 4
14
14
4
4
4
4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 449 actg
<210> 450
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 450 ataagagatt aaaa
<210> 451
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 451 tcccccttct catt
<210> 452
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 452 gggcattgtt aaaa
<210> 453
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 453 actg
<210> 454
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 454 4
14
14
14
4 actg
<210> 455
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 455 agaactcaca tctg
<210> 456
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 456 gagctggacg gagg
<210> 457
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 457 aagcttcatc ggag
<210> 458
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 458 ataatggcat cccg
<210> 459
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 459 actg
<210> 460
<211> 14
<212> DNA
<213> Artificial Sequence
4
4 14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 460 tgctgtccta taag
<210> 461
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 461 cacaaaggta attg
<210> 462
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 462 atcatttctt ccag
<210> 463
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 463 actg
<210> 464
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 464 actg
<210> 465
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 465 actg
<210> 466
14
14
14
4
4
4
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 466 ccattacctt ccag
<210> 467
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 467 gcataaacag ggtt
<210> 468
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 468 actg
<210> 469
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 469 actg
<210> 470
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 470 actg
<210> 471
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
4
4
4 <400> 471 actg
<210> 472
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 472 tatgaaagga atgt
<210> 473
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 473 actg
<210> 474
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 474 ttccttaagc ttcc
<210> 475
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 475 actg
<210> 476
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 476 actg
<210> 477
<211> 4
<212> DNA
<213> Artificial Sequence
4
14
4
14
4
4
<220>
<223> Synthetic Oligonucleotide
<400> 477 actg
<210> 478
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 478 actg
<210> 479
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 479 actg
<210> 480
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 480 actg
<210> 481
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 481 actg
<210> 482
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 482 actg
4
4
4
4
4
4
<210> 483
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 483 actg
<210> 484
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 484 actg
<210> 485
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 485 gaacagttaa acat
<210> 486
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 486 tagagcttcc acttct
<210> 487
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 487 gagcttccac ttct
<210> 488
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide 4
4
14
16
14
<400> 488 tgttggccgt ggta
<210> 489
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 489 atgttggccg tggt
<210> 490
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 490 gatgttggcc gtgg
<210> 491
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 491 agatgttggc cgtg
<210> 492
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 492 gagatgttgg ccgt
<210> 493
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 493 ggagatgttg gccg
<210> 494
<211> 14
<212> DNA
14
14
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 494 aggagatgtt ggcc
<210> 495
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 495 caggagatgt tggc
<210> 496
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 496 gcaggagatg ttgg
<210> 497
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 497 ggcaggagat gttg
<210> 498
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 498 gtggtgccaa ggca
<210> 499
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 499 tgtggtgcca aggc
14
14
14
14
14
14
<210> 500
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 500 ttgtggtgcc aagg
<210> 501
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 501 tttgtggtgc caag
<210> 502
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 502 ctttgtggtg ccaa
<210> 503
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 503 actttgtggt gcca
<210> 504
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 504 cactttgtgg tgcc
<210> 505
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
14
14
14
14
14
<223> Synthetic Oligonucleotide
<400> 505 gcactttgtg gtgc
<210> 506
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 506 tgcactttgt ggtg
<210> 507
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 507 ttgcactttg tggt
<210> 508
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 508 cggtgttgca cttt
<210> 509
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 509 gcggtgttgc actt
<210> 510
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 510 agcggtgttg cact
<210> 511
<211> 14
14
14
14
14
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 511 aagcggtgtt gcac
<210> 512
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 512 gaagcggtgt tgca
<210> 513
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 513 cgaagcggtg ttgc
<210> 514
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 514 acgaagcggt gttg
<210> 515
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 515 cacgaagcgg tgtt
<210> 516
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 516
14
14
14
14
14
acacgaagcg gtgt
<210> 517
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 517 aacacgaagc ggtg
<210> 518
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 518 gctgctgtac atct
<210> 519
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 519 actg
<210> 520
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 520 agctgctgta catc
<210> 521
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 521 aagctgctgt acat
<210> 522
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
4
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 522 gaagctgctg taca
<210> 523
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 523 ggaagctgct gtac
<210> 524
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 524 tggaagctgc tgta
<210> 525
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 525 ctggaagctg ctgt
<210> 526
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 526 cctggaagct gctg
<210> 527
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 527 acctggaagc tgct
<210> 528
14
14
14
14
14

tggaccccca gcagag

16

<210> 641 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 641 gacccccagc agag

14

<210> 642 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 642 caaaggcaaa gacc

14

<210> 643 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 643 tcacaaaggc aaag

14

<210> 644 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 644 cagtcacaaa ggca

14

<210> 645 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 645 cgtcagtcac aaag

14

<210> 646 <211> 14 <212> ADN <213> Secuencia Artificial

<220>
<223> Oligonucleótido Sintético
<400> 646 gctcgtcagt caca
<210> 647
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 647 catgctcgtc agtc
<210> 648
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 648 gggcatgctc gtca
<210> 649
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 649 actg
<210> 650
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 650 actg
<210> 651
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 651 actg
<210> 652
14
14
14
4
4
4
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 652 actg
<210> 653
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 653 actg
<210> 654
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 654 cttgggcatg ctcg
<210> 655
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 655 actg
<210> 656
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 656 actg
<210> 657
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético 4
4
14
4
4 <400> 657 tgccttgggc atgc
<210> 658
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 658 gggtgccttg ggca
<210> 659
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 528 cacctggaag ctgc
<210> 529
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 529 tcacctggaa gctg
<210> 530
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 530 atcacctgga agct
<210> 531
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 531 catcacctgg aagc
<210> 532
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 532 acatcacctg gaag
<210> 533
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 533 tacatcacct ggaa
<210> 534
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 534 gtacatcacc tgga
<210> 535
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 535 tgtacatcac ctgg
<210> 536
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 536 gtgtacatca cctg
<210> 537
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 537 tagcgggtcc tgag
<210> 538
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 538 gtagcgggtc ctga
<210> 539
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 539 tgtagcgggt cctg
<210> 540
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 540 ctgtagcggg tcct
<210> 541
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 541 gctgtagcgg gtcc
<210> 542
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 542 ggctgtagcg ggtc
<210> 543
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 543 tggctgtagc gggt
<210> 544
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 544 ctggctgtag cggg
14
14
14
14
14
14
<210> 545
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 545 tctggctgta gcgg
<210> 546
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 546 ttctggctgt agcg
<210> 547
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 547 tgaacaccgc ggcc
<210> 548
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 548 atgaacaccg cggc
<210> 549
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 549 catgaacacc gcgg
<210> 550
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 550 gcatgaacac cgcg
<210> 551
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 551 tgcatgaaca ccgc
<210> 552
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 552 ttgcatgaac accg
<210> 553
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 553 attgcatgaa cacc
<210> 554
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 554 tattgcatga acac
<210> 555
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 555 atattgcatg aaca
<210> 556
<211> 14
<212> DNA
14
14
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 556 catattgcat gaac
<210> 557
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 557 aggttgtgca ggta
<210> 558
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 558 caggttgtgc aggt
<210> 559
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 559 gcaggttgtg cagg
<210> 560
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 560 agcaggttgt gcag
<210> 561
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 561 cagcaggttg tgca
14
14
14
14
14
14
<210> 562
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 562 ccagcaggtt gtgc
<210> 563
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 563 cccagcaggt tgtg
<210> 564
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 564 gcccagcagg ttgt
<210> 565
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 565 ggcccagcag gttg
<210> 566
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 566 aggcccagca ggtt
<210> 567
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
14
14
14
14
14
<223> Synthetic Oligonucleotide
<400> 567 tgtcattgct ggtcca
<210> 568
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 568 tcattgctgg tcca
<210> 569
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 569 tggccagccg gaactt
<210> 570
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 570 gccagccgga actt
<210> 571
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 571 gggatgaggg tcagcg
<210> 572
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 572 gatgagggtc agcg
<210> 573
<211> 14
16
14
16
14
16
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 573 aaggcaaaga ccac
<210> 574
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 574 ggagcgcagg gtgc
<210> 575
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 575 tgcacctcct tgtt
<210> 576
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 576 cagcagaccc tgga
<210> 577
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 577 acatctggca gaggtt
<210> 578
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 578
14
14
14
14
16
atctggcaga ggtt
<210> 579
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 579 caggccagca ggagta
<210> 580
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 580 ggccagcagg agta
<210> 581
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 581 ctcaaacaaa aagtcc
<210> 582
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 582 caaacaaaaa gtcc
<210> 583
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 583 gtggtgacat tggtca
<210> 584
<211> 14
<212> DNA
<213> Artificial Sequence
14 16
14
16
14
16
<220>
<223> Synthetic Oligonucleotide
<400> 584 ggtgacattg gtca
<210> 585
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 585 actg
<210> 586
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 586 actg
<210> 587
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 587 ttggcagtgg tgtt
<210> 588
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 588 atgttggcag tggt
<210> 589
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 589 aggaaatgtt ggcagt
<210> 590
14
4
4
14
14
16
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 590 gaaatgttgg cagt
<210> 591
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 591 caggaaatgt tggc
<210> 592
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 592 gggcaggaaa tgtt
<210> 593
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 593 aaggtaggta ccag
<210> 594
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 594 accaaggtag gtac
<210> 595
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 595 ctttgtggca ccaa
<210> 596
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 596 gcactttgtg gcac
<210> 597
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 597 tgcactttgt ggca
<210> 598
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 598 gctgcacttt gtgg
<210> 599
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 599 ggtgctgcac tttg
<210> 600
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 600 ggcggtgctg cact
<210> 601
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 601 tgaacactag gcgg
<210> 602
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 602 tcttgaacac tagg
<210> 603
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 603 cacctcttga acacta
<210> 604
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 604 cctcttgaac minutes
<210> 605
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 605 acctcttgaa cact
<210> 606
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 606 cacacctctt gaac
14
14
16
14
14
14
<210> 607
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 607 cctcgaaccc actg
<210> 608
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 608 cttctggacc tcgatc
<210> 609
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 609 tctggacctc gatc
<210> 610
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 610 ctgctataca tcttgg
<210> 611
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 611 gctatacatc ttgg
<210> 612
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
16
14
16
14
<400> 612 cacggtgtac atcacc
<210> 613
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 613 cggtgtacat cacc
<210> 614
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 614 ggacagactg tagccc
<210> 615
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 615 acagactgta gccc
<210> 616
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 616 gtcatcgcca atcttc
<210> 617
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 617 catcgccaat cttc
<210> 618
<211> 16
<212> DNA
16
14
16
14
16
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 618 tcacactgag gtcatc
<210> 619
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 619 acactgaggt catc
<210> 620
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 620 cgccccgtca ctga
<210> 621
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 621 ccagcaacca gcaata
<210> 622
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 622 agcaaccagc aata
<210> 623
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 623 caggctgtac aggtac
16
14
14
16
14
16
<210> 624
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 624 ggctgtacag gtac
<210> 625
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 625 gaagctcctc tcagag
<210> 626
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 626 agctcctctc agag
<210> 627
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 627 cccagccaat gcccag
<210> 628
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 628 cagccaatgc ccag
<210> 629
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
14
16
14
16
14
<223> Synthetic Oligonucleotide
<400> 629 tcaaacagac acttga
<210> 630
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 630 aaacagacac ttga
<210> 631
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 631 agcactgaac attctc
<210> 632
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 632 cactgaacat tctc
<210> 633
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 633 ggatccacca gaatcc
<210> 634
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 634 atccaccaga atcc
<210> 635
<211> 14
16
14
16
14
16
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 635 tgatcagtaa ggcc
<210> 636
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 636 ggacaaagat gaaaaa
<210> 637
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 637 acaaagatga aaaa
<210> 638
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 638 ggcacgcagc ttggcc
<210> 639
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 639 cacgcagctt ggcc
<210> 640
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 640
14
16
14
16
14

tggaccccca gcagag

16

<210> 641 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 641 gacccccagc agag

