RU2773197C2 - Antisense oligonucleotides to alpha-synuclein and applications thereof - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: described is a group of inventions including an antisense oligonucleotide targeting an alpha-synuclein (SNCA) transcript, a pharmaceutical composition for treating synucleopathy, and an application of the antisense oligonucleotide or the composition for manufacturing a medicinal product for treating synucleopathy in a subject in need thereof. In one of the variants of implementation, the antisense oligonucleotide has a sequence selected from the group consisting of SEQ ID NO: 276; 278; 325; 328; 326; 329; 330; 327; 332; 333 and 559.

EFFECT: invention expands the range of products for treating synucleopathy.

8 cl, 6 dwg, 7 tbl, 5 ex

Description

FIELD OF THE INVENTION

The present disclosure relates to antisense oligomeric compounds (ASOs) that target the alpha synuclein (SNCA) transcript in the cell, resulting in reduced expression of the alpha synuclein (SNCA) protein. Reducing SNCA protein expression may be beneficial for a range of medical disorders such as multiple system atrophy, Parkinson's disease, Parkinson's disease dementia (PDD), and Lewy body dementia.

PRIOR ART

Alpha synuclein (SNCA), a member of the synuclein family of proteins, is a small, soluble protein that is expressed primarily within neural tissues. See Marques O. et al., Cell Death Dis. 19: e350 (2012). It is expressed in many cell types, but is predominantly localized within the presynaptic endings of neurons. While the exact function is still to be fully elucidated, SNCA has been hypothesized to play an important role in the regulation of synaptic transmission. For example, SNCA functions as a molecular chaperone in the formation of SNARE complexes that mediate the docking of synaptic vesicles to neuronal presynaptic membranes. SNCA can also interact with other proteins like the microtubule-associated protein tau to help stabilize microtubules and regulate vesicle transport.

Due to the role of SNCA in the regulation of synaptic transmission, changes in SNCA expression and/or function can disrupt critical biological processes. It was believed that such disorders contribute to α-synucleinopathies, which are neurodegenerative diseases characterized by abnormal accumulation of SNCA protein aggregates within the brain. Accordingly, insoluble inclusions of misfolded, aggregated and phosphorylated SNCA protein are a pathological feature of diseases such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), Lewy body dementia (DLB), and multiple system atrophy (MSA). See Galvin JE et al., Archives of Neurology 58: 186-190 (2001); and Valera E et al., J Neurochem 139 Suppl 1: 346-352 (Oct. 2016).

α-Synucleinopathies such as Parkinson's disease are widespread progressive neurodegenerative disorders of the brain, especially among the elderly. See Recchia A et al., FASEB J. 18: 617-26 (2004). It is estimated that approximately seven to ten million people worldwide are living with such disorders, with approximately 60,000 new cases each year in the United States alone. Drug costs for an individual can easily exceed $2,500 per year, and therapeutic surgery can cost up to $100,000 per patient. Therefore, more reliable and cost-effective treatment options are much needed.

US 2008/0003570 describes translational enhancer elements on alpha synuclein and methods for identifying compounds that modulate alpha synuclein.

WO 2012/068405 discloses modified antisense oligonucleotides targeting alpha-synuclein.

All of WO 2005/004794, WO 2005/045034, WO 2006/039253, WO 2007/135426, US 2008/0139799, WO 2008/109509, WO 2009/079399, WO 2012/027713 describe molecules acting through complexes of nucleic acids RISCs in the cytoplasm, such as siRNA molecules (small interfering nucleic acids). Such molecules are not capable of targeting introns in the SNCA transcript.

WO 2011/041897, WO 2011/131693 and WO 2014/064257 describe conjugates of nucleic acid molecules for delivery to the CNS (central nervous system) to modulate target molecules in the CNS, alpha-synuclein being one of them.

SUMMARY OF THE INVENTION

The present disclosure is directed to an antisense oligonucleotide (ASO) comprising a contiguous nucleotide sequence of 10-30 nucleotides in length, wherein the contiguous nucleotide sequence is at least 90% complementary to an intron nucleic acid region within an alpha-synuclein (SNCA) transcript. In some embodiments, the SNCA transcript contains SEQ ID NO: 1, and the ACO of the present disclosure is capable of inhibiting the expression of a human SNCA transcript in a cell that expresses a human SNCA transcript.

In some embodiments, the intron region is selected from intron 1 corresponding to nucleotides 6336-7604 of SEQ ID NO: 1; intron 2 corresponding to nucleotides 7751-15112 of SEQ ID NO: 1; intron 3 corresponding to nucleotides 15155-20908 of SEQ ID NO: 1; or intron 4 corresponding to nucleotides 21052-114019 of SEQ ID NO: 1.

In other embodiments, the antisense oligonucleotides (ASOs) comprise a contiguous nucleotide sequence of 10-30 nucleotides in length, where the contiguous nucleotide sequence is at least 90% complementary to a nucleic acid sequence within an alpha-synuclein (SNCA) transcript, where the nucleic acid sequence is the acid is selected from the group consisting of: i) nucleotides 21052-29654 of SEQ ID NO: 1; ii) nucleotides 30931-33938 of SEQ ID NO: 1; iii) nucleotides 44640-44861 of SEQ ID NO: 1; iv) nucleotides 47924-58752 of SEQ ID NO: 1; v) nucleotides 4942-5343 of SEQ ID NO: 1; vi) nucleotides 6336-7041 of SEQ ID NO: 1; vii) nucleotides 7329-7600 of SEQ ID NO: 1; viii) nucleotides 7751-7783 of SEQ ID NO: 1; ix) nucleotides 8277-8501 of SEQ ID NO: 1; x) nucleotides 9034-9526 of SEQ ID NO: 1; xi) nucleotides 9982-14279 of SEQ ID NO: 1; xii) nucleotides 15204-19041 of SEQ ID NO: 1; xiii) nucleotides 20351-20908 of SEQ ID NO: 1; xiv) nucleotides 34932-37077 of SEQ ID NO: 1; xv) nucleotides 38081-42869 of SEQ ID NO: 1; xvi) nucleotides 38081-38303 of SEQ ID NO: 1; xvii) nucleotides 40218-42869 of SEQ ID NO: 1; xvii) nucleotides 46173-46920 of SEQ ID NO: 1; xix) nucleotides 60678-60905 of SEQ ID NO: 1; xx) nucleotides 62066-62397 of SEQ ID NO: 1; xxi) nucleotides 67759-71625 of SEQ ID NO: 1; xxii) nucleotides 72926-86991 of SEQ ID NO: 1; xxiii) nucleotides 88168-93783 of SEQ ID NO: 1; xxiv) nucleotides 94976-102573 of SEQ ID NO: 1; xxv) nucleotides 104920-107438 of SEQ ID NO: 1; xxvi) nucleotides 106378-106755 of SEQ ID NO: 1; xxvii) nucleotides 106700-106755 of SEQ ID NO: 1; xxviii) nucleotides 108948-114019 SEQ ID NO: 1 and xxix) nucleotides 114292-116636 SEQ ID NO: 1.

In some embodiments, the continuous nucleotide sequence contains or consists of a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353.

In some embodiments, the continuous nucleotide sequence contains at least one nucleotide analog. In some embodiments, the antisense oligonucleotide is a gapmer. This gapmer may consist of the formula 5'-A-B-C-3', wherein (i) region B is a contiguous sequence of at least 6 DNA units that are capable of recruiting an RNase; (ii) region A is a first wing sequence of 1-10 nucleotides, where the first wing sequence contains one or more nucleotide analogs and optionally one or more DNA units, and where at least one of the nucleotide analogs located at the 3' end of A; and (iii) the C region is a second wing sequence of 1-10 nucleotides, where the second wing sequence contains one or more nucleotide analogs and optionally one or more DNA units, and where at least one of the nucleotide analogues located at the 5' end of C.

In some embodiments, the nucleotide analog or analogs are high affinity analogs such as 2'-sugar modified nucleosides selected from the group consisting of locked nucleic acid (LNA); 2'-O-alkyl-RNA; 2'-amino-DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'-fluoro-AMA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), hindered ethyl nucleoside (cEt), 2'-O-methyl nucleic acid (2'-OMe), 2'-O-methoxyethyl nucleic acid (2 '-MOE) and any combination of them. In some embodiments, the nucleotide analog or analogs contain a bicyclic sugar. In some embodiments, this bicyclic sugar contains cEt, 2',4'-hindered-2'-O-methoxyethyl (cMOE), LNA, α-L-LNA, β-D-LNA, 2'-O,4'-C -ethylene-bridged nucleic acids (ENA), amino-LNA, oxy-LNA or thio-LNA. In some embodiments, the nucleotide analog or analogs contains LNA.

In some embodiments, the antisense oligonucleotide has an in vivo tolerability less than or equal to a total score of 4, where the total score is the sum of the single scores of the five categories, which are 1) hyperactivity; 2) reduced activity and activation; 3) motor dysfunction and/or ataxia; 4) abnormal position and breathing; and 5) tremor and/or seizures, and where a single score for each category is measured on a scale of 0-4. In some embodiments, in vivo tolerability is less than or equal to a total score of 3, a total score of 2, a total score of 1, or a total score of 0.

In some embodiments, the nucleotide sequence of the antisense oligonucleotides comprises, essentially consists of, or consists of a sequence selected from the group consisting of SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353, with a construct selected from the group, consisting of the structures in Fig. 1A-1C, where the capital letter is the sugar-modified nucleoside and the lowercase letter is DNA. In some embodiments, the antisense oligonucleotide, or continuous nucleotide sequence thereof, has a chemical structure selected from the group consisting of ASO-008387; ASO-008388; ASO-008501; ASO-008502; ASO-008529; ASO-008530; ASO-008531; ASO-008532; ASO-008533; ASO-008534; ASO-008535; ASO-008536; ASO-008537; ASO-008543; ASO-008545; ASO-008584; ASO-008226 and ASO-008261.

Also provided herein is a pharmaceutical composition comprising an antisense oligonucleotide or conjugate thereof as disclosed herein and a pharmaceutically acceptable carrier.

The present disclosure further provides a kit containing an antisense oligonucleotide, conjugate or composition thereof, as disclosed herein.

Provided herein is a method for treating synucleinopathy in a subject in need thereof, comprising administering an effective amount of an antisense oligonucleotide, conjugate thereof, or composition of the present disclosure. In some embodiments, the synucleinopathy is selected from the group consisting of Parkinson's disease, Parkinson's disease dementia (PDD), multiple system atrophy, Lewy body dementia, and any combinations thereof.

This document also proposes the use of an antisense oligonucleotide, its conjugate or composition of the present disclosure for the manufacture of a medicinal product. The present disclosure also provides the use of an antisense oligonucleotide, conjugate or composition thereof for the manufacture of a medicament for the treatment of synucleinopathy in a subject in need thereof. In some embodiments, the antisense oligonucleotide, conjugate thereof, or composition of the present disclosure is for use in the treatment of synucleinopathy in a subject in need thereof. In other embodiments, the antisense oligonucleotide, conjugate or composition thereof of the present disclosure is for use in therapy.

In some embodiments, the subject is a human. In some embodiments, the antisense oligonucleotide, its conjugate, or compositions are administered orally, parenterally, intrathecally, intracerebroventricularly, pulmonary, topically, or intraventricularly.

BRIEF DESCRIPTION OF GRAPHICS

On FIG. 1A-1C show exemplary ASOs targeting the SNCA pre-mRNA region. FIG. 1A shows exemplary ASOs that target wild-type SNCA mRNA (SEQ ID NO: 2). FIG. 1B shows exemplary ASOs that target the SNCA mRNA variant (“variant 4”/SEQ ID NO: 5; or “variant 2”/SEQ ID NO: 3). FIG. 1C shows exemplary ASOs that target a different SNCA mRNA variant ("variant 3"/SEQ ID NO: 4). In each column of FIG. 1A-1C show a sequence identification number (SEQ ID No.) reserved for this sequence only, target start and end positions on the SNCA pre-mRNA sequence, target start and end positions on the SNCA mRNA sequence, construct number (DES No.), the ASO sequence with the construct, the ASO number (ASO No.) and the ASO sequence with the chemical structure. In these graphics, the ASO chemistry abstract is as follows: LNA beta-D-hydroxy nucleotides are denoted OxyB, where B denotes a nucleotide base such as thymine (T), uridine (U), cytosine (C), 5-methylcytosine (MC), adenine (A) or guanine (G), and thus includes OxyA, OxyT, OxyMS, OxyC and OxyG. DNA nucleotides are designated DNAb, where the lowercase b denotes a nucleotide base such as thymine (T), uridine (U), cytosine (C), 5-methylcytosine (Mc), adenine (A), or guanine (G), and thus , includes DNAa, DNAt, DNA and DNAg. The letter M before C or c indicates 5-methylcytosine. The letter s represents a phosphorothioate internucleotide bond.

On FIG. 2 shows ASOs targeting SNCA pre-mRNA with a typical wing design modification. In each column of FIG. 2 shows a sequence identification number (SEQ ID No.) reserved for this sequence only, target start and end positions on the SNCA pre-mRNA sequence, construct number (DES No.), ASO sequence with construct, ASO number (ASO No.) and an ASO sequence with identified chemical structure and wing design modification. DES-287033, DES-287041, DES-287053, DES-287965, DES-288902, DES-288903, DES-288905, DES-290315, and DES-292378 show different possible ASO designs for SEQ ID NO: 1467. DES-286762 , DES-286785, and DES-286783 show different possible ASO constructs for SEQ ID NO: 1764. For ASO constructs, uppercase letters indicate nucleotide analogs (eg, LNA or 2'-O-Methyl (OMe)), and lowercase letters indicate DNA. Capital letters with or without underscores indicate that the two letters may represent different nucleotide analogs, eg LNA or 2'-O-Methyl. For example, underlined capital letters may represent 2'-O-methyl, while capital letters without underline represent LNA. In ASO, in the chemical structure column, OMe is 2'-O-methylnucleotide, L is LNA, D is DNA, and the numbers followed by L or D are the number of LNA or DNA.