14

<210> 642 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 642 caaaggcaaa gacc

14

<210> 643 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 643 tcacaaaggc aaag

14

<210> 644 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 644 cagtcacaaa ggca

14

<210> 645 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 645 cgtcagtcac aaag

14

<210> 646 <211> 14 <212> DNA <213> Artificial Sequence

<220>
<223> Synthetic Oligonucleotide
<400> 646 gctcgtcagt poop
<210> 647
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 647 catgctcgtc agtc
<210> 648
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 648 gggcatgctc gtca
<210> 649
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 649 actg
<210> 650
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 650 actg
<210> 651
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 651 actg
<210> 652
14
14
14
4
4
4
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 652 actg
<210> 653
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 653 actg
<210> 654
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 654 cttgggcatg ctcg
<210> 655
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 655 actg
<210> 656
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 656 actg
<210> 657
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide 4
4
14
4
4 <400> 657 tgccttgggc atgc
<210> 658
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 658 gggtgccttg ggca
<210> 659
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide

<210> 669 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 669 caaaaaagag cttg

14

<210> 670 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 670 aaggagctga ggaaca

16

<210> 671 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 671 ggagctgagg aaca

14

<210> 672 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 672 gcagaccctg gaagga

16

<210> 673 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 673 agaccctgga agga

14

<210> 674 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 674 accagcagac cctgga
<210> 675
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 675 actg
<210> 676
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 676 cagtagagaa cagcca
<210> 677
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 677 gtagagaaca gcca
<210> 678
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 678 tgttgaggaa acagta
<210> 679
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 679 ttgaggaaac agta
<210> 680
<211> 16
<212> ADN
16
4
16
14
16
14
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 680 cctgcacctc cttgtt
<210> 681
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 681 atgagggtct tcat
<210> 682
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 682 accccggagt aggc
<210> 683
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 683 cccggagtag gc
<210> 684
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 684 caggaccccg gagtag
<210> 685
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 685 gcaggacccc ggagta
16
14
14
12
16
16
<210> 686
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 686 aggaccccgg agta
<210> 687
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 687 caggaccccg gagt
<210> 688
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 688 cagacccctc gc
<210> 689
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 689 agaggatgct gg
<210> 690
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 690 gagccaggtg acagag
<210> 691
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
14
14
12
12
16
<223> Oligonucleótido Sintético
<400> 691 agccaggtga caga
<210> 692
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 692 tgagccaggt ga
<210> 693
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 693 ttttccacct tgga
<210> 694
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 694 ctgcaggcca ct
<210> 695
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 695 tcaccagctg gatggg
<210> 696
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 696 ttcaccagct ggatgg
<210> 697
<211> 14
14
12
14
12
16
16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 697 caccagctgg atgg
<210> 698
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 698 tcaccagctg gatg
<210> 699
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 699 tcaccagctg ga
<210> 700
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 700 tgtcttcacc agctgg
<210> 701
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 701 gtcttcacca gctg
<210> 702
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 702
14
14
12
16
14
gtgtgtcttc accagc
<210> 703
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 703 tgtgtcttca ccag
<210> 704
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 704 ttgtgtgtct tcacca
<210> 705
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 705 tgtgtgtctt cacc
<210> 706
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 706 aggttgtgtg tcttca
<210> 707
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 707 ggttgtgtgt cttc
<210> 708
<211> 16
<212> ADN
<213> Secuencia Artificial
16
14
16
14
16
14
<220>
<223> Oligonucleótido Sintético
<400> 708 gcaggttgtg tgtctt
<210> 709
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 709 caggttgtgt gtct
<210> 710
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 710 tcagcaggtt gtgtgt
<210> 711
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 711 cagcaggttg tgtg
<210> 712
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 712 ggtcagcagg ttgtgt
<210> 713
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 713 tggtcagcag gttgtg
<210> 714
16
14
16
14
16
16
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 714 gtcagcaggt tgtg
<210> 715
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 715 ggtcagcagg ttgt
<210> 716
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 716 ctggtggtca gcaggt
<210> 717
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 717 tggtggtcag cagg
<210> 718
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 718 ctggtggtca gc
<210> 719
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
14
16
14
12
<400> 719 agttcctggt ggtcag
<210> 720
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 720 gttcctggtg gtca
<210> 721
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 721 tatagttcct ggtggt
<210> 722
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 722 atagttcctg gtgg
<210> 723
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 723 gatatagttc ctggtg
<210> 724
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 724 atatagttcc tggt
<210> 725
<211> 16
<212> ADN
<213> Secuencia Artificial
16
14
16
14
16
14
<220>
<223> Oligonucleótido Sintético
<400> 725 ccaaagatat agttcc
<210> 726
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 726 tccaaagata tagttc
<210> 727
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 727 caaagatata gttc
<210> 728
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 728 ccaaagatat agtt
<210> 729
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 729 ccaggcccat ga
<210> 730
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 730 ggcacccagg cccatg
16
16
14
14
12
16
<210> 731
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 731 gcacccaggc ccat
<210> 732
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 732 cagaaggcac ccaggc
<210> 733
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 733 agaaggcacc cagg
<210> 734
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 734 ccagacatca gg
<210> 735
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 735 gacagggcag at
<210> 736
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
14
16
14
12
12
<400> 736 tgacagggca ga
<210> 737
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 737 ccactcccat tc
<210> 738
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 738 gccaggcatg gagctc
<210> 739
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 739 ccaggcatgg agct
<210> 740
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 740 ccaggcatgg ag
<210> 741
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 741 cagggtgact gc
<210> 742
<211> 16
<212> ADN
12
12
16
14
12
12
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 742 gttccgcagg gtgact
<210> 743
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 743 ttccgcaggg tgac
<210> 744
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 744 gcggttccgc agggtg
<210> 745
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 745 cggttccgca gggt
<210> 746
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 746 tcggccccag gagccc
<210> 747
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 747 cggccccagg agcc
16
14
16
14
16
14

<210> 748 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 748 ccatcggccc caggag

16

<210> 749 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 749 catcggcccc agga

14

<210> 750 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 750 gacccatcgg ccccag

16

<210> 751 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 751 acccatcggc ccca

14

<210> 752 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 752 ttctggaccc atcggc

16

<210> 753 <211> 12 <212> ADN <213> Secuencia Artificial

<220>

<223> Oligonucleótido Sintético
<400> 753 ggacccatcg gc
<210> 754
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 754 tctggaccca tcgg
<210> 755
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 755 caccagcccc caggtg
<210> 756
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 756 accagccccc aggt
<210> 757
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 757 tagggcacca gccccc
<210> 758
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 758 agggcaccag cccc
<210> 759
<211> 16
12
14
16
14
16
14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 759 tggagtaggg caccag
<210> 760
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 760 ggagtagggc acca
<210> 761
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 761 cttggagtag gg
<210> 762
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 762 tgatgggctt ggagta
<210> 763
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 763 gatgggcttg gagt
<210> 764
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 764
16
14
12
16
14
tgtggtacag gtcgat
<210> 765
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 765 gtggtacagg tcga
<210> 766
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 766 ggtacaggtc ga
<210> 767
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 767 ggtgtggtac aggtcg
<210> 768
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 768 gtgtggtaca ggtc
<210> 769
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 769 catggtgtgg tacagg
<210> 770
<211> 14
<212> ADN
<213> Secuencia Artificial
16
14
12
16
14
16
<220>
<223> Oligonucleótido Sintético
<400> 770 atggtgtggt acag
<210> 771
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 771 tacatggtgt ggtaca
<210> 772
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 772 acatggtgtg gtac
<210> 773
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 773 atgtacatgg tgtggt
<210> 774
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 774 tgtacatggt gtgg
<210> 775
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 775 gcctccatgt ac
<210> 776
14
16
14
16
14
12
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 776 agcttcacca gg
<210> 777
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 777 gttcacctcc ag
<210> 778
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 778 catgccccag ccgccg
<210> 779
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 779 atgccccagc cgcc
<210> 780
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 780 gatgagggtc ttcatg
<210> 781
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
12
12
16
14
16
<400> 781 gaccccggag taggca
<210> 782
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 782 atgctggagc cagtgc
<210> 783
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 783 tgctggagcc agtg
<210> 784
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 784 gtcttggagg gccg
<210> 785
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 785 cccaggtgtc agag
<210> 786
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 786 ttttccacct tggatc
<210> 787
<211> 14
<212> ADN
<213> Secuencia Artificial
16
16
14
14
14
16
<220>
<223> Oligonucleótido Sintético
<400> 787 tttccacctt ggat
<210> 788
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 788 tttttccacc ttggat
<210> 789
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 789 aggtgttttt ccacct
<210> 790
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 790 ggtgtttttc cacc
<210> 791
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 791 ccaggaagga taggac
<210> 792
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 792 caggaaggat agga
14
16
16
14
16
14

<210> 793 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 793 tgacactgca ggccac

16

<210> 794 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 794 gacactgcag gcca

14

<210> 795 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 795 acatgaggat gacact

16

<210> 796 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 796 catgaggatg acac

14

<210> 797 <211> 16 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 797 gcagaaggtg tacatg

16

<210> 798 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 798 cagaaggtgt acat
<210> 799
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 799 gcagtcagtg cagaag
<210> 800
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 800 cagtcagtgc agaa
<210> 801
<211> 16
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 801 acacggccca gtttcg
<210> 802
<211> 14
<400> 659 gcagggtgcc ttgg
<210> 660
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 660 agcgcagggt gcct
<210> 661
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 661 gtggagcgca gggtgc
<210> 662
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 662 tggagcgcag ggtg
<210> 663
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
16
14
<220>
<223> Synthetic Oligonucleotide
<400> 663 tggtggagcg cagg
<210> 664
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 664 gcttggtgga gcgc
<210> 665
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 665 agagcttggt ggag
<210> 666
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 666 aaaagagctt ggtgga
<210> 667
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 667 aagagcttgg tgga
<210> 668
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 668 aaaagagctt ggtg
14
14
14
16
14
14

<210> 669 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 669 caaaaaagag cttg

14

<210> 670 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 670 aaggagctga ggaaca

16

<210> 671 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 671 ggagctgagg aaca

14

<210> 672 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 672 gcagaccctg gaagga

16

<210> 673 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 673 agaccctgga agga

14

<210> 674 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 674 accagcagac cctgga
<210> 675
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 675 actg
<210> 676
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 676 cagtagagaa cagcca
<210> 677
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 677 gtagagaaca gcca
<210> 678
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 678 tgttgaggaa acagta
<210> 679
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 679 ttgaggaaac agta
<210> 680
<211> 16
<212> DNA
16
4
16
14
16
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 680 cctgcacctc cttgtt
<210> 681
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 681 atgagggtct tcat
<210> 682
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 682 accccggagt aggc
<210> 683
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 683 cccggagtag gc
<210> 684
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 684 caggaccccg gagtag
<210> 685
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 685 gcaggacccc ggagta
16
14
14
12
16
16
<210> 686
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 686 aggaccccgg agta
<210> 687
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 687 caggaccccg gagt
<210> 688
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 688 cagacccctc gc
<210> 689
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 689 agaggatgct gg
<210> 690
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 690 gagccaggtg acagag
<210> 691
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
14
14
12
12
16
<223> Synthetic Oligonucleotide
<400> 691 agccaggtga caga
<210> 692
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 692 tgagccaggt ga
<210> 693
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 693 ttttccacct tgga
<210> 694
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 694 ctgcaggcca ct
<210> 695
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 695 tcaccagctg gatggg
<210> 696
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 696 ttcaccagct ggatgg
<210> 697
<211> 14
14
12
14
12
16
16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 697 caccagctgg atgg
<210> 698
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 698 tcaccagctg gatg
<210> 699
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 699 tcaccagctg ga
<210> 700
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 700 tgtcttcacc agctgg
<210> 701
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 701 gtcttcacca gctg
<210> 702
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 702
14
14
12
16
14
gtgtgtcttc accagc
<210> 703
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 703 tgtgtcttca ccag
<210> 704
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 704 ttgtgtgtct tcacca
<210> 705
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 705 tgtgtgtctt cacc
<210> 706
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 706 aggttgtgtg tcttca
<210> 707
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 707 ggttgtgtgt cttc
<210> 708
<211> 16
<212> DNA
<213> Artificial Sequence
16
14
16
14
16
14
<220>
<223> Synthetic Oligonucleotide
<400> 708 gcaggttgtg tgtctt
<210> 709
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 709 caggttgtgt gtct
<210> 710
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 710 tcagcaggtt gtgtgt
<210> 711
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 711 cagcaggttg tgtg
<210> 712
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 712 ggtcagcagg ttgtgt
<210> 713
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 713 tggtcagcag gttgtg
<210> 714
16
14
16
14
16
16
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 714 gtcagcaggt tgtg
<210> 715
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 715 ggtcagcagg ttgt
<210> 716
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 716 ctggtggtca gcaggt
<210> 717
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 717 tggtggtcag cagg
<210> 718
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 718 ctggtggtca gc
<210> 719
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
16
14
12
<400> 719 agttcctggt ggtcag
<210> 720
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 720 gttcctggtg gtca
<210> 721
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 721 tatagttcct ggtggt
<210> 722
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 722 atagttcctg gtgg
<210> 723
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 723 gatatagttc ctggtg
<210> 724
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 724 atatagttcc tggt
<210> 725
<211> 16
<212> DNA
<213> Artificial Sequence
16
14
16
14
16
14
<220>
<223> Synthetic Oligonucleotide
<400> 725 ccaaagatat agttcc
<210> 726
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 726 tccaaagata tagttc
<210> 727
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 727 caaagatata gttc
<210> 728
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 728 ccaaagatat agtt
<210> 729
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 729 ccaggcccat ga
<210> 730
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 730 ggcacccagg cccatg
16
16
14
14
12
16
<210> 731
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 731 gcacccaggc ccat
<210> 732
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 732 cagaaggcac ccaggc
<210> 733
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 733 agaaggcacc cagg
<210> 734
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 734 ccagacatca gg
<210> 735
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 735 gacagggcag at
<210> 736
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
16
14
12
12
<400> 736 tgacagggca ga
<210> 737
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 737 ccactcccat tc
<210> 738
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 738 gccaggcatg gagctc
<210> 739
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 739 ccaggcatgg agct
<210> 740
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 740 ccaggcatgg ag
<210> 741
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 741 cagggtgact gc
<210> 742
<211> 16
<212> DNA
12
12
16
14
12
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 742 gttccgcagg gtgact
<210> 743
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 743 ttccgcaggg tgac
<210> 744
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 744 gcggttccgc agggtg
<210> 745
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 745 cggttccgca gggt
<210> 746
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 746 tcggccccag gagccc
<210> 747
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 747 cggccccagg agcc
16
14
16
14
16
14

<210> 748 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 748 ccatcggccc caggag

16

<210> 749 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 749 catcggcccc agga

14

<210> 750 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 750 gacccatcgg ccccag

16

<210> 751 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 751 acccatcggc ccca

14

<210> 752 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 752 ttctggaccc atcggc

16

<210> 753 <211> 12 <212> DNA <213> Artificial Sequence

<220>

<223> Synthetic Oligonucleotide
<400> 753 ggacccatcg gc
<210> 754
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 754 tctggaccca tcgg
<210> 755
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 755 caccagcccc caggtg
<210> 756
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 756 accagccccc aggt
<210> 757
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 757 tagggcacca gccccc
<210> 758
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 758 agggcaccag cccc
<210> 759
<211> 16
12
14
16
14
16
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 759 tggagtaggg caccag
<210> 760
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 760 ggagtagggc acca
<210> 761
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 761 cttggagtag gg
<210> 762
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 762 tgatgggctt ggagta
<210> 763
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 763 gatgggcttg gagt
<210> 764
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 764
16
14
12
16
14
tgtggtacag gtcgat
<210> 765
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 765 gtggtacagg tcga
<210> 766
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 766 ggtacaggtc ga
<210> 767
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 767 ggtgtggtac aggtcg
<210> 768
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 768 gtgtggtaca ggtc
<210> 769
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 769 catggtgtgg tacagg
<210> 770
<211> 14
<212> DNA
<213> Artificial Sequence
16
14
12
16
14
16
<220>
<223> Synthetic Oligonucleotide
<400> 770 atggtgtggt acag
<210> 771
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 771 tacatggtgt ggtaca
<210> 772
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 772 acatggtgtg gtac
<210> 773
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 773 atgtacatgg tgtggt
<210> 774
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 774 tgtacatggt gtgg
<210> 775
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 775 gcctccatgt ac
<210> 776
14
16
14
16
14
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 776 agcttcacca gg
<210> 777
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 777 gttcacctcc ag
<210> 778
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 778 catgccccag ccgccg
<210> 779
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 779 atgccccagc cgcc
<210> 780
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 780 gatgagggtc ttcatg
<210> 781
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
16
14
16
<400> 781 gaccccggag taggca
<210> 782
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 782 atgctggagc cagtgc
<210> 783
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 783 tgctggagcc agtg
<210> 784
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 784 gtcttggagg gccg
<210> 785
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 785 cccaggtgtc agag
<210> 786
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 786 ttttccacct tggatc
<210> 787
<211> 14
<212> DNA
<213> Artificial Sequence
16
16
14
14
14
16
<220>
<223> Synthetic Oligonucleotide
<400> 787 tttccacctt ggat
<210> 788
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 788 tttttccacc ttggat
<210> 789
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 789 aggtgttttt ccacct
<210> 790
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 790 ggtgtttttc cacc
<210> 791
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 791 ccaggaagga taggac
<210> 792
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 792 caggaaggat agga
14
16
16
14
16
14

<210> 793 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 793 tgacactgca ggccac

16

<210> 794 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 794 gacactgcag gcca

14

<210> 795 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 795 acatgaggat gacact

16

<210> 796 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 796 catgaggatg acac

14

<210> 797 <211> 16 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 797 gcagaaggtg tacatg

16

<210> 798 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 798 cagaaggtgt acat
<210> 799
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 799 gcagtcagtg cagaag
<210> 800
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 800 cagtcagtgc agaa
<210> 801
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 801 acacggccca gtttcg
<210> 802
<211> 14