On FIG. 3 shows the relative level of SNCA mRNA expression (as a percentage of vehicle control) in cynomolgus monkeys after administration of ASO-003179. Animals received vehicle control (circle), 8 mg ASO-003179 (square) or 16 mg ASO-003179 (triangle) via ICV (intracerebroventricular - intracerebral ventricular) injection. Animals were then sacrificed at 2 weeks post dosing and SNCA mRNA expression levels were assessed in the following tissues: medulla (upper left panel), dorsal striatum (upper middle panel), pons (upper right panel), cerebellum (lower left panel), lumbar spinal cord (lower middle panel) and frontal cortex (lower right panel). Both data for individual animals and the average are shown. The horizontal line marks the reference value of 100% (ie the value at which SNCA mRNA expression would be equivalent to the level of expression seen in the vehicle control group).

On FIG. 4 shows the effect of ASO-003092 on the level of SNCA mRNA expression in cynomolgus monkey brain tissues. Animals were dosed with either 4 mg (square) or 8 mg (triangle) of ASO-003092, and then the level of SNCA mRNA expression in different brain tissues was assessed at 2 weeks post dosing. Animals receiving vehicle controls were used as controls (circle). SNCA mRNA expression levels were assessed in the following tissues: medulla (upper left panel), dorsal striatum (upper middle panel), pons (upper right panel), cerebellum (lower left panel), lumbar spinal cord (lower middle panel), and frontal bark (lower right panel). SNCA mRNA expression levels were normalized to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and then displayed as a percentage of vehicle control. Both data for individual animals and the average are shown. The horizontal line marks the reference value of 100% (ie the value at which SNCA mRNA expression would be equivalent to the level of expression seen in the vehicle control group).

DETAILED DESCRIPTION OF THE INVENTION

I Definitions

It should be understood that the term "element" in the singular refers to one or more than one given element; for example, it is understood that "nucleotide sequence" represents one or more than one nucleotide sequence. The terms "one", "one or more than one" and "at least one", as such, can be used interchangeably herein.

In addition, the term "and/or" as used herein should be taken as a specific disclosure of each of the two defined characteristics or components, with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" is intended to include "A and B", "A or B", "A" (one) and "B" (one). Similarly, the term "and/or" as used in a phrase such as "A, B and/or C" is intended to cover each of the following: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (one); B (one) and C (one).

It is understood that in all cases where aspects are described herein by the wording "comprising", otherwise similar aspects described in terms of "consisting of" and/or and "substantially consisting of" are also contemplated.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is generally understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ^ed ., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ^ed ., 1999, Academic Press and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide the skilled artisan with a general vocabulary of many of the terms used in this disclosure.

International de Unites (SI) форме. Числовые интервалы включают числа, ограничивающие данный интервал. Если не указано иное, нуклеотидные последовательности пишутся слева направо в ориентации от 5' к 3'. Аминокислотные последовательности пишутся слева направо в ориентации от амино до карбокси. Предложенные в данном документе заголовки не являются ограничениями разных аспектов данного раскрытия, которые можно иметь посредством ссылки на описание изобретения в целом. Соответственно, термины, определенные сразу ниже, являются более понятными посредством ссылки на описание изобретения во всей его полноте.Units, prefixes and symbols are designated in their adopted

International de Unites (SI) form. Numeric intervals include the numbers that limit the given interval. Unless otherwise indicated, nucleotide sequences are written from left to right in a 5' to 3' orientation. Amino acid sequences are written from left to right in the amino to carboxy orientation. The headings proposed herein are not intended to limit the various aspects of this disclosure that may be made by reference to the specification as a whole. Accordingly, the terms defined immediately below are more readily understood by reference to the description of the invention in its entirety.

The term "about" is used herein to mean approximately, roughly, about, or in areas. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" can modify a numerical value above and below the asserted value by a deviation, such as 10 percent up or down (above or below). For example, if it is stated that "ASO reduces SNCA protein expression in a cell after administration of ASO by at least about 60%", it is understood that SNCA levels are reduced in the range of 50% to 70%.

The term "antisense oligonucleotide" (ASO) refers to an oligomer or polymer of nucleosides, such as naturally occurring nucleosides or modified forms thereof, that are covalently linked to each other via internucleotide bonds. Useful for this disclosure ASO includes at least one nucleoside that is not naturally occurring. The ASO is complementary to the target nucleic acid such that the ASO hybridizes to the target nucleic acid sequence. The terms "antisense ASO", "ASO" and "oligomer" as used herein are used interchangeably with the term "ASO".

The term "nucleic acids" or "nucleotides" is intended to encompass numerous nucleic acids. In some embodiments, the term "nucleic acids" or "nucleotides" refers to a target sequence, such as pre-mRNA, mRNA or DNA in vivo or in vitro. When the term refers to nucleic acids or nucleotides in a target sequence, these nucleic acids or nucleotides may be sequences naturally occurring in a cell. In other embodiments, the terms "nucleic acids" or "nucleotides" refer to a sequence in the ASO of this disclosure. When the term refers to a sequence in an ASO, the nucleic acids or nucleotides are not naturally occurring, ie. are chemically synthesized, enzymatically produced, recombinantly produced, or any combination thereof. In one embodiment, the nucleic acids or nucleotides in the ASO are produced synthetically or recombinantly, but are not a naturally occurring sequence or fragment thereof. In another embodiment, the nucleic acids or nucleotides in the ASO are not naturally occurring because they contain at least one nucleotide analog that is not naturally occurring. The term "nucleic acid" or "nucleoside" refers to a single stretch of nucleic acid, such as DNA, RNA, or an analogue thereof, present in a polynucleotide. "Nucleic acid" or "nucleoside" includes naturally occurring nucleic acids or non-naturally occurring nucleic acids. In some embodiments, the terms "nucleotide", "link" and "monomer" are used interchangeably. It will be understood that when referring to the sequence of nucleotides or monomers, reference is made to the sequence of bases such as A, T, G, C or U and their analogues.

The term "nucleotide" as used herein refers to a glycoside containing a sugar moiety, a base moiety, and a covalently linked group (linking group) such as a phosphate or phosphorothioate internucleotide linking group, and encompasses naturally occurring nucleotides such as DNA or RNA, and non-naturally occurring nucleotides containing a modified sugar and/or base, also referred to herein as "nucleotide analogs". In this document, one nucleotide (unit) may also be referred to as a monomer or nucleic acid unit. In some embodiments, the term "nucleotide analogs" refers to nucleotides having modified sugar moieties. Non-limiting examples of nucleotides having modified sugar moieties (eg, LNA) are disclosed elsewhere herein. In other embodiments, the term "nucleotide analogs" refers to nucleotides having modified nucleobase moieties. Nucleotides having modified nucleic base moieties include 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine.

The term "nucleoside" as used herein is used to refer to a glycoside containing a sugar moiety and a base moiety, which can be covalently linked by internucleotide bonds between ASO nucleosides. In the field of biotechnology, the term "nucleoside" is often used to refer to the monomer or unit of a nucleic acid. In the context of ASO, the term "nucleoside" can refer to a single base, i.e. a nucleic base sequence containing cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA) and uracil (RNA), which implies the presence of a sugar backbone and internucleotide bonds. Similarly, especially in the case of oligonucleotides where one or more internucleotide linking groups are modified, the term "nucleotide" may refer to "nucleoside". For example, the term "nucleotide" can be used even when specifying the presence or nature of bonds between nucleosides.

The term "nucleotide length" as used herein means the total number of nucleotides (monomers) in a given sequence. For example, the sequence ctaacaacttctgaacaaca (SEQ ID NO: 1436) has 20 nucleotides; thus, the nucleotide length of this sequence is 20. The term "nucleotide length" is therefore used interchangeably with the term "number of nucleotides" herein.

As one of ordinary skill in the art would know, the 5' nucleotide of the oligonucleotide does not contain a 5' internucleotide linking group, although it may contain a 5' end group.

The term "coding region" or "coding sequence" as used herein is the portion of a polynucleotide that consists of codons translated into amino acids. Although a "terminator codon" (TAG, TGA, or TTA) is not typically translated into an amino acid, it may be considered part of the coding region, but any flanking sequences, e.g., promoters, ribosome binding sites, transcription terminators, introns, untranslated regions ("UTRs") and the like are not part of the coding region. The boundaries of the coding region are typically defined by an initiation codon at the 5' end, encoding the amino end of the nascent polypeptide, and a translation termination codon at the 3' end, encoding the carboxyl end of the nascent polypeptide.

The term "non-coding region" as used herein means a nucleotide sequence that is not a coding region. Examples of non-coding regions include, but are not limited to, promoters, ribosome binding sites, transcription terminators, introns, untranslated regions ("UTRs"), non-coding exons, and the like. Some exons, in whole or in part, may be the 5' untranslated region (5' UTR) or the 3' untranslated region (3' UTR) of each transcript. The untranslated regions are important for the efficient translation of the transcript and for controlling the rate of translation and the half-life of the transcript.

The term "region", when used in the context of a nucleotide sequence, refers to a stretch of that sequence. For example, the phrase "region within a nucleotide sequence" or "region within a complementary strand of a nucleotide sequence" refers to a sequence shorter than a nucleotide sequence but longer than at least 10 nucleotides located within a particular nucleotide sequence or complementary strand of a nucleotide sequence. sequences respectively. The term "subsequence" or "target region" can also refer to a region of a nucleotide sequence.

The term "below", when referring to a nucleotide sequence, means that the nucleic acid or nucleotide sequence is located 3' with respect to the reference nucleotide sequence. In some embodiments, the downstream nucleotide sequences refer to sequences that follow the transcription start point. For example, the translation initiation codon of a gene is located downstream of the transcription start site.

The term "above" refers to a nucleotide sequence that is located 5' from a reference nucleotide sequence.

Unless otherwise indicated, the sequences given herein are listed from the 5' end (left) to the 3' end (right).

The term "regulatory region", as used herein, refers to nucleotide sequences located upstream (5' non-coding sequences), within or downstream (3' non-coding sequences) of the coding region, and which affects transcription, RNA processing, stability or translation of the associated coding region. Regulatory regions may include promoters, translation leaders, introns, polyadenylation recognition sequences, RNA processing sites, effector binding sites, UTRs, and stem-loop structures. If the coding region is intended to be expressed in a eukaryotic cell, the polyadenylation signal and transcription termination sequence will typically be 3' to the coding sequence.

The term "transcript", as used herein, may refer to a primary transcript that is synthesized by transcription of DNA and becomes messenger RNA (mRNA) after processing, i.e. to the messenger RNA precursor (pre-mRNA), and to the processed mRNA itself. The term "transcript" can be used interchangeably with "pre-mRNA" and "mRNA". After the DNA strands are transcribed into primary transcripts, the newly synthesized primary transcripts are modified in several ways to become their mature functional forms such as mRNA, tRNA, rRNA, IncRNA, miRNA, and others. Thus, the term "transcript" may include exons, introns, 5'-UTRs and 3'-UTRs.

The term "expression" as used herein refers to the method by which a polynucleotide produces a gene product, such as an RNA or a polypeptide. It includes, without limitation, transcription of a polynucleotide into messenger RNA (mRNA) and translation of an mRNA into a polypeptide. Expression produces a "gene product". A "gene product", as the term is used herein, can be either a nucleic acid, such as messenger RNA, produced by transcription of a gene, or a polypeptide that is translated from a transcript. The gene products described herein further include nucleic acids with post-transcriptional modifications, such as polyadenylation or splicing, or polypeptides with post-translational modifications, such as methylation, glycosylation, lipid addition, association with other protein subunits, or proteolytic cleavage.

The terms "identical" or percent "identity" in the context of two or more than two nucleic acids refer to two or more than two sequences that are the same or have a precisely defined percentage of nucleotides or amino acid residues that are the same when compared and aligned ( inserting spaces if necessary) for maximum matching without considering any conservative amino acid substitutions as part of the sequence identity. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and programs are known in the art that can be used to obtain amino acid or nucleotide sequence alignments.

One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al., 1990, Proc. Natl. Acad. Set, 87:2264-2268, as modified by Karlin et al., 1993, Proc. Natl. Acad. Sci., 90:5873-5877, and included in the NBLAST and XBLAST programs (Altschul et al., 1991, Nucleic Acids Res., 25:3389-3402). In some embodiments, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. BLAST-2, WU-BLAST-2 (Altschul et al., 1996, Methods in Enzymology, 266:460-480), ALIGN, ALIGN-2 (Genentech, South San Francisco, CA), or Megalign (DNASTAR) are additional public domain programs that can be used to align sequences. In some embodiments, percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (e.g., using the NWSgapdna.CMP template, a gap weight of 40, 50, 60, 70, or 90, and a length weight of 1, 2, 3, 4, 5 or 6). In some alternative embodiments, the GAP program in the GCG software package, which includes the algorithm of Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) (e.g., using either BLOSUM 62 matrices or PAM250 matrices and space weights 16, 14, 12, 10, 8, 6, or 4, and length weights 1, 2, 3, 4, 5). Alternatively, in some embodiments, percent identity between nucleotide and amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, percent identity can be determined using the ALIGN program (version 2.0) and using PAM120 with a residual table, gap length penalty of 12, and gap penalty of 4. One skilled in the art can determine the appropriate parameters for maximum alignment through a particular alignment program. . In some embodiments, the program's default parameters for alignment are used.

In some embodiments, the percentage identity "X" of the first nucleotide sequence with the second nucleotide sequence is calculated as 100 × (Y/Z), where Y is the number of amino acid residues counted as identical matches when aligning the first and second sequences (when aligned by visual inspection or a particular sequence alignment program), and Z is the total number of residues in the second sequence. If the length of the first sequence is greater than the second sequence, the percentage identity of the first sequence with the second sequence will be higher than the percentage identity of the second sequence with the first sequence.

The different regions within the target sequence of a single polynucleotide that align with the reference polynucleotide sequence may each have their own percentage of sequence identity. It is noted that the percent sequence identity value is rounded to the nearest tenth. For example, 80.11; 80.12; 80.13 and 80.14 are rounded down to the lower value of 80.1; while 80.15; 80.16; 80.17; 80.18 are rounded up to 80.2. It is also noted that the length value will always be an integer.

The terms "homologous" and "homology" as used herein are used interchangeably with the terms "identity" and "identical".

The term "naturally occurring variant thereof" refers to variants of an SNCA polypeptide sequence or SNCA nucleic acid sequence (e.g., transcript) that naturally exist within a particular taxonomic group, such as a mammal, such as a mouse, ape, and a human. Typically, when referring to "naturally occurring variants" of a polynucleotide, the term may also encompass any allelic variant of the SNCA-encoding genomic DNA that is located at chromosomal position 17q21 by chromosomal translocation or duplication, and RNA, such as mRNA, derived from it. "Naturally occurring variants" may also include variants resulting from alternative splicing of SNCA mRNA. When referring to a specific polypeptide sequence, for example, the term also includes naturally occurring forms of the protein, which can therefore be processed, for example, through co- or post-translational modifications such as signal peptide cleavage, proteolytic cleavage, glycosylation, etc. .

When determining the degree of "complementarity" between an ASO of this disclosure (or regions thereof) and a target region of a nucleic acid that encodes a mammalian SNCA protein (e.g., an SNCA gene), such as the target regions disclosed herein, the degree of "complementarity" (also "homology" or "identity") is expressed as the percentage identity (or percent homology) between the ASO sequence (or region thereof) and the target region sequence (or the reverse complement of the target region) that best aligns with it. This percentage is calculated by counting the number of aligned bases that are identical between two given sequences, divided by the total number of contiguous monomers in the ASO and multiplied by 100. In this comparison, if gaps exist, it is preferable that such gaps are simply mismatches rather than areas where the number of monomers within the gap differs between the ASO of this disclosure and the target region.

The term "complement" as used herein indicates a sequence that is complementary to a reference sequence. It is well known that complementarity is the basic principle of DNA replication and transcription, since it is a common property between two DNA or RNA sequences, such that when they are antiparallel aligned with each other, the nucleotide bases at each position in these sequences will be complementary, which is very similar to looking in a mirror and seeing the opposite of a thing. Therefore, for example, the complement of the sequence 5'''ATGC''3' can be written as 3'''TACG''5' or 5'''GCAT''3'. The terms "reverse complement", "reverse complementary" and "reverse complementarity" as used herein are interchangeable with the terms "complement", "complementary" and "complementarity".

The term "% complementarity", as used herein, refers to the proportion of nucleotides (in percent) of a contiguous nucleotide sequence in a nucleic acid molecule (e.g., an oligonucleotide) that, at that contiguous nucleotide sequence, are complementary to a reference sequence (e.g., , target sequence, or sequence motif). The percent complementarity is thus calculated by counting the number of aligned nucleobases that are complementary (from Watson-Crick base pairs) between two sequences (when aligned with the target sequence 5'-3' and the oligonucleotide sequence from 3'-5 ') by dividing this number by the total number of nucleotides in the oligonucleotide and multiplying by 100. In this comparison, a nucleobase/nucleotide that does not align (forms a base pair) is called a mismatch. Insertions and deletions are not allowed in the calculation of % complementarity of a contiguous nucleotide sequence. It will be understood that, in determining complementarity, chemical modifications of nucleobases are ignored, provided that the functionality of the Watson-Crick base pairing of the nucleobase is maintained (e.g., 5'-methylcytosine is considered identical to cytosine for the purpose of calculating % identity).

The term "fully complementary" refers to 100% complementarity.

The terms "corresponding" and "corresponding", when referring to two separate nucleic acids or nucleotide sequences, can be used to clarify regions of sequences that correspond or are similar to each other on the basis of homology and/or functionality, although nucleotides of specific sequences may be numbered according to in different ways. For example, different isoforms of a gene transcript may have similar or conserved parts of the nucleotide sequences, the numbering of which may differ in the respective isoforms based on alternative splicing and/or other modifications. In addition, it is recognized that different numbering systems (eg, gene transcript and whether to start sequence numbering with a translation initiation codon or include a 5'UTR) may be used when characterizing a nucleic acid or nucleotide sequence. In addition, it is recognized that the sequence of the nucleic acid or nucleotides of different variants of a gene or gene transcript may vary. However, variant regions that share nucleic acid or nucleotide sequence homology and/or functionality as used herein are considered to "correspond" to each other. For example, an SNCA transcript nucleotide sequence corresponding to nucleotides X-Y of SEQ ID NO: 1 ("reference sequence") refers to an SNCA transcript sequence (e.g., pre-mRNA or SNCA mRNA) that has the sequence identical or similar sequence to nucleotides X-Y of SEQ ID NO: : 1. One of ordinary skill in the art can identify the appropriate X and Y residues in the SNCA transcript sequence by aligning the SNCA transcript sequence to SEQ ID NO: 1.

The terms "corresponding nucleotide analog" and "corresponding nucleotide" are meant to indicate that the nucleobase in a given nucleotide analog and the naturally occurring nucleotide have the same pairing or hybridizing ability. For example, when linking a 2-deoxyribose unit of a nucleotide to adenine, the "corresponding nucleotide analogue" contains a pentose unit (other than 2-deoxyribose) linked to adenine.

The term "DES number" or "DES #" as used herein refers to a unique number given to a nucleotide sequence having a specific pattern of nucleosides (eg DNA) and nucleoside analogs (eg LNA). The ASO construct as used here is shown in a combination of uppercase and lowercase letters. For example, DES-003092 refers to the ASO sequence ctaacaacttctgaacaaca (SEQ ID NO: 1436) with the ASO construct LDDLLDDDDDDDDDDLDLLL (i.e., CtaACaacttctgaaCaACA), where L (i.e., capital letter) indicates the nucleoside analog (for example, LNA), and D (i.e., lower case) indicates a nucleoside (i.e., DNA).

The term "ASO number" or "ASO #" as used herein refers to a unique number given to a nucleotide sequence having a detailed chemical structure of components, e.g. nucleosides (e.g. DNA), nucleoside analogs (e.g. , beta-D-oxy-LNA), nucleobases (eg A, T, G, C, U or MC) and backbone structure (eg phosphorothioate or phosphodiester). For example, ASO-003092 refers to OxyMCs DNAts DNAas OxyAs OxyMCs DNAas DNAas DNAcs DNAts DNAts DNAcs DNAts DNAgs DNAas DNAas OxyMCs DNAas OxyAs OxyMCs OxyA.

"Efficacy" is usually expressed as an IC ₅₀ or EC ₅₀ value in µM, nM, or pM, unless otherwise stated. Efficacy can also be expressed in terms of percent inhibition. IC ₅₀ is the median inhibitory concentration of the therapeutic molecule. EC ₅₀ is the median effective concentration of the therapeutic molecule relative to the vehicle or control (eg saline). In functional assays, the IC ₅₀ is the concentration of a therapeutic molecule that reduces the biological response, eg, mRNA transcription or protein expression, by 50% of the biological response achieved by that therapeutic molecule. In functional assays, the EC ₅₀ is the concentration of a therapeutic molecule that produces 50% of the biological response, such as mRNA transcription or protein expression. IC ₅₀ or EC ₅₀ can be calculated by any number of methods known in the art.

By "subject" or "individual" or "animal" or "patient" or "mammal" is meant any subject, in particular a mammalian subject, for which a diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, sport animals, and zoo animals, including, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears and so on.

The term "pharmaceutical composition" refers to a preparation that is in such a form as to provide effective biological activity of the active ingredient, and which does not contain additional components that are unacceptably toxic to the subject to whom the composition would be administered. Such a composition may be sterile.

An "effective amount" of ASO, as disclosed herein, is an amount sufficient to accomplish the stated purpose. An "effective amount" may be determined empirically and conventionally in connection with the stated purpose.

Terms such as "administering treatment" or "treatment" or "treat" or "producing relief" or "alleviate" refer to both (1) therapeutic measures that cure, slow down, reduce symptoms and/or stop the progression of the diagnosed pathological condition or disorder, and (2) prophylactic or preventive measures that prevent and/or delay the development of the target pathological condition or disorder. Thus, those in need of treatment include those who already have the disorder; those who are prone to having the disorder; and those in whom the disorder should be prevented. In some embodiments, a subject is successfully "treated" against a disease or condition disclosed herein elsewhere, according to the methods provided herein, if the patient demonstrates, for example, general, partial or temporary relief or elimination of symptoms associated with the disease or disorder.

II. Antisense oligonucleotides

The present disclosure uses antisense oligonucleotides for use in modulating the function of mammalian α-Syn encoding nucleic acid molecules, such as an SNCA nucleic acid, e.g., an SNCA transcript, including SNCA pre-mRNA and SNCA mRNA, or naturally occurring variants of such nucleic acid molecules, encoding mammalian α-Syn. The term "ASO" in the context of the present disclosure refers to a molecule formed by a covalent bond of two or more than two nucleotides (ie, an oligonucleotide).

ASO contains a continuous nucleotide sequence of about 10 to about 30, such as 10-20, 16-20 or 15-25 nucleotides in length. The terms "antisense ASO", "antisense oligonucleotide", and "oligomer" as used herein are interchangeable with the term "ASO".

Reference to the SEQ ID number includes the specific nucleobase sequence, but does not include any construct or complete chemical structure shown in FIG. 1A-1C or 2. In addition, the ASOs disclosed in FIGS. herein show a representative design, but are not limited to the specific design shown in Fig., unless otherwise indicated. In this document, one nucleotide (unit) may also be referred to as a monomer or link. When this specification refers to a specific ASO number, the reference includes the sequence, specific ASO construct, and chemical structure. When this specification refers to a specific DES number, the reference includes the sequence and the specific ASO construct. For example, when a claim (or this specification) refers to SEQ ID NO: 1436, it only includes the nucleotide sequence ctaacaacttctgaacaaca. When a claim (or this specification) refers to DES-003092, it includes the ctaacaacttctgaacaaca nucleotide sequence with the ASO constructs shown in FIG. (i.e. CtaACaacttctgaaCaACA). Alternatively, construct ASO-003092 can also be written as SEQ ID NO: 1436, where each 1st nucleotide, 4th nucleotide, 5th nucleotide, 16th nucleotide, and 18-20th nucleotides with 5' -terminus is a modified nucleotide, eg LNA, and each of the other nucleotides is an unmodified nucleotide (eg DNA). The ASO number includes the sequence and construction of the ASO, as well as specific details about the ASO. Therefore, ASO-003092, which is referenced in this application, indicates OxyMCs DNAts DNAas OxyAs OxyMCs DNAas DNAas DNAcs DNAts DNAts DNAcs DNAts DNAgs DNAas DNAas OxyMCs DNAas OxyAs OxyMCs OxyA, where "s" indicates a phosphorothioate bond.

In various embodiments, the ASO of this disclosure does not contain RNA (links). In some embodiments, the ASO contains one or more DNA units. In one embodiment, the ASO of this disclosure is a linear molecule or is synthesized as a linear molecule. In some embodiments, the ASO is a single stranded molecule and does not contain short regions, e.g., of at least 3, 4, or 5 contiguous nucleotides, that are complementary to equivalent regions within the same ASO (i.e., duplexes) - in this respect ASO is (essentially) not double stranded. In some embodiments, the ASO is not substantially double stranded. In some embodiments, the ASO is not an siRNA (small interfering RNA). In various embodiments, the ASO of this disclosure may consist entirely of a contiguous nucleotide region. Thus, in some embodiments, the ASO is not substantially complementary to itself.

In one embodiment, the ASO of this disclosure may be in the form of any pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts", as used herein, refers to the ASO derivatives of this disclosure, where the ASO is modified (eg, by adding a cation) through the preparation of its salts. Such salts retain the desired biological activity of ASO without imparting undesirable toxicological effects. In some embodiments, the ASO of this disclosure is in the form of a sodium salt. In other embodiments, the ASO is in the form of a potassium salt.

II.A. Target

Suitably, the ASO of this disclosure is capable of down-regulating (eg, reducing or eliminating) the expression of an SNCA mRNA or SNCA protein. In this regard, the ASO of this disclosure can mediate inhibition of the SNCA protein through a decrease in SNCA mRNA levels, typically in a mammalian cell, such as a human cell, such as a neuron. In particular, the present disclosure is directed to ASOs that target one or more regions of the SNCA pre-mRNA.

Synonyms for SNCA are known and include NACP, the non-A-beta component of AD amyloid, PARK1, PARK4, and PD1. The SNCA gene sequence can be found under the public accession number NC_000004.12, and the SNCA pre-mRNA transcript sequence can be found under the public accession number NG_011851.1 (SEQ ID NO: 1). The SNCA protein sequence can be found under the public accession numbers P37840, A8K2A4, Q13701, Q4JHI3 and Q6IAU6, each of which is incorporated herein by reference in its entirety. Natural variants of the SNCA gene are known. For example, natural variants of the SNCA protein may contain one or more amino acid substitutions selected from: A30P, E46K, H50Q, A53T, and any combination thereof. Therefore, the ASO of the present disclosure can be engineered to reduce or inhibit the expression of naturally occurring SNCA protein variants.