<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 802 cacggcccag tttc
<210> 803
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 803 ggcccatgat gccatg
<210> 804
<211> 14
<212> DNA
14
16
14
16
14
16
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 804 gcccatgatg ccat
<210> 805
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 805 tacagaaggc acccag
<210> 806
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 806 acagaaggca ccca
<210> 807
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 807 gaagttgcca gccaat
<210> 808
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 808 aagttgccag ccaa
<210> 809
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 809 cagggcagat cctt
14
16
14
16
14
14
<210> 810
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 810 caagtagtct atggtg
<210> 811
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 811 aagtagtcta tggt
<210> 812
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 812 tggaaagcaa gtagtc
<210> 813
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 813 ggaaagcaag tagt
<210> 814
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 814 ggccagcttt acaaag
<210> 815
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
16
14
16
14
16
<223> Synthetic Oligonucleotide
<400> 815 gccagcttta caaa
<210> 816
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 816 cgcagggcca gctt
<210> 817
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 817 aaaggaatag gtggga
<210> 818
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 818 aaggaatagg tggg
<210> 819
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 819 gcgaaaccaa tatact
<210> 820
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 820 cgaaaccaat atac
<210> 821
<211> 16
14
14
16
14
16
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 821 ccccaggtgt cagagg
<210> 822
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 822 actg
<210> 823
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 823 gattgtcaaa gagctt
<210> 824
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 824 attgtcaaag agct
<210> 825
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 825 ttggtcttgt gattgt
<210> 826
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 826
16
4
16
14
16
tggtcttgtg attg
<210> 827
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 827 aaggccgaat ttggtc
<210> 828
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 828 aggccgaatt tggt
<210> 829
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 829 aatccgactg tg
<210> 830
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 830 aatttaatcc ga
<210> 831
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 831 accttcgatc acag
<210> 832
<211> 12
<212> DNA
<213> Artificial Sequence
14 16
14
12
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 832 actgatcctg ca
<210> 833
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 833 actgtggtca aa
<210> 834
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 834 agccgcccag tt
<210> 835
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 835 agccttgtcg at
<210> 836
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 836 agttcccagc ct
<210> 837
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 837 atccgactgt gg
<210> 838
12
12
12
12
12
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 838 atcctgcact ga
<210> 839
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 839 atttaatccg ac
<210> 840
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 840 caatttaatc cg
<210> 841
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 841 cactgacgag tc
<210> 842
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 842 cactgatcct gc
<210> 843
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12
12
<400> 843 cagccttgtc ga
<210> 844
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 844 cagttcccag cc
<210> 845
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 845 ccactgatcc tg
<210> 846
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 846 ccagccttgt cg
<210> 847
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 847 ccagttccca gc
<210> 848
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 848 cccagccttg tc
<210> 849
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 849 cccagttccc ag
<210> 850
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 850 ccgcccagtt cc
<210> 851
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 851 cctgcactga cg
<210> 852
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 852 ccttggaatg tctg
<210> 853
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 853 ccttgtcgat ct
<210> 854
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 854 cgactgtggt ca
12
12
12
14
12
12
<210> 855
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 855 cgcccagttc cc
<210> 856
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 856 ctgatcctgc ac
<210> 857
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 857 ctgcactgac ga
<210> 858
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 858 ctgtggtcaa aa
<210> 859
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 859 cttgtcgatc tc
<210> 860
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12
12
<400> 860 gatcctgcac tg
<210> 861
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 861 gcaatttaat cc
<210> 862
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 862 gcactgacga gt
<210> 863
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 863 gcccagttcc ca
<210> 864
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 864 gccgcccagt tc
<210> 865
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 865 gccttgtcga tc
<210> 866
<211> 12
<212> DNA
12
12
12
12
12
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 866 ggtcaaaagg gc
<210> 867
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 867 ggtcatgcac aggc
<210> 868
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 868 gtcgatctcc tc
<210> 869
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 869 gtggtcaaaa gg
<210> 870
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 870 gttcccagcc tt
<210> 871
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 871 taatccgact gt
12
14
12
12
12
12
<210> 872
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 872 tattccatgg ccat
<210> 873
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 873 tcaggtcatg poop
<210> 874
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 874 tcccagcctt gt
<210> 875
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 875 tccgactgtg gt
<210> 876
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 876 tcctgcactg ac
<210> 877
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
14
14
12
12
12
<223> Synthetic Oligonucleotide
<400> 877 tcgatctcct cg
<210> 878
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 878 tgatcctgca ct
<210> 879
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 879 tgcaatttaa tc
<210> 880
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 880 tgcactgacg ag
<210> 881
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 881 tggtcaaaag gg
<210> 882
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 882 tgtcgatctc ct
<210> 883
<211> 12
12
12
12
12
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 883 tgtggtcaaa ag
<210> 884
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 884 ttaatccgac tg
<210> 885
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 885 ttcccagcct tg
<210> 886
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 886 ttgtcgatct cc
<210> 887
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 887 tttaatccga ct
<210> 888
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 888
12
12
12
12
12
gactgtggtc aa
<210> 889
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 889 ccgactgtgg tc
<210> 890
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 890 cccagtgggt ttga
<210> 891
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 891 ttcttgatgt cc
<210> 892
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 892 gactccaaag tc
<210> 893
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 893 tcctgcactg acgagt
<210> 894
<211> 16
<212> DNA
<213> Artificial Sequence
12
12
14
12
12
16
<220>
<223> Synthetic Oligonucleotide
<400> 894 cactgatcct gcactg
<210> 895
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 895 cttccactga tcctta
<210> 896
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 896 gaaagctcct tccact
<210> 897
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 897 ggcagtcttt atcc
<210> 898
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 898 ctggtaaata gc
<210> 899
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 899 ctacctgagg attt
<210> 900
16
16
16
14
12
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 900 cccagtacta cctg
<210> 901
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 901 tgttccctct ac
<210> 902
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 902 tattcctgga aaac
<210> 903
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 903 caagaagtgt ggtt
<210> 904
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 904 gtgaaaatgc tggc
<210> 905
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
12
14
14
14
<400> 905 aggaggttaa acca
<210> 906
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 906 tggatgattg gc
<210> 907
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 907 caaaaggatc cc
<210> 908
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 908 atgtcaaccg gc
<210> 909
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 909 tcagccagac ag
<210> 910
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 910 taagtgtccc tttg
<210> 911
<211> 14
<212> DNA
<213> Artificial Sequence
14
12
12
12
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 911 ctaaatttag ttca
<210> 912
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 912 gactacattt taca
<210> 913
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 913 cagtaaggaa tttt
<210> 914
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 914 tgtgtccctc agtc
<210> 915
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 915 ccgttggacc cc
<210> 916
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 916 gacagcttct ataa
14
14
14
14
12
14
<210> 917
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 917 agtgactgac poop
<210> 918
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 918 gtagcataga gcct
<210> 919
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 919 cagatcttgt caag
<210> 920
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 920 gtaagaggca gg
<210> 921
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 921 ccatggcggg ac
<210> 922
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
12
12
<400> 922 gcttacgatt gt
<210> 923
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 923 ccagcacact ggaa
<210> 924
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 924 gtcagtccca gcta
<210> 925
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 925 ttagtatgac agct
<210> 926
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 926 tcagtgtagg aaga
<210> 927
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 927 tgaatataca gatg
<210> 928

<211> 12
<212> DNA
12 14
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 928 cccgccacca cc
<210> 929
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 929 ttgttccctc ta
<210> 930
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 930 tctacctgag tcca
<210> 931
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 931 aacatcaagc ttga
<210> 932
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 932 gatcaccttc agag
<210> 933
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 933 tgaacacatc minutes
12
12
14
14
14
14
<210> 934
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 934 tttcctcttg tc
<210> 935
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 935 taattgatgt caat
<210> 936
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 936 agtaattgat gtca
<210> 937
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 937 acagtaattg atgt
<210> 938
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 938 ttacagtaat tgat
<210> 939
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
12
14
14
14
14
<223> Synthetic Oligonucleotide
<400> 939 acttacagta attg
<210> 940
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 940 agacttacag taat
<210> 941
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 941 tcagacttac agta
<210> 942
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 942 aatcagactt acag
<210> 943
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 943 tgaatcagac ttac
<210> 944
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 944 aatgaatcag actt
<210> 945
<211> 14
14
14
14
14
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 945 tgcaggatgt tgag
<210> 946
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 946 ctggtcagca ttga
<210> 947
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 947 caaagtccct tagc
<210> 948
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 948 atttctctta cagg
<210> 949
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 949 ttaacgagcc tt
<210> 950
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 950
14
14
14
14
12
cgacacggga ac
<210> 951
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 951 caagtaggat gt
<210> 952
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 952 gttccctttg cagg
<210> 953
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 953 attagccata tctc
<210> 954
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 954 agcattcagc agtg
<210> 955
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 955 ttccctctac ac
<210> 956
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
14
14
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 956 tccctctaca cc
<210> 957
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 957 ctacaggaca atac
<210> 958
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 958 aactgggtta agta
<210> 959
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 959 tgaacacgct atcc
<210> 960
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 960 tttccacttg ggtg
<210> 961
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 961 tctacaccag gt
<210> 962
12
14
14
14
14
12
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 962 gaaagctcct tcca
<210> 963
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 963 aggtaggaga ag
<210> 964
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 964 acccagtcag gg
<210> 965
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 965 atgtcattaa ac
<210> 966
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 966 gaggtgggaa aa
<210> 967
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
12
12
12
12
<400> 967 tttcctagga ggtg
<210> 968
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 968 gttcttagga ag
<210> 969
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 969 ctctacacca gg
<210> 970
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 970 tgtttttaca caga
<210> 971
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 971 tggcttcatg tc
<210> 972
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 972 ttgttcttag gaag
<210> 973
<211> 12
<212> DNA
<213> Artificial Sequence
14
12
12
14
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 973 tacaccaggt ca
<210> 974
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 974 tgagctacag tagg
<210> 975
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 975 ggctgacatt ca
<210> 976
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 976 tggtcaactg aaag
<210> 977
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 977 tagtcattat ct
<210> 978
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 978 ccatttttat ca
12
14
12
14
12
12
<210> 979
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 979 gggcttcttc catt
<210> 980
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 980 ggtgtggata acag
<210> 981
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 981 tcataactat taag
<210> 982
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 982 cctctacacc ag
<210> 983
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 983 cagcttaggc agag
<210> 984
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
12
14
<400> 984 tcattcccca ct
<210> 985
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 985 ctcccacacc at
<210> 986
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 986 ttctgctccc ac
<210> 987
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 987 cagagaaggt ct
<210> 988
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 988 gtatgcactg ct
<210> 989
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 989 caatgaagca cagg
<210> 990
<211> 12
<212> DNA
12
12
12
12
12 14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 990 tcccaaacaa at
<210> 991
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 991 attcttaaca caga
<210> 992
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 992 cgggtactat gg
<210> 993
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 993 ctacaccagg tc
<210> 994
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 994 tatagctcct ct
<210> 995
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 995 catttagggt ctaa
12
14
12
12
12
14
<210> 996
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 996 atcttcagag at
<210> 997
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 997 ttgatatagt ca
<210> 998
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 998 taatatgact tg
<210> 999
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 999 agccgcctga agtg
<210> 1000
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1000 ccccagcagc gg
<210> 1001
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
12
12
12
14
12
<223> Synthetic Oligonucleotide
<400> 1001 tccttccact ga
<210> 1002
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1002 cggtttttgt tc
<210> 1003
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1003 taaatcctct agca
<210> 1004
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1004 gttccctcta ca
<210> 1005
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1005 acaccatctc cc
<210> 1006
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1006 gctccttcca ct
<210> 1007
<211> 14
12
12
14
12
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1007 cactgatcct gcac
<210> 1008
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1008 tcggactttg aa
<210> 1009
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1009 tcggactttg aaaa
<210> 1010
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1010 atcagccaga caga
<210> 1011
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1011 catcagcaag aggc
<210> 1012
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1012
14
12
14
14
14
ttgttcttag ga
<210> 1013
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1013 gccagacaga ag
<210> 1014
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1014 ttgtcgatct gc
<210> 1015
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1015 ggagaagcgc agct
<210> 1016
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1016 ggagaagcgc ag
<210> 1017
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1017 ctgcactgac gagt
<210> 1018
<211> 12
<212> DNA
<213> Artificial Sequence
12 12
12
14
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 1018 ctgcaacatg at
<210> 1019
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1019 ctgatcctta gaag
<210> 1020
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1020 ccttccactg atcctg
<210> 1021
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1021 ctccttccac tg
<210> 1022
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1022 tgcagccatg tact
<210> 1023
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1023 cgtttgggtg gc
<210> 1024
12
14
16
12
14
12
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1024 tccactgatc ctgc
<210> 1025
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1025 ttccactgat cctg
<210> 1026
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1026 tccactgatc ct
<210> 1027
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1027 cttccactga tcct
<210> 1028
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1028 tccttccact gatcct
<210> 1029
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
12
14
16
<400> 1029 ttccactgat cc
<210> 1030
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1030 ctccttccac tgatcc
<210> 1031
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1031 tccttccact gatc
<210> 1032
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1032 gctccttcca ctgatc
<210> 1033
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1033 gctccttcca ctga
<210> 1034
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1034 aagctccttc cactga
<210> 1035
<211> 14
<212> DNA
<213> Artificial Sequence
12
16
14
16
14
16
<220>
<223> Synthetic Oligonucleotide
<400> 1035 aagctccttc cact
<210> 1036
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1036 agctccttcc ac
<210> 1037
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1037 gggaaagctc cttcca
<210> 1038
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1038 ttgcaatgtc tggc
<210> 1039
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1039 gatttatctg gctg
<210> 1040
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1040 aagggccctg gg
14
12
16
14
14
12
<210> 1041
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1041 aacttcagtg tc
<210> 1042
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1042 agggcttcca gt
<210> 1043
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1043 aggaagggct tc
<210> 1044
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1044 ccttccactg at
<210> 1045
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1045 ggaaacatac cctg
<210> 1046
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12 14
<400> 1046 ccttccactg atcc
<210> 1047
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1047 cttccactga tc
<210> 1048
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1048 gaataggtta aggc
<210> 1049
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1049 aacaatgtgt tgta
<210> 1050
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1050 ccctctacac ca
<210> 1051
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1051 gcacacagct gagg
<210> 1052
<211> 14
<212> DNA
14
12
14
14
12
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1052 gtgcacacag ctga
<210> 1053
<211> 14
<212> DNA
<213> Artificial Sequence