Mutations in SNCA are known to cause one or more pathological conditions. The ASO of this disclosure can be used to reduce or inhibit the expression of an SNP (single nucleotide polymorphism) or alternatively spliced SNCA transcript containing one or more mutations, and therefore to reduce the production of a mutated SNCA protein. Examples of SNCA protein mutants include an SNCA protein containing one or more mutations selected from: D2A, E35K, Y39F, H50A, E57K, G67_V71del, V71_V82del, A76_V77del, A76del, V77del, A78del, A85_F94del, Y125F, Y133F, Y136F and their any combination, but not limited to. The ASO of this disclosure can be engineered to reduce or inhibit the expression of any SNCA protein mutants.

An example of an ASO target nucleic acid sequence is SNCA pre-mRNA. SEQ ID NO: 1 represents the genomic sequence of SNCA. SEQ ID NO: 1 is identical to the SNCA pre-mRNA sequence, except that the "t" nucleotide in SEQ ID NO: 1 is shown as "and" in the pre-mRNA. In some embodiments, the "target nucleic acid" comprises the intron region of nucleic acids encoding the SNCA protein, or naturally occurring variants thereof, and RNA nucleic acids derived therefrom, eg, pre-mRNA. In other embodiments, the "target nucleic acid" includes the exon region of nucleic acids encoding the SNCA protein, or naturally occurring variants thereof, and RNA nucleic acids derived therefrom, such as mRNA, pre-mRNA, and mature mRNA. In some embodiments, for example, when used in research or diagnostics, the "target nucleic acid" may be a cDNA or synthetic oligonucleotide derived from the above DNA or RNA target nucleic acids. In one embodiment, the SNCA genomic sequence is shown as GenBank Accession No. NG_011851.1 (SEQ ID NO: 1). The mature mRNA encoding the SNCA protein is shown as SEQ ID NO: 2 (NM_000345.3). Variants of this sequence are shown in SEQ ID NO: 3 (NM_001146054.1), SEQ ID NO: 4 (NM_001146055.1) and SEQ ID NO: 5 (NM_007308.2) - options 2-4, respectively. Option 2 corresponds to GenBank Access No. NM_001146054.1. Option 3 corresponds to GenBank Access No. NM_001146055.1. Option 4 corresponds to GenBank Access No. NM_007308.2. The SNCA protein sequence encoded by the SNCA mRNA (SEQ ID NO: 2) is shown as SEQ ID NO: 6.

The target nucleic acid sequences to which the oligonucleotides of the invention are complementary are summarized in the table below:

The oligonucleotide of the invention, for example, can be targeted to the exon region of a mammalian SNCA, or, for example, can be targeted to the intron region of a pre-SNCA mRNA, as shown in the table below:

In one embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence of 10-30 nucleotides in length that is complementary to a nucleic acid sequence within an SNCA transcript, e.g., a region corresponding to an exon, an intron, or any combination thereof of SEQ ID NO: 1, or a region within SEQ ID NO: 2, 3, 4 or 5, where the given nucleic acid sequence corresponds to (i) nucleotides 4942-5343 of SEQ ID NO: 1; (ii) nucleotides 6326-7041 of SEQ ID NO: 1; (iia) nucleotides 6336-7041 of SEQ ID NO: 1; (iii) nucleotides 7329-7600 of SEQ ID NO: 1; (iv) nucleotides 7630-7783 of SEQ ID NO: 1; (iva) nucleotides 7750-7783 of SEQ ID NO: 1; (v) nucleotides 8277-8501 of SEQ ID NO: 1; (vi) nucleotides 9034-9526 of SEQ ID NO: 1; (vii) nucleotides 9982-14279 of SEQ ID NO: 1; (viii) nucleotides 15204-19041 of SEQ ID NO: 1; (ix) nucleotides 20351-29654 of SEQ ID NO: 1; (ixa) nucleotides 20351-20908 SEQ ID NO: 1; (ixb) nucleotides 21052-29654 of SEQ ID NO: 1; (x) nucleotides 30931-33938 of SEQ ID NO: 1; (xi) nucleotides 34932-37077 of SEQ ID NO: 1; (xii) nucleotides 38081-42869 of SEQ ID NO: 1; (xiii) nucleotides 44640-44861 of SEQ ID NO: 1; (xiv) nucleotides 46173-46920 of SEQ ID NO: 1; (xv) nucleotides 47924-58752 of SEQ ID NO: 1; (xvi) nucleotides 60678-60905 of SEQ ID NO: 1; (xvii) nucleotides 62066-62397 of SEQ ID NO: 1; (xviii) nucleotides 67759-71625 of SEQ ID NO: 1; (xix) nucleotides 72926-86991 of SEQ ID NO: 1; (xx) nucleotides 88168-93783 SEQ ID NO: 1; (xxi) nucleotides 94976-102573 SEQ ID NO: 1; (xxii) nucleotides 104920-107438 SEQ ID NO: 1; (xxiii) nucleotides 108948-119285 SEQ ID NO: 1; (xxiiia) nucleotides 108948-114019 SEQ ID NO: 1; (xxiib) nucleotides 114292-116636 SEQ ID NO: 1; (xxiv) nucleotides 131-678 of SEQ ID NO: 5; (xxv) nucleotides 131-348 of SEQ ID NO: 3; (xxvi) nucleotides 1-162 of SEQ ID NO: 4; (xxvii) nucleotides 126-352 of SEQ ID NO: 2; (xxviii) nucleotides 276-537 of SEQ ID NO: 2; (xxix) nucleotides 461-681 of SEQ ID NO: 2 and (xxx) nucleotides 541-766 of SEQ ID NO: 2.

In another embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence of 10-30 nucleotides that hybridizes to or is complementary, such as at least 90% complementary, such as a fully complementary region within an intron of an SNCA transcript, e.g. , the region corresponding to the intron of SEQ ID NO: 1 (eg, intron 1, 2, 3 or 4).

In some embodiments, this ASO contains a contiguous nucleotide sequence of 10-30 nucleotides in length that is at least 90% complementary, such as a fully complementary region of an intron present in human SNCA pre-mRNA selected from intron i0 (nucleotides 1-6097 SEQ ID NO: 1); i1 (nucleotides 6336-7604 of SEQ ID NO: 1); i2 (nucleotides 7751-15112 of SEQ ID NO: 1); i3 (nucleotides 15155-20908 SEQ ID NO: 1); i4 (nucleotides 21052-114019 of SEQ ID NO: 1); i5 (nucleotides 114104-116636 of SEQ ID NO: 1) or i6 (nucleotides 119199-121198 of SEQ ID NO: 1).

In some embodiments, this ASO contains a contiguous nucleotide sequence of 10-30 nucleotides in length that is at least 90% complementary, such as fully complementary to human SNCA, where the nucleic acid sequence corresponds to nucleotides 21052-20351-29654 of SEQ ID NO: 1; nucleotides 30931-33938 SEQ ID NO: 1; nucleotides 44640-44861 of SEQ ID NO: 1 or nucleotides 47924-58752 of SEQ ID NO: 1.

In particular, an ASO complementary to intron 4 (nucleotides 21025-114019 of SEQ ID NO: 1) is advantageous, such as regions of intron 4 selected from nucleotides 21052-29654 of SEQ ID NO: 1; nucleotides 24483-28791 SEQ ID NO: 1; nucleotides 30931-33938 SEQ ID NO: 1; nucleotides 32226-32242 SEQ ID NO: 1; nucleotides 44640-44861 SEQ ID NO: 1; nucleotides 44741-44758 SEQ ID NO: 1; nucleotides 47924-58752 of SEQ ID NO: 1 or nucleotides 48641-48659 of SEQ ID NO: 1.

In another embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence of 10-30 nucleotides that hybridizes to or is complementary, such as at least 90% complementary, such as fully complementary to the nucleic acid sequence, or a region within the sequence. an SNCA transcript, where the given nucleic acid sequence corresponds to nucleotides 6426-6825; 18569-20555 or 31398-107220 SEQ ID NO: 1, and where this ASO has one of the designs described herein (e.g., section II.G, e.g., gapmer design, e.g., gapmer design with interleaved flanks), or the chemical structure shown elsewhere in this document (eg, FIGS. 1A-1C and 2).

In another embodiment, the target region corresponds to nucleotides 5042-5243 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 6336-7604 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 6336-7041 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 6426-6941 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 7429-7600 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 7630-7683 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 7751-15112 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 7751-7783 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 8377-8401 of SEQ ID NO: 1.

In another embodiment, the target region corresponds to nucleotides 9134-9426 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 10082-14179 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 15304-18941 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 15155-20908 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 20451-29554 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 20351-20908 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 21052-114019 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 21052-29654 of SEQ ID NO: 1

In one embodiment, the target region corresponds to nucleotides 31031-33838 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 30931-33938 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 35032-36977 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 38181-42769 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 44640-44861 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 44740-44761 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 46273-46820 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 47924-58752 of SEQ ID NO: 1.

In other embodiments, the target region corresponds to nucleotides 48024-58752 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 60778-60805 of SEQ ID NO: 1.

In some embodiment, the target region corresponds to nucleotides 62166-62297 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 67859-71525 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 73026-86891 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 88268-93683 of SEQ ID NO: 1.

In some embodiment, the target region corresponds to nucleotides 95076-102473 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 105020-107338 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 109048-119185 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 108948-114019 of SEQ ID NO: 1.

In some embodiments, the target region corresponds to nucleotides 114292-116636 of SEQ ID NO: 1.

In one embodiment, the target region corresponds to nucleotides 231-248 or 563-578 of SEQ ID NO: 5.

In another embodiment, the target region corresponds to nucleotides 231-248 of SEQ ID NO: 3.

In some embodiments, the target region corresponds to nucleotides 38-62 of SEQ ID NO: 4.

In other embodiments, the target region corresponds to nucleotides 226-252 of SEQ ID NO: 2.

In one embodiment, the target region corresponds to nucleotides 376-437 of SEQ ID NO: 2.

In another embodiment, the target region corresponds to nucleotides 561-581 of SEQ ID NO: 2.

In one embodiment, the target region corresponds to nucleotides 641-666 of SEQ ID NO: 2.

In some embodiments, the ASOs hybridize to or are complementary, such as at least 90% complementary, such as fully complementary regions within the SNCA transcript, such as SEQ ID NO: 1, and have a sequence score equal to or greater than than about 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9 or 1.0. Sequence scoring methods are disclosed elsewhere herein.

In one embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence that hybridizes to a region within an exon of an SNCA transcript, e.g., the region corresponding to the exon of SEQ ID NO: 1, e.g., exon 2, 4, 5, or 6. In another embodiment, the ASO according to this disclosure, contains a contiguous nucleotide sequence that hybridizes to a nucleic acid sequence or region within an SNCA transcript sequence ("target region"), where the nucleic acid sequence corresponds to nucleotides 7630-7683; 20932-21032; 114059-114098 or 116659-119185 SEQ ID NO: 1, and where the given ASO has one of the designs described herein (e.g., section II.G, e.g., gapmer design, e.g., interleaved flank gapmer design), or the chemical structure shown elsewhere in this document (eg, FIGS. 1A-1C and 2).

In another embodiment, the target region corresponds to nucleotides 7630-7683 of SEQ ID NO: 1. In some embodiments, the target region corresponds to nucleotides 20932-21032 of SEQ ID NO: 1. In certain embodiments, the target region corresponds to nucleotides 114059-114098 of SEQ ID NO: 1 In one embodiment, the target region corresponds to nucleotides 116659-119185 of SEQ ID NO: 1. In another embodiment, the target region corresponds to nucleotides 116981-117212 of SEQ ID NO: 1. In some embodiments, the target region corresponds to nucleotides 116981-117019 of SEQ ID NO: 1. In other embodiments, the target region corresponds to nucleotides 117068-117098 of SEQ ID NO: 1. In certain embodiments, the target region corresponds to nucleotides 117185-117212 of SEQ ID NO: 1. In another embodiment, the target region corresponds to nucleotides 118706-118725 of SEQ ID NO. : 1. In certain embodiments, ASOs hybridize to a region within an exon of an SNCA transcript, e.g., SEQ ID NO: 1, and have a sequence score equal to or greater than about 0, one; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9 or 1.0. Sequence scoring methods are disclosed elsewhere herein.

In other embodiments, the target region corresponds to nucleotides 6426-6825 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In some embodiments, the target region corresponds to nucleotides 18569-20555 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In another embodiment, the target region corresponds to nucleotides 20926-21032 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In other embodiments, the target region corresponds to nucleotides 31398-31413 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5' end or both. In some embodiments, the target region corresponds to nucleotides 35032-35049 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In certain embodiments, the target region corresponds to nucleotides 68373-69827 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In another embodiment, the target region corresponds to nucleotides 78418-78487 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In other embodiments, the target region corresponds to nucleotides 91630-91646 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In some embodiments, the target region corresponds to nucleotides 100028-101160 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In certain embodiments, the target region corresponds to nucleotides 107205-107220 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In another embodiment, the target region corresponds to nucleotides 114059-114098 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In other embodiments, the target region corresponds to nucleotides 116659-119185 of SEQ ID NO: 1 ± 10, ± 20, ± 30, ± 40, ± 50, ± 60, ± 70, ± 80, or ± 90 nucleotides at the 3' end, 5 '-end or both. In other embodiments, the target region corresponds to nucleotides 7604-7620 of SEQ ID NO: 1 ± 1, ± 2, ± 3, ± 4, ± 5, ± 6, ± 7, ± 8, or ± 9 nucleotides at the 3' end, 5 '-end or both.

In certain embodiments, the ASO of this disclosure is capable of hybridizing to a target nucleic acid (eg, an SNCA transcript) under physiological conditions, ie. conditions in vivo. In some embodiments, the ASO of this disclosure is capable of hybridizing to a target nucleic acid (eg, an SNCA transcript) in vitro. In some embodiments, the ASO of this disclosure is capable of hybridizing to a target nucleic acid (eg, an SNCA transcript) in vitro under stringent conditions. The stringency of conditions for in vitro hybridization depends on, among others, productive cellular uptake, RNA availability, temperature, association free energy, salt concentration, and time (see, for example, Stanley T Crooks, Antisense Drug Technology: Principles, Strategies and Applications, 2 ^nd Edition, CRC Press (2007)). In general, conditions of high to moderate stringency are used for in vitro hybridization to ensure hybridization between substantially similar nucleic acids, but not between dissimilar nucleic acids. An example of stringent hybridization conditions includes hybridization in 5× saline-sodium citrate (SSC) buffer (0.75 M sodium chloride/0.075 M sodium citrate) for 1 hour at 40°C, followed by washing the sample 10 times in 1 × SSC at 40°C and 5 times in 1× SSC buffer at room temperature. In vivo hybridization conditions are within the intracellular conditions (eg, physiological pH and intracellular ionic conditions) that govern the hybridization of antisense oligonucleotides to target sequences. In vivo conditions can be mimicked in vitro by relatively low stringency conditions. For example, hybridization can be carried out in vitro in 2× SSC (0.3 M sodium chloride/0.03 M sodium citrate), 0.1% SDS (sodium dodecyl sulfate) at 37°C. A wash solution containing 4x SSC, 0.1% SDS can be used at 37°C with a final wash in 1x SSC at 45°C.

II.B. ASO sequences

The ASOs of this disclosure comprise a contiguous nucleotide sequence that corresponds to the complementary strand of a region of the SNCA transcript, e.g., the nucleotide sequence corresponding to SEQ ID NO: 1.

In some embodiments, this disclosure provides an ASO that contains a contiguous nucleotide sequence of only 10-30 nucleotides, such as 10-25 nucleotides, such as 16-22, such as 10-20 nucleotides, such as , 14-20 nucleotides, such as 17-20 nucleotides, such as 10-15 nucleotides, such as 12-14 nucleotides in length, where this contiguous nucleotide sequence is at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% sequence identity with a region within the complementary strand of a mammalian SNCA transcript, such as SEQ ID NO: 1 or SEQ ID NO: 2, or a naturally occurring variant thereof (SEQ ID NO: 3, 4 or 5). Thus, for example, ASO hybridizes to a single stranded nucleic acid molecule having the sequence of SEQ ID NOs: 1-5 or a portion thereof.

In some embodiments, the oligonucleotide contains a contiguous sequence of 10-30 nucleotides, such as 10-25 nucleotides, such as 16-22, such as 10-20 nucleotides, such as 14-20 nucleotides, such as , such as 17-20 nucleotides, such as 10-15 nucleotides, such as 12-14 nucleotides in length, which has at least 90% complementarity, such as at least 91% , such as, for example, at least 92%, such as, for example, at least 93%, such as, for example, at least 94%, such as, for example, at least 95%, as , such as at least 96%, such as, for example, at least 97%, such as, for example, at least 98% or 100% complementarity with a mammalian SNCA transcript region, such as SEQ ID NO: 1, 2, 3, 4 and/or 5.

The ASO may comprise a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the equivalent region of the target nucleic acid that encodes a mammalian SNCA protein (eg, SEQ ID NOs: 1-5). This ASO may contain a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the target nucleic acid sequence, or a region within the sequence, such as the intron region corresponding to nucleotides X-Y of SEQ ID NO: 1, where X and Y represent the start site pre-mRNA and pre-mRNA end site NG_011851.1, respectively. Examples of such areas are listed in section II.A "Target". In addition, a given ASO may have the design described elsewhere in this document (e.g., section II.C, e.g., gapmer design, e.g., gapmer design with interleaved flanks), or the chemical structure shown elsewhere in this document. (for example, FIG. 1A-1C and 2). In some embodiments, the ASO contains a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the target nucleic acid sequence, or a region within that sequence corresponding to nucleotides X-Y of SEQ ID NO: 2, where X and Y are the start site of the mRNA and the end site mRNA, respectively. Examples of such areas are listed in section II.A "Target". In other embodiments, the ASO comprises a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the target nucleic acid sequence, or a region within that sequence corresponding to nucleotides X-Y of SEQ ID NO: 3, where X and Y represent the start site of the mRNA and the end site mRNA, respectively. Examples of such areas are listed in section II.A "Target". In other embodiments, the ASO comprises a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the target nucleic acid sequence, or a region within the sequence corresponding to nucleotides X-Y of SEQ ID NO: 4, where X and Y are the mRNA start site and the site end of the mRNA, respectively. Examples of such areas are listed in section II.A "Target". In other embodiments, this ASO comprises a contiguous nucleotide sequence that is fully complementary (perfectly complementary) to the target nucleic acid sequence, or a region within the sequence corresponding to nucleotides X-Y of SEQ ID NO: 5, where X and Y are the mRNA start site and the site end of the mRNA, respectively. Examples of such areas are listed in section II.A "Target".

In some embodiments, an ASO nucleotide sequence of this disclosure or a given contiguous nucleoid sequence has at least about 80% sequence identity relative to a sequence selected from SEQ ID NOs: 7-1878 (i.e., the sequences in FIGS. 1A-1C and 2), such as at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93% - at least about 94%, at least about 95%, at least about 96% sequence identity, at least about 97% sequence identity, at least about 98% sequence identity, at least about 99% sequence identity, such as about 100% sequence identity (homologous). In some embodiments, the ASO has the construct described elsewhere herein (e.g., section II.G.I, e.g., gapmer construct, e.g., alternating flank gapmer construct), or the nucleoside chemical structure shown elsewhere herein ( for example, FIGS 1A-1C and 2).

In some embodiments, the ASO nucleotide sequence of this disclosure, or given contiguous nucleotide sequence, has at least about 80% sequence identity relative to a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353, such as at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96% sequence identity, at least about 97% sequence identity, at least about 98% sequence identity, at least about 99% sequence identity, such as about 100% sequence identity (homologous). In some embodiments, the ASO has the construct described elsewhere herein (e.g., section II.G.I, e.g., gapmer construct, e.g., alternating flank gapmer construct), or the nucleoside chemical structure shown elsewhere herein ( for example, FIGS 1A-1C and 2).

In another embodiment, the ASO nucleotide sequence of this disclosure, or this contiguous nucleotide sequence, consists of a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353.

In one embodiment, the ASO nucleotide sequence of this disclosure, or this contiguous nucleotide sequence, comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 276; 278; 296; 295; 325; 328; 326; 329; 330; 327; 332; 333; 331; 339; 341; 390; 522 and 559.

In some embodiments, the ASO of this disclosure comprises at least one ASO with the construct (eg, DES number) disclosed in FIG. 1A-1C and 2. In some embodiments, the ASO of this disclosure comprises at least one ASO with the construct (eg, DES number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 3' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2. In other embodiments, the ASO of this disclosure comprises at least one ASO with the construct (eg, DES number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 5' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2. In other embodiments, the ASO of this disclosure comprises at least one ASO with the construct (eg, DES number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 5' end and/or 3' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2.

In one embodiment, the contiguous nucleotide sequence comprises or consists of a sequence and a construct selected from the group consisting of:

TTCtctatataacatCACT (SEQ ID NO: 276)

TTTCtctatataacaTCAC (SEQ ID NO: 278);

AACTttttacataccACAT (SEQ ID NO: 296);

AACTttacataccaCATT (SEQ ID NO: 295);

ATTAttcatcacaatCCA (SEQ ID NO: 325);

ATTAttcatcacaATCC (SEQ ID NO: 328);

CattattcatcacaaTCCA (SEQ ID NO: 326);

CATtattcatcacaATCC (SEQ ID NO: 329);

ACattattcatcacaaTCC (SEQ ID NO: 330);

AcattattcatcacaaTCCA (SEQ ID NO: 327);

ACATtattcatcacAATC (SEQ ID NO: 332);

TACAttattcatcacAATC (SEQ ID NO: 333);

TAcattattcatcacaaTCC (SEQ ID NO: 331);

TTCaacatttttatttCACA (SEQ ID NO: 339);

ATTCaacatttttattTCAC (SEQ ID NO: 341);

ACTAtgatacttcACTC (SEQ ID NO: 390);

ACACattaactactCATA (SEQ ID NO: 522) and

GTCAaaatattcttaCTTC (SEQ ID NO: 559),

where capital letters denote the sugar-modified nucleoside analog and lowercase letters denote DNA.

In other embodiments, the ASO of this disclosure comprises at least one ASO with the chemical structure (eg, ASO number) disclosed in FIG. 1A-1C and 2. In some embodiments, the ASO of this disclosure comprises at least one ASO with the chemical structure (eg, ASO number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 3' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2. In other embodiments, the ASO of this disclosure comprises at least one ASO with the chemical structure (eg, ASO number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 5' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2. In other embodiments, the ASO of this disclosure comprises at least one ASO with the chemical structure (eg, ASO number) disclosed in FIG. 1A-1C and 2, where a given ASO is shorter at the 5' end and/or 3' end by one nucleotide, two nucleotides, three nucleotides, or four nucleotides than the ASOs disclosed in FIG. 1A-1C and 2.

In some embodiments, the ASO (or a contiguous nucleotide portion thereof) is selected from or contains one of the sequences selected from the group consisting of SEQ ID NO: 7-1878 and a region of at least 10 contiguous nucleotides thereof, where the ASO (or its contiguous nucleotide portion) may possibly contain one, two, three or four mismatches compared to the corresponding SNCA transcript. It is useful if there is no more than 1 inconsistency or no more than 2 inconsistencies.

In some embodiments, the ASO (or a continuous nucleotide portion thereof) is selected from or contains one of the sequences selected from the group consisting of SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353 and a region of at least their 10 contiguous nucleotides, where a given ASO (or a continuous nucleotide portion thereof) may possibly contain one, two, three, or four mismatches compared to the corresponding SNCA transcript. It is useful if there is no more than 1 inconsistency or no more than 2 inconsistencies.

In one embodiment, this ASO contains a sequence selected from the group consisting of SEQ ID NO: 1436 (sequence ASO-003092) and SEQ ID NO: 1547 (sequence ASO-003179)).

In another embodiment, this ASO contains a sequence selected from the group consisting of ASO-008387; ASO-008388; ASO-008501; ASO-008502; ASO-008529; ASO-008530; ASO-008531; ASO-008532; ASO-008533; ASO-008534; ASO-008535; ASO-008536; ASO-008537; ASO-008543; ASO-008545; ASO-008584; ASO-008226 and ASO-008261.

In some embodiments, the ASO of this disclosure binds to a target nucleic acid sequence (e.g., an SNCA transcript) and is capable of inhibiting or reducing the expression of the SNCA transcript by at least about 10%, at least about 20%, at least about 30%. %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or approximately 100% in tissue (e.g., brain region) of a mouse expressing the human SNCA gene (e.g., A53T-PAC) when administered in vivo at doses of 3.13 μg, 12.5 μg, 25 μg, 50 μg, or 100 μg compared to a control (e.g., an internal control such as GAPDH (glyceraldehyde-3-phosphate dehydrogenase) or tubulin, or a mouse administered vehicle control alone), as measured by analysis, such as quantitative PCR (polymerase chain reaction), or ^QUANTIGENE® analysis disclosed in this document.

In some embodiments, the ASO of this disclosure is capable of reducing SNCA protein expression by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%. %, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% in tissue (e.g., a brain region) of a mouse expressing human SNCA gene (e.g., A53T-PAC), when administered in vivo at doses of 3.13 µg, 12.5 µg, 25 µg, 50 µg, or 100 µg compared to a control (eg, an internal control such as GAPDH or tubulin, or a mouse treated with a single vehicle control), as measured by an assay, eg, the high content assay disclosed herein (see Example 2A).

In some embodiments, the ASO of this disclosure binds to a target nucleic acid sequence (e.g., an SNCA transcript) and is capable of inhibiting or reducing the expression of the SNCA transcript by at least about 10%, at least about 20%, at least about 30%. %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or approximately 100% in tissue (e.g. brain area) of wild type cynomolgus monkey expressing the SNCA gene when administered once or twice in vivo at doses of 4 mg, 8 mg or 16 mg compared to a control (e.g. an internal control such as GAPDH or tubulin, or cynomolgus monkey treated with one vehicle control), as measured by assay, eg, quantitative PCR or QUANTIGENE ^® assay disclosed herein.

In some embodiments, the ASO of this disclosure is capable of reducing SNCA protein expression by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%. %, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% in tissue (e.g., a brain region) of a cynomolgus monkey expressing wild-type SNCA gene when administered once or twice in vivo at doses of 4 mg, 8 mg, or 16 mg compared to a control (e.g., an internal control such as GAPDH or tubulin, or cynomolgus monkeys administered one vehicle control ), when measured by assay, such as the high content assay disclosed herein (see Example 2A).

In other embodiments, the ASO of this disclosure is capable of reducing in vitro SNCA mRNA expression by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% in mouse primary neurons expressing the full-length human SNCA gene (e.g., PAC neurons), when exposure of these neurons to 5 μM, 3.3 μM, 1 μM, 4 nM, 40 nM, or 200 nM antisense oligonucleotide compared to a control (e.g., an internal control such as GAPDH or tubulin, or mouse primary neurons expressing full-length human SNCA gene, in contact with saline alone), when measured by an assay, eg, the ^QUANTIGENE® assay disclosed herein.