<220>
<223> Synthetic Oligonucleotide
<400> 1053 cagtgtgcac acag
<210> 1054
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1054 ctcagtgtgc acac
<210> 1055
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1055 cacccactgg tg
<210> 1056
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1056 catttccatg gcca
<210> 1057
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1057 accaaacagt tcag
14
14
14
12
14
14
<210> 1058
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1058 ttgaccagga ag
<210> 1059
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1059 caggccatgt gg
<210> 1060
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1060 agtcaggcca tgtg
<210> 1061
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1061 gcgcgagccc ga
<210> 1062
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1062 tgtgaggctc ca
<210> 1063
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
12
12
14
12
12
<223> Synthetic Oligonucleotide
<400> 1063 ccctgaaggt tc
<210> 1064
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1064 tttgataaag ccct
<210> 1065
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1065 caagaagacc ttac
<210> 1066
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1066 tgcacaggca ggtt
<210> 1067
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1067 acagccaggt ag
<210> 1068
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1068 tggaaaactg cacc
<210> 1069
<211> 12
12
14
14
14
12
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1069 tgggtggccg gg
<210> 1070
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1070 gggcttcttc ca
<210> 1071
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1071 gctgacatct cg
<210> 1072
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1072 cagcctggca ccta
<210> 1073
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1073 taaaaacaac aa
<210> 1074
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1074
12
12
12
14
12
tttataaaac tg
<210> 1075
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1075 actg
<210> 1076
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1076 agtaaatatt ggct
<210> 1077
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1077 gttgagcatg ac
<210> 1078
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1078 gtgcgctccc at
<210> 1079
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1079 tcctgcactg acga
<210> 1080
<211> 16
<212> DNA
<213> Artificial Sequence
12
4
14
12
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 1080 gatcctgcac tgacga
<210> 1081
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1081 gatcctgcac tgac
<210> 1082
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1082 ctgatcctgc actgac
<210> 1083
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1083 tccactgatc ctgcac
<210> 1084
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1084 cgcgagatat ctaa
<210> 1085
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1085 cgcacctggt aaat
<210> 1086
16
14
16
16
14
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1086 gttcaagcgg ccta
<210> 1087
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1087 ccctttacac aagt
<210> 1088
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1088 ctcaaaatag attt
<210> 1089
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1089 cacatgagct attc
<210> 1090
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1090 gtgaagtgag tcat
<210> 1091
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
14
<400> 1091 ggtcactcaa gatg
<210> 1092
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1092 ggactcactc agca
<210> 1093
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1093 tcagggctac tcat
<210> 1094
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1094 cagcactaga ttca
<210> 1095
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1095 tagcttaatg taac
<210> 1096
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1096 ttgtgacatc tagg
<210> 1097
<211> 14
<212> DNA
<213> Artificial Sequence
14
14
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 1097 gtgcctagca caga
<210> 1098
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1098 cagcctacca gt
<210> 1099
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1099 acatgtcagt aatt
<210> 1100
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1100 ctcatggaca caaa
<210> 1101
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1101 ggaagttttc aagt
<210> 1102
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1102 gaatctggag gtaa
14
12
14
14
14
14
<210> 1103
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1103 agccccttgg ccgt
<210> 1104
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1104 gaatacttca aatc
<210> 1105
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1105 ctgatcctgc actg
<210> 1106
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1106 tttgaggagc tatt
<210> 1107
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1107 ttgttgttcc ct
<210> 1108
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
14
12
<400> 1108 gagttgttgt tc
<210> 1109
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1109 cgagttgttg tt
<210> 1110
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1110 gcgctaggcc gc
<210> 1111
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1111 gttgttgttc cc
<210> 1112
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1112 agttgttgtt cc
<210> 1113
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1113 ctcaccttca tg
<210> 1114
<211> 14
<212> DNA
12
12
12
12
12
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1114 cttagaaggc agca
<210> 1115
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1115 gttgttccct ct
<210> 1116
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1116 ccaactccaa ct
<210> 1117
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1117 gatctctcga gt
<210> 1118
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1118 aatgcaggat ct
<210> 1119
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1119 ctcggacttt ga
14
12
12
12
12
12
<210> 1120
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1120 tgactctcgg ac
<210> 1121
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1121 cttgtccatc ag
<210> 1122
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1122 gggtctttcc tc
<210> 1123
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1123 cactgatcct tagaag
<210> 1124
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1124 cactgatcct taga
<210> 1125
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
12
12
12
16
14
<223> Synthetic Oligonucleotide
<400> 1125 tccactgatc cttaga
<210> 1126
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1126 cttccactga tcctgc
<210> 1127
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1127 tccactgatc ctta
<210> 1128
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1128 cagtggacca ca
<210> 1129
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1129 tgcgagttgt tg
<210> 1130
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1130 aaagtcaggc ca
<210> 1131
<211> 14
16
16
14
12
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1131 taacttcagt gtct
<210> 1132
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1132 gaagggcttc cagt
<210> 1133
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1133 tgaccaggaa gggc
<210> 1134
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1134 aggccctgag atta
<210> 1135
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1135 ggttaaggcc ctga
<210> 1136
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1136
14
14
14
14
14
ggaatgtctg agtt
<210> 1137
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1137 taatgacctg atga
<210> 1138
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1138 tgaagttaat tc
<210> 1139
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1139 gaaattgagg aa
<210> 1140
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1140 gtattcaagt aa
<210> 1141
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1141 acaattatgg ca
<210> 1142
<211> 12
<212> DNA
<213> Artificial Sequence
14
14
12
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 1142 cagtttattc aa
<210> 1143
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1143 gaagctgctg gt
<210> 1144
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1144 gtgaaacatt tt
<210> 1145
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1145 aaaagtgaaa catt
<210> 1146
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1146 ttcttaaagg tg
<210> 1147
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1147 gcacaaattt tc
<210> 1148
12
12
12
14
12
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1148 gtttagtgca ca
<210> 1149
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1149 tctggatcag ag
<210> 1150
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1150 tgctgcacat cc
<210> 1151
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1151 tctgactggg aa
<210> 1152
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1152 acaaagagtc cc
<210> 1153
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
12
12
<400> 1153 agagagctga gc
<210> 1154
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1154 tggcctcaca gc
<210> 1155
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1155 ggaccgcagc cg
<210> 1156
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1156 gttagaacag ac
<210> 1157
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1157 cctgaaactg ca
<210> 1158
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1158 tgctcacagg cg
<210> 1159
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 1159 agagagcaac tc
<210> 1160
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1160 atggctgctg cg
<210> 1161
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1161 catggctgca gc
<210> 1162
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1162 cttggccctg gacc
<210> 1163
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1163 gctagcctct gga
<210> 1164
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1164 tggccctgga cc
12
12
12
14
13
12
<210> 1165
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1165 tttctgcagg aa
<210> 1166
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1166 tacaggtcaa gtct
<210> 1167
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1167 acaggtcaag tc
<210> 1168
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1168 ttggataaat atct
<210> 1169
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1169 tggataaata tc
<210> 1170
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
14
12
14
12
<400> 1170 ttctgcagga tg
<210> 1171
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1171 caccttcaag tc
<210> 1172
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1172 catagattgt at
<210> 1173
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1173 gtcagaatat ct
<210> 1174
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1174 tctgcagtta aa
<210> 1175
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1175 atcttgtgaa ac
<210> 1176
<211> 12
<212> DNA
12
12
12
12
12
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1176 tcatcaaaag gt
<210> 1177
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1177 ctttgtcaag at
<210> 1178
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1178 tatgcacaaa tc
<210> 1179
<211> 12