In other embodiments, the ASO of this disclosure is capable of reducing in vitro SNCA protein expression by at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% in mouse primary neurons expressing the full-length human SNCA gene (e.g., PAC neurons) when these neurons are in contact with 5 μM, 3.3 μM, 1 μM, 4 nM, 40 nM, or 200 nM antisense oligonucleotide compared with a control (e.g., an internal control such as GAPDH or tubulin, or mouse primary neurons expressing the full-length human SNCA gene in contact with saline alone), as measured by assay, such as the high content assay disclosed herein (see .Example 2A).

In some embodiments, the ASO of this disclosure is capable of reducing in vitro SNCA mRNA expression by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% in a human neuroblastoma cell line (e.g., SK- N-BE(2)) expressing the full length human SNCA gene when these neuroblastoma cells are in contact with 25 μM antisense oligonucleotide compared to a control (e.g., an internal control such as GAPDH or tubulin, or neuroblastoma cells expressing the full length human gene SNCAs in contact with saline alone) when measured by assay, such as quantitative PCR, as disclosed herein.

In some embodiments, the ASO disclosed herein is capable of reducing in vitro SNCA protein expression by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% in a human neuroblastoma cell line (e.g. , SK-N-BE(2)), expressing the full-length human SNCA gene, when these neuroblastoma cells are in contact with 25 μM antisense oligonucleotide compared to a control (e.g., an internal control such as GAPDH or tubulin, or neuroblastoma cells expressing full-length human SNCA gene in contact with a single saline solution), as measured by assay, for example, the high content assay disclosed herein (see Example 2A).

In some embodiments, the ASO of this disclosure binds to an SNCA transcript and inhibits or reduces SNCA mRNA expression by at least about 10% or about 20% compared to normal (i.e., control) expression levels in the cell, e.g., at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% of normal expression levels (such as expression in the absence of ASO or conjugate(s)) in the cell. In some embodiments, ASO reduces SNCA protein expression in a cell following ASO administration by at least 60%, at least 70%, at least 80%, or at least 90% compared to a cell not exposed to ASO ( i.e. control). In some embodiments, ASO reduces SNCA protein expression in a cell following administration of the ASO by at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to the cell, not exposed to ASO (i.e. control).

In some embodiments, the ASO of this disclosure has at least one property selected from the following: (1) reduces SNCA mRNA expression in a cell compared to a control cell that has not been exposed to ASO; (2) does not significantly reduce fluctuations in calcium levels in the cell; (3) does not significantly reduce the intensity of tubulin in the cell; (4) reduces α-Syn protein expression in the cell; and (5) any combination of the two compared to a control cell that was not exposed to ASO.

In some embodiments, the ASO of this disclosure does not significantly reduce fluctuations in calcium levels in a cell, such as neurons. If ASO does not significantly reduce fluctuations in calcium levels in the cell, this property of ASO corresponds to the reduced neurotoxicity of ASO. In some embodiments, fluctuations in calcium levels are greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 85%, greater than or equal to 80%, greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 65%, greater than or equal to 60%, greater than or equal to 55%, or greater than or equal to 50% fluctuations in a cell not exposed to ASO.

Fluctuations in calcium levels are important for proper neuronal function. It has been shown that networks of cortical neurons undergo spontaneous fluctuations in calcium levels, leading to the release of the neurotransmitter glutamate. Fluctuations in calcium levels also regulate the interactions of neurons with associated glia, in addition to other associated neurons in the network, with the release of neurotransmitters other than glutamate. Regulated fluctuations in calcium levels are required for the homeostasis of neural networks for normal brain function. (See Shashank et al., Brain Research, 1006(1): 8-17 (2004); Rose et al., Nature Neurosci, 4:773-774 (2001); Zonta et al., J Physiol Paris., 96(3-4):193-8 (2002); Pasti et al., J. Neurosci., 21(2): 477-484 (2001).) Glutamate also activates two distinct ion channels: α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors.

In some embodiments, the calcium fluctuations measured in the present methods are AMPA-dependent calcium fluctuations. In some embodiments, the calcium fluctuations are NMDA dependent calcium fluctuations. In some embodiments, the calcium fluctuations are gamma-aminobutyric acid (GABA) dependent calcium fluctuations. In some embodiments, the calcium fluctuation is a combination of two or more AMPA-dependent, NMDA-dependent, or GABA-dependent calcium fluctuations.

In some embodiments, the calcium fluctuations measured in the present methods are AMPA-dependent calcium fluctuations. In order to measure AMPA-dependent calcium fluctuations, calcium fluctuations can be measured in the presence of Mg ^{2+ ions} (eg, MgCl ₂ ). In some embodiments, this method will further include the addition of Mg ^{2+ ions} (eg, MgCl ₂ ) in an amount that allows the detection of AMPA-dependent fluctuations in calcium levels. In some embodiments, an effective ion concentration to detect AMPA-dependent calcium fluctuations is at least about 0.5 mM. In other embodiments, the effective ion concentration to induce AMPA-dependent calcium fluctuations is at least about 0.6 mM, at least about 0.7 mM, at least about 0.8 mM, at least about 0.9 mM. , at least about 1 mM, at least about 1.5 mM, at least about 2.0 mM, at least about 2.5 mM, at least about 3.0 mM, at least about 4 mM , at least about 5 mM, at least about 6 mM, at least about 7 mM, at least about 8 mM, at least about 9 mM, or at least about 10 mM. In a specific embodiment, the concentration of Mg ^{2+ ions} (eg, MgCl ₂ ) useful for these methods is 1 mM. In some embodiments, the concentration of Mg ^{2+ ions} (eg, MgCl ₂ ) useful for the present methods is from about 1 mM to about 10 mM, from about 1 mM to about 15 mM, from about 1 mM to about 20 mM, from about 1 mM up to about 25 mm. Mg ^{2+ ions} can be added by adding magnesium salts such as magnesium carbonate, magnesium chloride, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium sulfate and magnesium sulfate heptahydrate.

In some embodiments, fluctuations in calcium levels are measured in the present method through the use of fluorescent probes that detect fluctuations in intracellular calcium levels. For example, detection of intracellular calcium flux can be achieved by staining cells with fluorescent dyes that bind to calcium ions (known as calcium fluorescent tracers) with a detectable change in fluorescence as a result (for example, Fluo-4 AM and Fura Red AM dyes available from Molecular Probes. Eugene, OR, United States of America).

In other embodiments, the ASOs of this disclosure do not significantly reduce the intensity of tubulin in the cell. In some embodiments, the tubulin intensity is greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 85%, greater than or equal to 80%, greater than or equal to 75%, greater than or equal to 70%, greater than or equal to equal to 65%, greater than or equal to 60%, greater than or equal to 55%, or greater than or equal to 50% of the tubulin intensity in a cell not exposed to ASO (or exposed to saline).

In some embodiments, this property is observed when using from 0.04 nm to 400 μm concentration of ASO according to this disclosure. In the same or another embodiment, inhibition or reduction of SNCA mRNA and/or SNCA protein expression in a cell results in less than 100%, such as, for example, less than 98%, less than 95%, less than 90%, less than 80% such as less than 70% mRNA or protein levels compared to cells not exposed to ASO. Expression level modulation can be determined by measuring SNCA protein levels, for example, by methods such as SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), followed by Western blotting using appropriate antibodies induced against the target protein. Alternatively, modulation of expression levels can be determined by measuring SNCA mRNA levels, such as Northern blotting or quantitative PCR-RT (Reverse Transcription-Coupled Polymerase Chain Reaction). When measuring inhibition by mRNA levels, the level of downregulation, when using a suitable dosage, such as a concentration of from about 0.04 nM to about 400 μM, is in some embodiments typically a level from about 10-20% of normal levels in the cell in the absence of ASO .

In some embodiments, the ASO of this disclosure has an in vivo tolerability less than or equal to a total score of 4, where this total score is the sum of the unit scores of the five categories that are: 1) hyperactivity; 2) reduced activity and arousal; 3) motor dysfunction and/or ataxia; 4) abnormal position and breathing; and 5) trembling and/or convulsions, and where a single score for each category is measured on a scale of 0-4. In some embodiments, in vivo tolerability is less than or equal to a total score of 3, a total score of 2, a total score of 1, or a total score of 0. In some embodiment, an in vivo tolerability score is determined as described in the examples below.

In some embodiments, a given ASO can tolerate 1, 2, 3, or 4 (or more) mismatches when hybridized to a target sequence and still binds enough to the target to demonstrate the desired effect, i.e. down regulation of the mRNA and/or target protein. Mismatches, for example, can be compensated for by the increased length of the ASO nucleotide sequence and/or the increased number of nucleotide analogs, which are disclosed elsewhere herein.

In some embodiments, the ASO of this disclosure contains no more than 3 mismatches when hybridized to a target sequence. In other embodiments, the contiguous nucleotide sequence contains no more than 2 mismatches when hybridized to the target sequence. In other embodiments, the contiguous nucleotide sequence contains no more than 1 mismatch when hybridized to the target sequence.

In some embodiments, an ASO according to this disclosure contains a nucleotide sequence or a region within this sequence according to any of SEQ ID NO: 7-1878, an ASO sequence with a construct as described in FIG. 1A-1C and 2, and an ASO sequence with a chemical structure as described in FIG. 1A-1C and 2.

However, it is understood that in some embodiments, the ASO nucleotide sequence may contain an additional 5' or 3' nucleotides, such as 1-5, such as 2-3 additional nucleotides, such as, independently, 1, 2, 3 , 4 or 5 additional nucleotides. These additional 5' and/or 3' nucleotides are preferably not complementary to the target sequence. In this regard, the ASO of this disclosure may, in some embodiments, comprise a contiguous nucleotide sequence that is flanked by 5' and/or 3' additional nucleotides. In some embodiments, the additional 5' and/or 3' nucleotides are naturally occurring nucleotides such as DNA or RNA. In another embodiment, naturally occurring nucleotides at the 5' or 3' end are linked by phosphodiester (PO) internucleotide bonds. Such terminal PO bonds are cleavable nucleases upon entry into the target cell, also referred to as biocleavable linkers, and are described in detail in WO 2014/076195.

In some embodiments, the ASO of this disclosure has a sequence score greater than or equal to 0.2, where this sequence score is calculated by Formula I:

In other embodiments, the ASO of this disclosure has a sequence score greater than or equal to 0.2, where this sequence score is calculated using the formula IA:

In these embodiments, a sequence score greater than or equal to the cut-off value corresponds to reduced ASO neurotoxicity.

In some embodiments, the ASO of this disclosure has a sequence score greater than or equal to about 0.1; 0.2; 0.25; 0.3; 0.35; 0.4; 0.45; 0.5; 0.55; 0.6; 0.65; 0.7; 0.75; 0.8; 0.85; 0.9; 0.95 or 1.0.

In one embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence that hybridizes to a non-coding region of an SNCA transcript, wherein the ASO sequence score is greater than or equal to about 0.1; 0.2; 0.25; 0.3; 0.35; 0.4; 0.45; 0.5; 0.55; 0.6; 0.65; 0.7; 0.75; 0.8; 0.85; 0.9; 0.95 or 1.0.

In another embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence hybridizing to an intron region of an SNCA transcript, wherein the ASO sequence score is greater than or equal to about 0.1; 0.2; 0.25; 0.3; 0.35; 0.4; 0.45; 0.5; 0.55; 0.6; 0.65; 0.7; 0.75; 0.8; 0.85; 0.9; 0.95 or 1.0.

In another embodiment, the ASO of this disclosure comprises a contiguous nucleotide sequence hybridizing to the intron-exon junction of an SNCA transcript, wherein the ASO sequence score is greater than or equal to about 0.1; 0.2; 0.25; 0.3; 0.35; 0.4; 0.45; 0.5; 0.55; 0.6; 0.65; 0.7; 0.75; 0.8; 0.85; 0.9; 0.95 or 1.0.

In all of these embodiments, when the sequence score is greater than or equal to the cut-off value, ASO is considered to have reduced neurotoxicity.

II.C. ASO Length

ASO data may contain a contiguous nucleotide sequence of as few as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 contiguous nucleotides in length.

In some embodiments, these ASOs comprise a contiguous nucleotide sequence of all of about 10-22, such as 10-21, such as 12-20, such as 15-20, such as 17-20, such as, eg 12-18, such as 13-17 or 12-16, such as 13, 14, 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides in length.

In some embodiments, these ASOs contain a contiguous nucleotide sequence of only 10, 11, 12, 13, or 14 contiguous nucleotides in length.

In some embodiments, these ASOs contain a contiguous nucleotide sequence of only 16, 17, 18, 19, or 20 contiguous nucleotides in length.

In some embodiments, the ASO of this disclosure consists of no more than 22 nucleotides, such as no more than 21 or 20 nucleotides, such as no more than 18 nucleotides, such as 15, 16 or 17 nucleotides. In some embodiments, the ASO of this disclosure contains less than 22 nucleotides. It should be understood that when a range or length of a contiguous nucleotide sequence is given for ASO, that range includes the shortest and longest lengths given in the given range, e.g. from (or between) 10-30 and includes both 10 and 30.

II.D. Nucleosides and nucleoside analogues

In one aspect of this disclosure, the ASOs comprise one or more non-naturally occurring nucleotide analogs. "Nucleotide analogs" as used herein are variants of natural nucleotides, such as DNA or RNA nucleotides, through modifications to the sugar and/or base moieties. Analogues, in principle, could simply be "silent" or "equivalent" to natural nucleotides in the context of an oligonucleotide, i.e. have no functional effect on the way the oligonucleotide works to inhibit target gene expression. Such "equivalent" analogues, however, may be useful if, for example, they are easier or cheaper to manufacture, or are more stable during storage or under manufacturing conditions, or represent a label. In some embodiments, however, these analogs will have a functional effect on the way ASO works to inhibit expression; for example, by obtaining increased target binding affinity and/or increased resistance to intracellular nucleases, and/or increased ease of transport into the cell. Specific examples of nucleoside analogs are described, for example, by Freier &Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213, and are illustrated in section II.D.a and in Scheme 1 (section IID.2b).

II.D.1. Nucleic base

The term "nucleic base" includes the purine (eg, adenine and guanine) and pyrimidine (eg, uracil, thymine, and cytosine) moieties present in nucleosides and nucleotides that form hydrogen bonds upon hybridization of nucleic acids. In the context of the present invention, the term nucleic base also encompasses modified nucleic bases that may differ from naturally occurring nucleic bases but are functional during nucleic acid hybridization. In some embodiments, the nucleobase moiety is modified by modifying or replacing the nucleobase. In this context, the term "nucleic base" refers to naturally occurring nucleic bases such as adenine, guanine, cytosine, thymine, uracil, xanthine, and hypoxanthine, as well as non-naturally occurring variants. Such variants are, for example, described in Hirao et al. (2012) Accounts of Chemical Research, volume 45, page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In some embodiments, the nucleobase moiety is modified by replacing the purine or pyrimidine with a modified purine or pyrimidine, such as a substituted purine or substituted pyrimidine, such as, for example, a nucleobase selected from isocytosine, pseudoisocytosine, 5-methylcytosine, 5-thiozolocytosine, 5-propynylcytosine, 5-propynyluracil, 5-bromouracil-5-thiazolouracil, 2-thiouracil, 2'-thiothymidine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and 2-chloro-6-aminopurine.

Nucleobase groupings may be indicated by a letter code for each respective nucleobase, eg, A, T, G, C, or U, where each letter may optionally include modified nucleobases with equivalent function. For example, in the illustrated oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methylcytosine. Possibly for LNA gapmers, 5-methylcytosine LNA (MC) nucleosides can be used.

II.D.2. Sugar modification

The ASO of this disclosure may contain one or more nucleosides that have a modified sugar moiety, i. e. modification of the sugar group compared to the ribose sugar group found in DNA and RNA. Numerous nucleosides have been prepared with the modification of the ribose sugar moiety, mainly with the aim of improving certain properties of the oligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include modifications where the structure of the ribose ring is modified, for example by replacement with a hexose ring (HNA) or a bicyclic ring that typically has a biradical bridge between the C2' and C4' carbons on the ribose ring (LNA), or with an unlinked ribose ring, which typically lacks a bond between C2' and C3' carbons (eg UNA). Other sugar-modified nucleosides include, for example, bicyclohexose nucleic acids (WO 2011/017521) or tricyclic nucleic acids (WO 2013/154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non-sugar moiety, such as in the case of peptide nucleic acids (PNAs) or morpholino nucleic acids.

Sugar modifications also include modifications made by changing substituent groups on the ribose ring to groups other than hydrogen or 2'-OH groups naturally found in RNA nucleosides. Substituents, for example, can be introduced at the 2', 3', 4' or 5' positions. Nucleosides with modified sugar moieties also include 2'-modified nucleosides such as 2'-substituted nucleosides. Indeed, much attention has been spent on the development of 2'-substituted nucleosides, and many 2'-substituted nucleosides have been found to have beneficial properties when incorporated into oligonucleotides, such as increased nucleoside stability and increased affinity.

In some embodiments, the sugar modification includes an affinity-enhancing sugar modification, such as LNA. An affinity-enhancing sugar modification increases the binding affinity of ASO to a target RNA sequence. In some embodiments, an ASO containing a sugar modification disclosed herein has a binding affinity for a target RNA sequence that is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to a control (e.g. , ASO without this sugar modification).

II.D.2.a 2'-modified nucleosides

A 2'-sugar-modified nucleoside is a nucleoside that has a substituent at the 2' position other than H or -OH (2'-substituted nucleoside) or contains a 2'-linked diradical capable of forming a bridge between the 2' carbon and the second carbon in the ribose ring, such as LNA nucleosides (linked by a 2'-4' biradical bridge).

Indeed, much attention has been devoted to the development of 2'-substituted sugar nucleosides and many 2'-substituted nucleosides have been found to have useful properties when incorporated into oligonucleotides. For example, a 2'-modified sugar can give an oligonucleotide increased binding affinity and/or increased nuclease resistance. Examples of 2'-substituted modified nucleosides are 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2'-amino- DNA, 2'-fluoro-RNA and 2'-F-ANA nucleoside. For additional examples, see, for example, Freier &Altmann; Nucl. Acid Res., 1997, 25, 4429-4443; Uhlman; Curr. Opinion in Drug Development, 2000, 3(2), 293-213 and Deleavey and Damha, Chemistry and Biology 2012, 19, 937. The following are illustrations of some 2'-substituted modified nucleosides.

In connection with the present invention, modified 2'-substituted sugar nucleosides do not include 2'-bridged nucleosides like LNA.

II.D.2.b Locked nucleic acids (LNA) nucleosides

LNA nucleosides are modified nucleosides that contain a linker group (called a diradical or bridge) between the C2' and C4' of the ribose sugar ring of the nucleoside. These nucleosides are also referred to in the literature as bridging nucleic acid or bicyclic nucleic acid (BNA).

In some embodiments, the modified ASO nucleoside or nucleosides of this disclosure have the general structure of Formula II or III:

where W is selected from -O-, -S-, -N(R ^a )-, -C(R ^a R ^b )-, such that in some embodiments -O-; B is a nucleobase or a modified nucleobase moiety; Z is an internucleoside bond to an adjacent nucleoside or a 5' end group; Z* is an internucleoside bond to an adjacent nucleoside or a 3' end group; and X is a group selected from the group consisting of -C(R ^a R ^b )-, -C(R ^a )=C(R ^b )-, -C(R ^a )=N-, -O-, - Si(R ^a ) ₂ -, -S-, -SO ₂ -, -N(R ^a )- and >C=Z.

In some embodiments, X is selected from the group consisting of: -O-, -S-, NH-, NR ^a R ^b , -CH ₂ -, CR ^a R ^b , -C(=CH ₂ )- and -C(= CR ^a R ^b )-. In some embodiments, X is -O-.

In some embodiments, Y is a group selected from the group consisting of -C(R ^a R ^b )-, -C(R ^a )=C(R ^b )-, -C(R ^a )=N-, -O- , -Si(R ^a ) ₂ -, -S-, -SO ₂ , -N(R ^a )- and >C=Z. In some embodiments, Y is selected from the group consisting of: -CH ₂ -, -C(R ^a R ^b )-, -CH ₂ CH ₂ -, -C(R ^a R ^b )-C(R ^a R ^b )- , -CH ₂ CH ₂ CH ₂ , -C(R ^a R ^b )C(R ^a R ^b )C(R ^a R ^b )-, - C(R ^a )=C(R ^b ) and -C(R ^a )=N-.

In some embodiments, Y is selected from the group consisting of: -CH ₂ -, -CHR ^a -, -CHCH ₃ -, CR ^a R ^b -, and -XY- together denote a divalent linker group (also referred to as a radical) denoting a joint divalent a linker group consisting of 1, 2, 3 or 4 groups/atoms selected from the group consisting of -C(R ^a R ^b )-, -C(R ^a )=C(R ^b )-, -C(R ^a )=N-, -O-, -Si(R ^a ) ₂ -, -S-, -SO ₂ , -N(R ^a )- and >C=Z.

In some embodiments, -XY- is a diradical selected from the groups consisting of: -X-CH ₂ -, -X-CR ^a R ^b -, -X-CHR ^a- , -X-C(HCH ₃ ) ^- , - OY-, -O-CH ₂ -, -S-CH ₂ -, -NH-CH ₂ -, -O-CHCH ₃ -, -CH ₂ -O-CH ₂ , -O-CH (CH ₃ CH ₃ ) -, -O-CH ₂ -CH ₂ -, OCH ₂ -CH ₂ -CH ₂ -, -O-CH ₂ OCH ₂ -, -O-NCH ₂ -, -C (=CH ₂ ) -CH ₂ -, -NR ^a -CH ₂ -, NO-CH ₂ , -S-CR ^a R ^b - and -S-CRa-.

In some embodiments, -XY- is -O-CH ₂ - or -O-CH(CH ₃ )-.

In some embodiments, Z is selected from -O-, -S- and -N(R ^a )-, and R ^a , and, in the presence of R ^b , each independently selected from hydrogen, optionally substituted with C _1-6 -alkyl, optionally substituted C _2-6 -alkenyl, possibly substituted with C _2-6 -alkynyl, hydroxy, possibly substituted with C _1-6 -alkoxy, C _2-6 -alkoxyalkyl, C _2-6 -alkenyloxy, carboxy, C _1-6 -alkoxycarbonyl, C _1-6 -alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di (C _1-6 -alkyl) amino, carbamoyl, mono- and di (C _{1 -6} -alkyl)-amino-carbonyl, amino-C _1-6 -alkyl-aminocarbonyl, mono- and di (C _1-6 -alkyl) amino-C _1-6 -alkyl-aminocarbonyl, C _1-6 -alkyl -carbonylamino, carbamido, C _1-6 -alkanoyloxy, sulphono, C _1-6 -alkylsulfonyloxy, nitro, azido, sulfanyl, C _1-6 -alkylthio, halogen, where aryl and heteroaryl may optionally be substituted, and where two geminal substituents R ^a and R ^b may together represent optionally substituted methyl en (=CH ₂ ), where for all chiral centers asymmetric groups can be in either R or S orientation.

In some embodiments, R ¹ , R ² , R ³ , R ⁵ and R ^5* are independently selected from the group consisting of: hydrogen, optionally substituted with C _1-6 alkyl, optionally substituted with C _2-6 alkenyl, optionally substituted with C _{2 -6} -alkynyl, hydroxy, C _1-6 -alkoxy, C _2-6 -alkoxyalkyl, C _2-6 -alkenyloxy, carboxy, C _1-6 -alkoxycarbonyl, C _1-6 -alkylcarbonyl, formyl, aryl, aryloxy- carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C _1-6 -alkyl)amino, carbamoyl, mono- and di(C _1-6 -alkyl)-amino-carbonyl , amino-C _1-6 -alkyl-aminocarbonyl, mono- and di (C _1-6 -alkyl) amino-C _1-6 -alkyl-aminocarbonyl, C _1-6 -alkyl-carbonylamino, urea, C _1-6 -alkanoyloxy, sulfono, C _1-6 -alkylsulfonyloxy, nitro, azido, sulfanyl, C _1-6 -alkylthio, halogen, where aryl and heteroaryl may optionally be substituted, and where the two geminal substituents may together be oxo, thioxo, imino or possibly substituted methylene.

In some embodiments, R ¹ , R ² , R ³ , R ⁵ and R ^5* are independently selected from C _1-6 alkyl such as methyl and hydrogen.

In some embodiments, all R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms.

In some embodiments, R ¹ , R ² , R ³ are all hydrogen atoms, and either R ⁵ or R ^5* is also a hydrogen atom, and the other of R ⁵ and R ^5* is other than a hydrogen atom, such as, for example, is C _1-6 alkyl such as methyl.

In some embodiments, R ^a is either a hydrogen atom or methyl. In some embodiments, R ^b , if present, is either a hydrogen atom or methyl.

In some embodiments, one or both of R ^a and R ^b is a hydrogen atom.

In some embodiments, one of R ^a and R ^b is a hydrogen atom and the other is other than a hydrogen atom.

In some embodiments, one of R ^a and R ^b is methyl and the other is hydrogen.

In some embodiments, both of R ^a and R ^b are methyl.

In some embodiments, the -XY- biradical is -O-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such LNA nucleosides are disclosed in WO 99/014226, WO 00/66604, WO 98/039352 and WO 2004/046160, all of which are hereby incorporated by reference, and include what are commonly known as beta-D-oxy LNA nucleosides and alpha-L-hydroxy LNA.

In some embodiments, the -XY- biradical is -S-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such thio LNA nucleosides are disclosed in WO 99/014226 and WO 2004/046160.

In some embodiments, the -XY- biradical is -NH-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such amino LNA nucleosides are disclosed in WO 99/014226 and WO 2004/046160.

In some embodiments, the -XY- biradical is -O-CH ₂ -CH ₂ - or -O-CH ₂ -CH ₂ -CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such LNA nucleosides are disclosed in WO 00/047599 and Morita et al., Bioorganic & Med. Chem. Lett. 12 73-76, which are hereby incorporated by reference and include what are commonly known as 2'-O-4'C-ethylene bridged (ENA) nucleic acids.

In some embodiments, the -XY- biradical is -O-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ and one of R ⁵ and R ^5* are hydrogen atoms and the other of R ⁵ and R ^5* is different from a hydrogen atom, such as C _1-6 alkyl such as methyl. Such 5'-substituted LNA nucleosides are disclosed in WO 2007/134181.

In some embodiments, the -XY- biradical is -O-CR ^a R ^b , where one or both of R ^a and R ^b are other than a hydrogen atom, such as methyl, W is O, and all of R ¹ , R ² , R ³ and one of R ⁵ and R ^5* represent a hydrogen atom, and the other of R ⁵ and R ^5* other than a hydrogen atom, such as C _1-6 alkyl, such as methyl. Such bis-modified LNA nucleosides are disclosed in WO 2010/077578.