<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1179 taatccaggt ga
<210> 1180
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1180 cacacaggca at
<210> 1181
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1181 ttgagcatct tg
12
12
12
12
12
12
<210> 1182
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1182 cattttgtcc tttt
<210> 1183
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1183 gatttcctga tc
<210> 1184
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1184 ctggatttga tggct
<210> 1185
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1185 tctggatttg atggc
<210> 1186
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1186 tggacttggc gg
<210> 1187
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
14
12
fifteen
fifteen
12
<223> Synthetic Oligonucleotide
<400> 1187 ctctggattt gatgg
<210> 1188
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1188 cctctggatt tgatg
<210> 1189
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1189 gcctctggat ttgat
<210> 1190
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1190 tttagcctct ggattt
<210> 1191
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1191 tctagcctct ggattt
<210> 1192
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1192 agtagttgta ct
<210> 1193
<211> 12
fifteen
fifteen
fifteen
16
16
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1193 tctggagtca ca
<210> 1194
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1194 gtcataatgt ct
<210> 1195
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1195 gtgtcataat gtct
<210> 1196
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1196 cttcaaaagg at
<210> 1197
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1197 gtcttcaaaa gg
<210> 1198
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1198
12
12
14
12
12
atcctcttga ta
<210> 1199
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1199 gtgcctttaa aa
<210> 1200
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1200 tgtcataatg tc
<210> 1201
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1201 caatctgaca ca
<210> 1202
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1202 aatattgttc ct
<210> 1203
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1203 gtcaggagaa ga
<210> 1204
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
12 12
<220>
<223> Synthetic Oligonucleotide
<400> 1204 tgtcaaaacc ac
<210> 1205
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1205 gtcctattgc ca
<210> 1206
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1206 aggtatatac at
<210> 1207
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1207 cagctggtga ca
<210> 1208
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1208 ttcacttagc ca
<210> 1209
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1209 aaccctgcag aa
<210> 1210
12
12
12
12
12
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1210 tgtcaaaacc ct
<210> 1211
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1211 gtgtcaaaac cc
<210> 1212
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1212 atggtccaga gccc
<210> 1213
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1213 tggtccagag cc
<210> 1214
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1214 tgggttatgg tc
<210> 1215
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
14
12
12
<400> 1215 caaagaatgg tg
<210> 1216
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1216 gtttagcatg ct
<210> 1217
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1217 tgcctttaaa aa
<210> 1218
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1218 accaatatgc tc
<210> 1219
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1219 caccaataag tt
<210> 1220
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1220 cctttagctg gc
<210> 1221
<211> 12
<212> DNA
<213> Artificial Sequence
12
12
12
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 1221 gttgaaagcc tc
<210> 1222
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1222 tttgatgatg gc
<210> 1223
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1223 tcattgtcaa at
<210> 1224
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1224 ttacaactga ga
<210> 1225
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1225 agatggagca gt
<210> 1226
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1226 cttagcactg gcct
12
12
12
12
12
14
<210> 1227
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1227 agagtatctg aa
<210> 1228
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1228 actgatgtag gg
<210> 1229
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1229 ccacagtagg ta
<210> 1230
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1230 ctggcagcca gcac
<210> 1231
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1231 tggcagccag ca
<210> 1232
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
12
12
14
12
<400> 1232 gcatcatcaa tc
<210> 1233
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1233 aaatcattgt ca
<210> 1234
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1234 gcaaaactca tt
<210> 1235
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1235 tgtgcaactc tgca
<210> 1236
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1236 gtgcaactct gc
<210> 1237
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1237 aatattcatg ta
<210> 1238
<211> 12
<212> DNA
12
12
12
14
12
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1238 ggattgcaag tt
<210> 1239
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1239 ataaagcatc tg
<210> 1240
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1240 ccactgaaca tt
<210> 1241
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1241 gaagccctaa tc
<210> 1242
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1242 taaattgtat gc
<210> 1243
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1243 aagatcttca ca
12
12
12
12
12
12
<210> 1244
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1244 caagatcttc ac
<210> 1245
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1245 atgtcaaggt ca
<210> 1246
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1246 ataatggctg ga
<210> 1247
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1247 agcaccaata tgct
<210> 1248
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1248 gcaccaatat gc
<210> 1249
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
12
12
12
14
12
<223> Synthetic Oligonucleotide
<400> 1249 tggcagacca ca
<210> 1250
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1250 tcctatgcaa tc
<210> 1251
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1251 tataaatgct tc
<210> 1252
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1252 gtcaaattct at
<210> 1253
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1253 ttcaggctaa tc
<210> 1254
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1254 ctgatgaggt at
<210> 1255
<211> 12
12
12
12
12
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1255 ggtgtcagaa ta
<210> 1256
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1256 tttgaaagac ac
<210> 1257
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1257 actg
<210> 1258
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1258 tgcaacagcc ca
<210> 1259
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1259 aaagagtccc gcca
<210> 1260
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1260
12
12
4
12
14
aagagtcccg cc
<210> 1261
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1261 tccgagagga gaga
<210> 1262
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1262 ccgagaggag ag
<210> 1263
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1263 tcatggctgc agct
<210> 1264
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1264 acagcggctc aact
<210> 1265
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1265 cagcggctca ac
<210> 1266
<211> 14
<212> DNA
<213> Artificial Sequence
12
14
12
14
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 1266 ggtgacaggc gact
<210> 1267
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1267 gtgacaggcg ac
<210> 1268
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1268 atggtgacag gc
<210> 1269
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1269 agaggcctgg ca
<210> 1270
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1270 ctggatggtt gc
<210> 1271
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1271 aatggctgct gcgg
<210> 1272
14
12
12
12
12
14
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1272 ccgggtaatg gc
<210> 1273
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1273 tggaccgcag ccgg
<210> 1274
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1274 tgatgcccct cgct
<210> 1275
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1275 gatgcccctc gc
<210> 1276
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1276 ctggacttgg cggt
<210> 1277
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
14
14
12
14
<400> 1277 ggaaatggct ctgg
<210> 1278
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1278 gaaatggctc tg
<210> 1279
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1279 agaagctgct ggtg
<210> 1280
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1280 gatggcagaa gc
<210> 1281
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1281 agagagatgg caga
<210> 1282
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1282 gagagatggc ag
<210> 1283
<211> 14
<212> DNA
<213> Artificial Sequence
14
12
14
12
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 1283 gtggctgaag aaaa
<210> 1284
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1284 tggctgaaga aa
<210> 1285
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1285 atgtctggga gcct
<210> 1286
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1286 tgtctgggag cc
<210> 1287
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1287 atgatggctg tcat
<210> 1288
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1288 tgatgatggc tg
14
12
14
12
14
12
<210> 1289
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1289 ctttgatgat ggct
<210> 1290
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1290 acgatctctt tgat
<210> 1291
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1291 tgtttctgct aacg
<210> 1292
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1292 gtttctgcta ac
<210> 1293
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1293 tttgtttctg ctaa
<210> 1294
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
14
12
14
<400> 1294 cttgatatct cctt
<210> 1295
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1295 catcctcttg atat
<210> 1296
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1296 aatccatcct cttg
<210> 1297
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1297 gaatccatcc tc
<210> 1298
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1298 gtctaagtcg aatc
<210> 1299
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1299 caagtctaag tc
<210> 1300
<211> 12
<212> DNA
14
14
14
12
14
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1300 aggtcaagtc ta
<210> 1301
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1301 cgcagaaatg cat
<210> 1302
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1302 gcagaaatgg at
<210> 1303
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1303 ttcgcatccg tcta
<210> 1304
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1304 tcgcatccgt ct
<210> 1305

<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1305 ccctaggttg aata
12
14
12
14
12
14
<210> 1306
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1306 cctaggttga at
<210> 1307
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1307 gttatgcaaa tcag
<210> 1308
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1308 ttatgcaaat ca
<210> 1309
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1309 tgactcagta aatt
<210> 1310
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1310 gactcagtaa at
<210> 1311
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
12
14
12
14
12
<223> Synthetic Oligonucleotide
<400> 1311 ttaaaattct tggg
<210> 1312
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1312 taaaattctt gg
<210> 1313
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1313 cctaactttt agac
<210> 1314
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1314 ctaactttta ga
<210> 1315
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1315 acctgaaact gcaa
<210> 1316
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1316 gtgtcaaaac cact
<210> 1317
<211> 14
14
12
14
12
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1317 cctattccca ctga
<210> 1318
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1318 ctattcccac tg
<210> 1319
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1319 cccatagcaa taat
<210> 1320
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1320 ccatagcaat aa
<210> 1321
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1321 atcccatagc aa
<210> 1322
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1322
14
12
14
12
12
tctgcaggaa atcc
<210> 1323
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1323 ctgcaggaaa tc
<210> 1324
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1324 ttctgcagga aatc
<210> 1325
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1325 ccttcaagtc tttc
<210> 1326
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1326 ttgttcctgt atac
<210> 1327
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1327 caatattgtt cctg
<210> 1328
<211> 12
<212> DNA
<213> Artificial Sequence
14
12
14
14
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 1328 caatattgtt cc
<210> 1329
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1329 acatcatcaa tatt
<210> 1330
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1330 ctttgaatcc aaaa
<210> 1331
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1331 tttgaatcca aa
<210> 1332
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1332 tatgctttga atcc
<210> 1333
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1333 ttgtaatggt tttt
<210> 1334
12
14
14
12
14
14
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1334 atcttgtaat gg
<210> 1335
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1335 agattgtata tctt
<210> 1336
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1336 cggtgtcata atgt
<210> 1337
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1337 aaatttggcg gtgt
<210> 1338
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1338 ttaaatttgg cggt
<210> 1339
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
14
14
14
14
<400> 1339 taaatttggc gg
<210> 1340
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1340 tcttcaaaag cat
<210> 1341
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1341 tggtcttcaa aa
<210> 1342
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1342 gtgggttatg gtct
<210> 1343
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1343 aagttctagc tgtg
<210> 1344
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1344 ataagttcta gc
<210> 1345
<211> 14
<212> DNA
<213> Artificial Sequence
12
14
12
14
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 1345 aagggtttga taag
<210> 1346
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1346 tcaagatctt poop
<210> 1347
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1347 agccattggt caag
<210> 1348
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1348 tcttcactta gcca
<210> 1349
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1349 tgctgcaaca tgat
<210> 1350
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1350 gctgcaacat ga
14
14
14
14
14
12
<210> 1351
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1351 ttacagtgaa ttgc
<210> 1352
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1352 ccagctttac ag
<210> 1353
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1353 cattacacca gt
<210> 1354
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1354 atcattacac cagt
<210> 1355
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1355 tcattacacc ag
<210> 1356
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
12
12
14
12
<400> 1356 aataaatatg poop
<210> 1357
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1357 tgtgccttta aaaa
<210> 1358
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1358 ttgtgccttt aaaa
<210> 1359
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1359 gggcctcttg tgcc
<210> 1360
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1360 ccttacttcc ccat
<210> 1361
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1361 ctctggtcct tact
<210> 1362
<211> 16
<212> DNA
14
14
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1362 gtctctggtc cttact
<210> 1363
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1363 tctctggtcc ttac
<210> 1364
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1364 cctctgactg ggaa
<210> 1365
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1365 catagcgcct ctga
<210> 1366
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1366 caggtagcta taat
<210> 1367
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1367 caggtagcta ta
16
14
14
14
14
12
<210> 1368
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1368 tcatcttgtg aaac
<210> 1369
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1369 catcttgtga aa
<210> 1370
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1370 gtttcaaaca tcat
<210> 1371
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1371 tagtttcaaa catc
<210> 1372
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1372 agtttcaaac at
<210> 1373
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
14
12
14
14
12
<223> Synthetic Oligonucleotide
<400> 1373 gaatagtttc aa
<210> 1374
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1374 cattggaata gttt
<210> 1375
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1375 cactgaacat tgga
<210> 1376
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1376 actgaacatt gg
<210> 1377
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1377 ccgccactga acat
<210> 1378
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1378 cagaccacaa actg
<210> 1379
<211> 12
12
14
14
12
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1379 agaccacaaa ct
<210> 1380
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1380 ctggcagacc acaa
<210> 1381
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1381 agctggcaga ccac
<210> 1382
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1382 acctttagct ggca
<210> 1383
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1383 tcttcacctt tagc
<210> 1384
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1384
12
14
14
14
14
tcaaagtaca tg
<210> 1385
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1385 gaactcaaag taca
<210> 1386
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1386 ggaactcaaa gt
<210> 1387
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1387 agggaactca aagt
<210> 1388
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1388 gggaactcaa ag
<210> 1389
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1389 gctgagggaa ctca
<210> 1390
<211> 14
<212> DNA
<213> Artificial Sequence
12
14
12
14
12
14
<220>
<223> Synthetic Oligonucleotide
<400> 1390 tcaccacaca cagg
<210> 1391
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1391 gaactctact ttga
<210> 1392
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1392 gaagaactct ac
<210> 1393
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1393 gtggaagaac tcta
<210> 1394
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1394 tggaagaact ct
<210> 1395
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1395 tgtttgtgga agaa
<210> 1396
14
14
12
14
12
14
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1396 catcttgttc tgtt
<210> 1397
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1397 agtgaaacat tttg
<210> 1398
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1398 ttacccaaaa gt
<210> 1399
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1399 tatttaccca aaag
<210> 1400
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1400 gtatttaccc aaaa
<210> 1401
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
14
12
14
14
<400> 1401 tatttaccca aa
<210> 1402
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1402 tcctggtatg aaga
<210> 1403
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1403 cctggtatga ag
<210> 1404
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1404 ggtcctggta tg
<210> 1405
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1405 ttcctctggt cctg
<210> 1406
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1406 aggtttcctc tggt
<210> 1407
<211> 12
<212> DNA
<213> Artificial Sequence
12
14
12
12
14
14
<220>
<223> Synthetic Oligonucleotide
<400> 1407 ggtttcctct gg
<210> 1408
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1408 ttttctgagg tttc
<210> 1409
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1409 agacttccat tttc
<210> 1410
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1410 agacttccat tt
<210> 1411
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1411 caaatgctat cgat
<210> 1412
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1412 gcacgctcta tact
12
14
14
12
14
14
<210> 1413
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1413 cacgctctat ac
<210> 1414
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1414 tccttgtcat tatc
<210> 1415
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1415 gctttgtcaa gatc
<210> 1416
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1416 tgctttgtca agat
<210> 1417
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1417 aagtatcggt tggc
<210> 1418
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
14
14
14
14
<400> 1418 agtatcggtt gg
<210> 1419
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1419 ttaaaatttg gaga
<210> 1420
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1420 ccttaaaatt tgga
<210> 1421
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1421 cttaaaattt gg
<210> 1422
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1422 tctactgttt ttgt
<210> 1423
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1423 ggctcctcta ctgt
<210> 1424
<211> 15
<212> DNA
12
14
14
12
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1424 agcctctgga tttga
<210> 1425
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1425 agcctctgga tttg
<210> 1426
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1426 tagcctctgg atttg
<210> 1427
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1427 tagcctctgg attt
<210> 1428
<211> 16
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1428 gctagcctct ggattt
<210> 1429
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1429 ctagcctctg gattt
fifteen
14
fifteen
14
16
fifteen

<400> 1525 agtcatttct gcctttgcgt c

21

<210> 1526 <211> 22 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1526 ccaatggtcg ggcactgctc aa

22

<210> 1527 <211> 30 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1527 gaaaatagac ttcctgaata actatgcatt

30

<210> 1528 <211> 18 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1528 actcgcttgc cagcttgc

18

<210> 1529 <211> 23 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1529 tttctgagtc cccgtgccca aca

23

<210> 1530 <211> 20 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1530 tgagccttgc caccttctct

20

<210> 1531 <211> 15 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1531 gcgcacccca gccaa

15

<210> 1532 <211> 29 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1532 agaggagctt cttttccctc tacctgggc

29

<210> 1533 <211> 20 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1533 atttcctgcc cctggtacct

20

<210> 1534 <211> 17 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1534 cgggcccaca cctcttg

17

<210> 1535 <211> 26 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1535 ccacaaagtg cagcaccgcc tagtgt

26

<210> 1536 <211> 19 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1536 gccacaggct cccagacat

19

<210> 1537 <211> 25 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1537 tccatcctct tgatatctcc ttttg

25

<210> 1538 <211> 31 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1538 acagccatca tcaaagagat cgttagcaga a

31

<210> 1539 <211> 24 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1539 atgacaatca tgttgcagca attc

24

<210> 1540 <211> 25 <212> ADN <213> Secuencia Artificial

<220> <223> Cebador

<400> 1540 cgatgcaata aatatgcaca aatca

25

<210> 1541 <211> 28 <212> ADN <213> Secuencia Artificial

<220> <223> Sonda

<400> 1541 ctgtaaagct ggaaagggac ggactggt

28

<210> 1542 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 1542 gtgtgcacac agct
<210> 1543
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1543 cagcctgggc ac
<210> 1544
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1544 tgctcgaact cctt
<210> 1545
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1545 gaagtcactg gctt
<210> 1546
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1546 gggaagtcac tggc
<210> 1547
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1547 gttaggcaaa gggc
<210> 1548
<211> 14
<212> ADN
14
12
14
14
14
14
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1548 gggctgagtg accc
<210> 1549
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1549 atgctagtgc acta
<210> 1550
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1550 agctcgctac ctct
<210> 1551
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1551 gaggtatccc atct
<210> 1552
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1552 ggcaacttca acct
<210> 1553
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1553 gaagtagcca ccaactgtgc
14
14
14
14
14 20
<210> 1554
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1554 tagccaccaa ct
<210> 1555
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1555 actg
<210> 1556
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1556 actg
<210> 1557
<211> 10
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1557 agccaccaac
<210> 1558
<211> 8
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1558 gccaccaa
<210> 1559
<211> 13
<212> ADN
<213> Secuencia Artificial
<220>
12
4
4
10
8
<223> Oligonucleótido Sintético
<400> 1559 tagccaccaa ctg
<210> 1560
<211> 12
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1560 taccgaacac ct
<210> 1561
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1561 gtccctgaag atgtcaatgc
<210> 1562
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1562 tgcactttgt ggtaccaagg
<210> 1563
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1563 gcttctccat cata
<210> 1564
<211> 14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1564 tgtcttgctg cttt
<210> 1565
<211> 4
13
12
20
20
14
14
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1565 actg
<210> 1566
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1566 actg
<210> 1567
<211> 4
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1567 actg
<210> 1568
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1568 atggcttctc catcatatcc
<210> 1569
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1569 cttgggcatg ctcgtcagtc
<210> 1570
<211> 20
<212> ADN
<213> Secuencia Artificial
<220>
<223> Oligonucleótido Sintético
<400> 1570 4
4
4
20
20

ccttccctga aggttcctcc

20

<210> 1571 <211> 20 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 1571 ctgctagcct ctggatttga

20

<210> 1572 <211> 4 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 1572 actg

4

<210> 1573 <211> 14 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 1573 gaatatctat aatg

14

<210> 1574 <211> 12 <212> ADN <213> Secuencia Artificial

<220> <223> Oligonucleótido Sintético

<400> 1574 gtaagcaagg ct

12

<210> 1575 <211> 2254 <212> ADN <213> Rattus norvegicus

<400> 1575

imagen1
<210> 1576
<211> 3300
<212> ADN
<213> Mus musculus
<400> 1576 imagen1
<210> 1430
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1430 gctagcctct ggatt
<210> 1431
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1431 ctagcctctg gatt
<210> 1432
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1432 tagcctctgg att
<210> 1433
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1433 tgctagcctc tggat
<210> 1434
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1434 tagcctctgg at
<210> 1435
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
fifteen
14
13
fifteen
12
<223> Synthetic Oligonucleotide
<400> 1435 ctgctagcct ctgga
<210> 1436
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1436 actgctagcc tctgg
<210> 1437
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1437 aactgctagc ctctg
<210> 1438
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1438 gaactgctag cctct
<210> 1439
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1439 tgaactgcta gcctc
<210> 1440
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1440 ttgaactgct agcct
<210> 1441
<211> 14
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1441 tgaactgcta gcct
<210> 1442
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1442 agttgaactg ctag
<210> 1443
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1443 gttgaactgc ta
<210> 1444
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1444 gaagttgaac tg
<210> 1445
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1445 acagaagttg aact
<210> 1446
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1446
14
14
12
12
14
tcattgtcac taac
<210> 1447
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1447 cattgtcact aa
<210> 1448
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1448 tcaggttcat tg
<210> 1449
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1449 atgatcaggt tcat
<210> 1450
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1450 tataatgatc aggt
<210> 1451
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1451 ataatgatca gg
<210> 1452
<211> 14
<212> DNA
<213> Artificial Sequence
14
12
12
14
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 1452 tggtgtcaga atat
<210> 1453
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1453 tcagtggtgt caga
<210> 1454
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1454 ctctggatca gagt
<210> 1455
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1455 aaggttcatt ctct
<210> 1456
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1456 ttcatcaaaa ggtt
<210> 1457
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1457 cttcatcaaa aggt
<210> 1458
14
14
14
14
14
14
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1458 cttcatcaaa ag
<210> 1459
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1459 atgctgatct tcat
<210> 1460
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1460 ttttgtaatt tgtg
<210> 1461
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1461 tcagactttt gtaa
<210> 1462
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1462 tgtcctattg ccat
<210> 1463
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
12
14
14
14
14
<400> 1463 tctgacacaa tgtc
<210> 1464
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1464 ctgacacaat gt
<210> 1465
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1465 tgttcctata actg
<210> 1466
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1466 gttcctataa ct
<210> 1467
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1467 aagattggtc agga
<210> 1468
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1468 agattggtca gg
<210> 1469
<211> 14
<212> DNA
<213> Artificial Sequence
14
12
14
12
14
12
<220>
<223> Synthetic Oligonucleotide
<400> 1469 gtgtcaaaac cctg
<210> 1470
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1470 agctacacaa cc
<210> 1471
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1471 cacagctaca caac
<210> 1472
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1472 acagctacac aa
<210> 1473
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1473 tatatacatg acac
<210> 1474
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1474 atatacatga ca
14
12
14
12
14
12
<210> 1475
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1475 aattttaaat gtcc
<210> 1476
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1476 attttaaatg tc
<210> 1477
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1477 tcctaattga at
<210> 1478
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1478 aaagtgccat ct
<210> 1479
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1479 tttataaaac tgga
<210> 1480
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
14
12
12
12
14
<400> 1480 ttataaaact gg
<210> 1481
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1481 tgcaaactta tctg
<210> 1482
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1482 gcaaacttat ct
<210> 1483
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1483 agccaactgc aa
<210> 1484
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1484 cttagccaac tgca
<210> 1485
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1485 ttagccaact gc
<210> 1486
<211> 14
<212> DNA
12
14
12
12
14
12
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1486 taaatcattg tcaa
<210> 1487
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1487 gcactggcct tgat
<210> 1488
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1488 cactggcctt ga
<210> 1489
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1489 ttagcactgg cc
<210> 1490
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1490 tgtgtaaggt ca
<210> 1491
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1491 gttaatgaca tt
14
14
12
12
12
12
<210> 1492
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1492 gacaatttct ac
<210> 1493
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1493 aacactgcac at
<210> 1494
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1494 taggtcaagt ctaa
<210> 1495
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1495 tataggtcaa gtct
<210> 1496
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1496 tttggataaa tata
<210> 1497
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
12
12
14
14
14
<223> Synthetic Oligonucleotide
<400> 1497 tgggacttca cacc
<210> 1498
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1498 accacagcta gt
<210> 1499
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1499 gggacttcac ac
<210> 1500
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1500 ccaaaaacct tact
<210> 1501
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1501 gtggcaacca ca
<210> 1502
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1502 aaggcttaaa gt
<210> 1503
<211> 12
14
12
12
14
12
12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1503 aggacttggg at
<210> 1504
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1504 gggaatcaga gc
<210> 1505
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1505 atttgatgct gc
<210> 1506
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1506 ttccaatgac ta
<210> 1507
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1507 atcaacagct gc
<210> 1508
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1508
12
12
12
12
12
gattgcaagt tccg
<210> 1509
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1509 tgcttggaag ga
<210> 1510
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1510 ctgctgcaca tcca
<210> 1511
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1511 cacattaaca gt
<210> 1512
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1512 agttgaaatt tc
<210> 1513
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1513 accctcattc ag
<210> 1514
<211> 12
<212> DNA
<213> Artificial Sequence
14
12
14
12
12
12
<220>
<223> Synthetic Oligonucleotide
<400> 1514 agaatgagac tt
<210> 1515
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1515 gtaaatccta ag
<210> 1516
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1516 taaatatagg tc
<210> 1517
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1517 aatgccttat ta
<210> 1518
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1518 caccttaaaa tttg
<210> 1519
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1519 gtgtacagat tt
<210> 1520
12
12
12
12
14
12
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1520 ctttcagtca ta
<210> 1521
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1521 gggcatatca aa
<210> 1522
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1522 tgaggcatta tc
<210> 1523
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1523 actg
<210> 1524
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer
<400> 1524 cgtgggctcc agcattcta
<210> 1525
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Primer
12
12
12
4
19

<400> 1525 agtcatttct gcctttgcgt c

twenty-one

<210> 1526 <211> 22 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1526 ccaatggtcg ggcactgctc aa

22

<210> 1527 <211> 30 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1527 gaaaatagac ttcctgaata actatgcatt

30

<210> 1528 <211> 18 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1528 actcgcttgc cagcttgc

18

<210> 1529 <211> 23 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1529 tttctgagtc cccgtgccca here

2. 3

<210> 1530 <211> 20 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1530 tgagccttgc caccttctct

twenty

<210> 1531 <211> 15 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1531 gcgcacccca gccaa

fifteen

<210> 1532 <211> 29 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1532 agaggagctt cttttccctc tacctgggc

29

<210> 1533 <211> 20 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1533 atttcctgcc cctggtacct

twenty

<210> 1534 <211> 17 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1534 cgggcccaca cctcttg

17

<210> 1535 <211> 26 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1535 ccacaaagtg cagcaccgcc tagtgt

26

<210> 1536 <211> 19 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1536 gccacaggct cccagacat

19

<210> 1537 <211> 25 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1537 tccatcctct tgatatctcc ttttg

25

<210> 1538 <211> 31 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1538 acagccatca tcaaagagat cgttagcaga a

31

<210> 1539 <211> 24 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1539 atgacaatca tgttgcagca attc

24

<210> 1540 <211> 25 <212> DNA <213> Artificial Sequence

<220><223> Primer

<400> 1540 cgatgcaata aatatgcaca aatca

25

<210> 1541 <211> 28 <212> DNA <213> Artificial Sequence

<220><223> Probe

<400> 1541 ctgtaaagct ggaaagggac ggactggt

28

<210> 1542 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 1542 gtgtgcacac agct
<210> 1543
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1543 cagcctgggc ac
<210> 1544
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1544 tgctcgaact cctt
<210> 1545
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1545 gaagtcactg gctt
<210> 1546
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1546 gggaagtcac tggc
<210> 1547
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1547 gttaggcaaa gggc
<210> 1548
<211> 14
<212> DNA
14
12
14
14
14
14
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1548 gggctgagtg accc
<210> 1549
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1549 atgctagtgc minutes
<210> 1550
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1550 agctcgctac ctct
<210> 1551
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1551 gaggtatccc atct
<210> 1552
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1552 ggcaacttca acct
<210> 1553
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1553 gaagtagcca ccaactgtgc
14
14
14
14
14 20
<210> 1554
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1554 tagccaccaa ct
<210> 1555
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1555 actg
<210> 1556
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1556 actg
<210> 1557
<211> 10
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1557 agccaccaac
<210> 1558
<211> 8
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1558 gccaccaa
<210> 1559
<211> 13
<212> DNA
<213> Artificial Sequence
<220>
12
4
4
10
8
<223> Synthetic Oligonucleotide
<400> 1559 tagccaccaa ctg
<210> 1560
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1560 taccgaacac ct
<210> 1561
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1561 gtccctgaag atgtcaatgc
<210> 1562
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1562 tgcactttgt ggtaccaagg
<210> 1563
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1563 gcttctccat tasting
<210> 1564
<211> 14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1564 tgtcttgctg cttt
<210> 1565
<211> 4
13
12
twenty
twenty
14
14
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1565 actg
<210> 1566
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1566 actg
<210> 1567
<211> 4
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1567 actg
<210> 1568
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1568 atggcttctc catcatatcc
<210> 1569
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1569 cttgggcatg ctcgtcagtc
<210> 1570
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Oligonucleotide
<400> 1570 4
4
4
twenty
twenty

ccttccctga aggttcctcc

twenty

<210> 1571 <211> 20 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 1571 ctgctagcct ctggatttga

twenty

<210> 1572 <211> 4 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 1572 actg

4

<210> 1573 <211> 14 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 1573 gaatatctat aatg

14

<210> 1574 <211> 12 <212> DNA <213> Artificial Sequence

<220><223> Synthetic Oligonucleotide

<400> 1574 gtaagcaagg ct

12

<210> 1575 <211> 2254 <212> DNA <213> Rattus norvegicus

<400> 1575

image 1
<210> 1576
<211> 3300
<212> DNA
<213> Mus musculus
<400> 1576 image 1

Claims (13)

one.

A short antisense compound of 10 to 14 monomers in length, comprising a hollow region of 2'deoxyribonucleotide flanked on each side by a wing, in which each wing independently consists of 1 to 3 modified high affinity monomers that are nucleotides modified with sugar comprising a bridge between the 4 'and 2' position of sugar, for use in the treatment of a metabolic disorder in an animal.

2.

Use of a short antisense compound of 10 to 14 monomers in length, comprising a hollow region of 2'deoxyribonucleotide flanked on each side by a wing, in which each wing independently consists of 1 to 3 modified high affinity monomers that they are sugar-modified nucleotides that comprise a bridge between the 4 'and 2' position of sugar, for the preparation of a medicament for treating a metabolic disorder in an animal.

3.

A short antisense compound of 10 to 14 monomers in length, comprising a hollow region of 2'deoxyribonucleotide flanked on each side by a wing, in which each wing independently consists of 1 to 3 modified high affinity monomers that are nucleotides modified with sugar comprising a bridge between the 4 'and 2' position of sugar, for use in the treatment of a cardiovascular disorder in an animal.

Four.

Use of a short antisense compound of 10 to 14 monomers in length, comprising a hollow region of 2'deoxyribonucleotide flanked on each side by a wing, in which each wing independently consists of 1 to 3 modified high affinity monomers that they are sugar-modified nucleotides that comprise a bridge between the 4 'and 2' position of sugar, for the preparation of a medicament for treating a cardiovascular disorder in an animal.

5.

The short antisense compound or use of any of claims 1-4, wherein the conformation of each of said sugar modified nucleotides is, independently, β-D or α-L.

6.

The short antisense compound or use of any of claims 1-4, wherein each of said bridges independently comprises 1 or 2 to 4 linked groups independently selected from - [C (R1) (R2)] n- , -C (R1) = C (R2) -, -C (R1) = N-, -C (= NR1) -, -C (= O) -, -C (= S) -, -O-, -Si (R1) 2-, -S (= C) x- and -N (R1) -;

in which x is 0, 1 or 2; n is 1, 2, 3 or 4; each of R1 and R2 is, independently, H, a protecting group, hydroxyl, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, C2- alkynyl C12 substituted, C5-C20 aryl, C5C20 substituted aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5C7 alicyclic radical, C5-C7 substituted alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C (= O) -H), substituted acyl, CN, sulfonyl (S (= O) 2-J1) or sulfoxyl (S (= O) -J1); Y each of J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5- aryl C20, substituted C5-C20 aryl, acyl (C (= O) -H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-C12 aminoalkyl, substituted C1-C12 aminoalkyl or a protecting group.

7.

The short antisense compound or use of claim 6, wherein each of said bridges is independently 4'-CH2-2 ', 4' - (CH2) 2-2 ', 4'-CH2-O -2 ', 4' - (CH2) 2-O-2 '4'-CH2-ON (R1) -2' or 4'-CH2-N (R1) -O-2'- where each R1 is , independently, H, a protecting group or C1-C12 alkyl.

8.

The short antisense compound or use of claim 6, wherein each of said bridges is 4’-CH (CH3) -O2 ’.

9.

The short antisense compound or use of any of claims 1-4, wherein at least one monomeric bond is a modified monomeric bond such as a phosphorothioate bond.

10.

The short antisense compound or use of any of claims 1-4, wherein each monomeric bond is an internucleoside phosphorothioate bond.

eleven.

The short antisense compound or use of any of claims 1-10, wherein the antisense compound is 10-13 monomers in length, 10-12 monomers in length, 10-11 monomers in length, 10 monomers in length, 11 monomers in length, 12 monomers in length, 13 monomers in length or 14 monomers in length.

12.

The short antisense compound or use of any of claims 1-11, which has a motif selected from:

1-12-1; 2-10-2; 1-10-1; 1-10-2; 3-8-3; 2-8-2; 1-8-1; and 3-6-3 in which the first number represents the number of monomers in the 5 'wing, the second number represents the number of monomers in the recess and the third number represents the number of monomers in the 3' wing.

13.

The short antisense compound or use of any of claims 1-12, wherein the animal is a human being.