In some embodiments, the -XY- biradical is a divalent linker group -O-CH(CH ₂ OCH ₃ )-(2'O-methoxyethylbicyclic nucleic acid - Seth at al., 2010, J. Org. Chem. Vol 75(5) pp .1569-81). In some embodiments, the diradical -XY- denotes a divalent linker group -O-CH(CH ₂ CH ₃ )-(2'O-ethylbicyclic nucleic acid - Seth et al., 2010, J. Org. Chem. Vol 75(5), pp.1569-81). In some embodiments, the -XY- biradical is -O-CHR ^a , W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such 6'-substituted LNA nucleosides are disclosed in WO 10036698 and WO 07090071.

In some embodiments, the -XY- biradical is -O-CH(CH ₂ OCH ₃ )-, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such LNA nucleosides are also known in the art as cyclic MOEs (cMOEs) and are disclosed in WO 07090071.

In some embodiments, the -XY- biradical is a divalent linker group -O-CH(CH ₃ )- in either the R- or S-configuration. In some embodiments, the diradical -XY- together denotes a divalent linker group -O-CH ₂ -O-CH ₂ - (Seth et al., 2010, J. Org. Chem). In some embodiments, the biradical -XY- is -O-CH(CH ₃ )-, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such LNA 6'-methylnucleosides are also known in the art as cET nucleosides and can be either (S)cET or (R)cET stereoisomers as disclosed in WO 07090071 (beta-D) and WO 2010/036698 (alpha-L ).

In some embodiments, the -XY- biradical is -O-CR ^a R ^b -, wherein none of R ^a or R ^b is hydrogen, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. In some embodiments, both R ^a and R ^b are methyl. Such 6'-disubstituted LNA nucleosides are disclosed in WO 2009006478.

In some embodiments, the diradical -XY- is -S-CHR ^a -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. Such 6'-substituted thio LNA nucleosides are disclosed in WO 11156202. In some embodiments of 6'-substituted thio LNA R ^a is methyl.

In some embodiments, the -XY- biradical is -C(=CH ₂ )-C(R ^a R ^b )-, such as -C(=CH ₂ )-CH ₂ - or -C(=CH ₂ )- CH(CH ₃ )—, W is O, and R ¹ , R ² , R ³ , R ⁵ and R ^5* are all hydrogen atoms. Such LNA vinyl carbonucleosides are disclosed in WO 08154401 and WO 09067647.

In some embodiments, the diradical -XY- is -N(-OR ^a )-, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. In some embodiments, R ^a is C _1-6 alkyl, such as methyl. Such LNA nucleosides are also known as N-substituted LNAs and are disclosed in WO 2008/150729. In some embodiments, the diradical -XY- together denotes a divalent linker group -O-NR ^a -CH ₃ - (Seth at al., 2010, J. Org. Chem). In some embodiments, the -XY- biradical is -N(R ^a )-, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. In some embodiments, R ^a is C _1-6 alkyl, such as methyl.

In some embodiments, one or both of R ⁵ and R ^5* is a hydrogen atom, and, when substituted, the other of R ⁵ and R ^5* is C _1-6 alkyl, such as methyl. In such an embodiment, all of R ¹ , R ² , R ³ may be hydrogen atoms and the diradical -XY- may be selected from -O-CH ₂ - or -O-C(HCR ^a )- such as -O- C(HCH3)-.

In some embodiments, the diradical is -CR ^a R ^b -O-CR ^a R ^b - such as CH ₂ -O-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. In some embodiments, R ^a is C _1-6 alkyl, such as methyl. Such LNA nucleosides are also known as conformationally restricted nucleotides (CRN) and are disclosed in WO 2013036868.

In some embodiments, the diradical is -O-CR ^a R ^b -O-CR ^a R ^b - such as O-CH ₂ -O-CH ₂ -, W is O, and all of R ¹ , R ² , R ³ , R ⁵ and R ^5* are hydrogen atoms. In some embodiments, R ^a is C _1-6 alkyl, such as methyl. Such LNA nucleosides are also known as COS nucleotides and are disclosed in Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238.

It will be understood that, if not specified, LNA nucleosides may be in the beta-D or alpha-L stereoisoform.

Some examples of LNA nucleosides are shown in Scheme 1.

Scheme 1

Specific LNA nucleosides are beta-D-oxy-LNA, 6'-methyl-beta-D-oxy LNA, such as (S)-6'-methyl-beta-D-oxy-LNA (ScET) and ENA .

As illustrated in the Examples, in some embodiments of this disclosure, the LNA nucleosides in the oligonucleotides are beta-D-oxy-LNA nucleosides.

If one of the starting materials or compounds of the invention contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more of the reaction steps, suitable protecting groups may be introduced (as described, for example, in "Protective Groups in Organic Chemistry" by TW Greene and PGM ^Wuts , 3rd Ed., 1999, Wiley, New York) before the critical step of applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are t-butoxy carbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teos), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compounds described herein may contain multiple asymmetric centers and may be present as optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereomeric racemates, or mixtures of diastereomeric racemates.

The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Kahn-Ingold-Prelog convention, an asymmetric carbon atom can be in the "R" or "S" configuration.

As used herein, the term "alkyl", alone or in combination, means a straight chain or branched chain alkyl group of 1 to 8 carbon atoms, in particular a straight or branched chain alkyl group of 1 to 6 carbon atoms, and more specifically, a straight or branched chain alkyl group with 1 to 4 carbon atoms. Examples of C ₁ -C ₈ straight chain and branched chain alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls and isomeric octyls, in particular methyl, ethyl, propyl, butyl and pentyl. Specific examples of alkyl are methyl, ethyl and propyl.

The term "cycloalkyl", alone or in combination, means a cycloalkyl ring with 3-8 carbon atoms, and in particular a cycloalkyl ring with 3-6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, more specifically cyclopropyl and cyclobutyl. A specific example of "cycloalkyl" is cyclopropyl.

The term "alkoxy", alone or in combination, means a group of the formula alkyl-O-, in which the term "alkyl" has the meaning given previously, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Specific "alkoxy" are methoxy and ethoxy. Methoxyethoxy is a specific example of "alkoxyalkoxy".

The term "oxy", alone or in combination, means a -O- group.

The term "alkenyl", alone or in combination, means a straight chain or branched hydrocarbon residue containing an olefin bond and up to 8, preferably up to 6, in particular preferably up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.

The term "alkynyl", alone or in combination, means a straight chain or branched hydrocarbon residue containing a triple bond and up to 8, preferably up to 6, in particular preferably up to 4 carbon atoms.

The terms "halogen" or "halo", alone or in combination, mean fluorine, chlorine, bromine or iodine, and in particular fluorine, chlorine or bromine, more specifically fluorine. The term "halogen" in combination with another group means a substitution of said group with at least one halogen, in particular a substitution with one to five halogens, in particular one to four halogens, i. e. one, two, three or four halogens.

The term "haloalkyl", alone or in combination, means an alkyl group substituted with at least one halogen, in particular one to five halogens, in particular one to three halogens. Examples of haloalkyl include monofluoro-, difluoro- or trifluoromethyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. Fluoromethyl, difluoromethyl, and trifluoromethyl are specific "haloalkyls".

The term "halocycloalkyl", alone or in combination, means a cycloalkyl group as defined above substituted with at least one halogen, in particular substituted with one to five halogens, in particular one to three halogens. A specific example of "halocycloalkyl" is halocyclopropyl, in particular fluorocyclopropyl, difluorocyclopropyl and trifluorocyclopropyl.

The terms "hydroxyl" and "hydroxy", alone or in combination, mean a group-OH.

The terms "thiohydroxyl" and "thiohydroxy", alone or in combination, mean a -SH group.

The term "carbonyl", alone or in combination, means a -C(O)- group.

The term "carboxy" or "carboxyl", alone or in combination, means a -COOH group.

The term "amino", alone or in combination, means a primary amino group (-NH ₂ ), a secondary amino group (-NH-) or a tertiary amino group (-N-).

The term "alkylamino", alone or in combination, means an amino group as defined above substituted with one or two alkyl groups as defined above.

The term "sulfonyl", alone or in combination, means a -SO ₂ group.

The term "sulfinyl", alone or in combination, means the -SO- group.

The term "sulfanyl", alone or in combination, means the -S- group.

The term "cyano", alone or in combination, means a -CN group.

The term "azido", alone or in combination, means the -N ₃ group.

The term "nitro", alone or in combination, means a NO ₂ group.

The term "formyl", alone or in combination, means a -C(O)H group.

The term "carbamoyl", alone or in combination, means a -C(O)NH ₂ group.

The term "urea", alone or in combination, means a -NH-C(O)-NH ₂ group.

The term "aryl", alone or in combination, means a monovalent aromatic carbocyclic mono- or bicyclic ring system containing from 6 to 10 ring carbon atoms, optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkenyloxy, carboxyl, alkoxycarbonyl, alkylcarbonyl and formyl. Examples of aryl include phenyl and naphthyl, in particular phenyl.

The term "heteroaryl", alone or in combination, means a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms containing 1,2,3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms representing is carbon atoms optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkenyloxy, carboxyl, alkoxycarbonyl, alkylcarbonyl and formyl. Examples of heteroaryl include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, indolylbenzothienyl , isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl or acridinyl.

The term "heterocyclyl", alone or in combination, means a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4-12, in particular 4-9 ring atoms, containing 1, 2, 3 or 4 ring heteroatoms selected from N , O and S, the remaining ring atoms being carbon optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkenyloxy, carboxyl, alkoxycarbonyl, alkylcarbonyl and formyl. Examples of the monocyclic saturated heterocyclyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thio-4-a-morpholinyl, diazepanil, homopiperazinil or oxazepanil. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa -9-aza-bicyclo[3.3.1]nonyl or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl or dihydropyranyl.

II.E. Nuclease mediated degradation

The term "nuclease-mediated degradation" refers to an oligonucleotide capable of mediating the degradation of a complementary nucleotide sequence upon duplex formation with that sequence.

In some embodiments, an oligonucleotide can function through nuclease-mediated degradation of a target nucleic acid, wherein the oligonucleotides of this disclosure are capable of recruiting a nuclease, in particular an endonuclease, preferably an endoribonuclease (RNase), such as RNase H. Examples of oligonucleotide constructs that work through mechanisms, nuclease mediated are oligonucleotides that typically contain a region of at least 5 or 6 DNA nucleosides and are flanked on one or both sides by affinity increasing nucleosides, eg gapmers.

II.F. RNase H activity and recruitment

The RNase H activity of an antisense oligonucleotide refers to its ability, when in duplex with a complementary RNA molecule, to recruit RNase H and induce cleavage and subsequent degradation of the complementary RNA molecule. WO 01/23613 provides in vitro methods for determining RNase H activity that can be used to determine the ability to recruit RNase H. Typically, an oligonucleotide is considered capable of recruiting RNase H if it, when presented with a complementary target nucleic acid sequence, has an initial rate of measured in pmol/l/min, at least 5%, such as at least 10% or more than 20% of the initial rate determined using an oligonucleotide having the same base sequence as the modified oligonucleotide being tested, but containing only DNA monomers with phosphorothioate bonds between all monomers in the oligonucleotide, and using the methodology proposed in Examples 91-95 of WO 01/23613.

In some embodiments, an oligonucleotide is considered substantially unable to recruit RNase H if it, when presented with a complementary target nucleic acid, has an initial RNase H rate, measured in pmol/l/min, of less than 20%, such as less than 10%, such as less than 5% of the original rate determined using an oligonucleotide having the same base sequence as the test oligonucleotide but containing only DNA monomers with no 2' substitutions with phosphorothioate bonds between all monomers in the oligonucleotide, and using the methodology proposed in Examples 91-95 of WO 01/23613.

II.G. ASO design

The ASO of this disclosure may comprise a nucleotide sequence that contains both natural nucleotides and nucleotide analogs, and may be in the form of a gapmer. Examples of gapmer configurations that can be used with the ASO of this disclosure are described in US Patent Application Publication No. 2012/0322851.

The term "gapmer" as used herein refers to an antisense oligonucleotide that contains an RNase H (gap) recruiting oligonucleotide region that is flanked 5' and 3' by one or more modified affinity increasing nucleosides. (flanks). This document describes various gapmer designs. The term "LNA gapmer" refers to a gapmer oligonucleotide in which at least one modified affinity increasing nucleoside is an LNA nucleoside. The term "mixed-wing gapmer" refers to an LNA gapmer in which the flank regions contain at least one LNA nucleoside and at least one DNA nucleoside or a non-LNA modified nucleoside, such as at least one 2'-substituted modified nucleoside , such as, for example, nucleoside(s) 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-O-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2 '-amino-DNA, 2'-fluoro-RNA and 2'-F-ANA. In some embodiments, a mixed-wing gapmer has one flank that contains LNA nucleosides (e.g., 5' or 3') and the other flank (3' or 5', respectively) contains 2'-substituted(s) modified(s) nucleoside(s) ( dy).

In some embodiments, in addition to increasing the affinity of ASO for the target region, certain nucleoside analogs also mediate the binding and cleavage of an RNase (eg, RNase H). Because α-L-LNA monomers recruit RNase H activity to some extent, in some embodiments, gap regions (e.g., region B as referred to herein) of ASOs containing α-L-LNA monomers consists of fewer monomers recognized and cleaved by RNase H, and introduces more flexibility into mixer design.

II.G.1. Gapmer construction

In one embodiment, the ASO of this disclosure is a gapmer. A gapmeric ASO is an ASO that contains a contiguous stretch of nucleotides that is capable of recruiting an RNase such as RNase H, such as a region of at least 6 nucleotides of DNA, herein referred to as the B region (B), where the B region is flanked by 5 ' and 3' regions of nucleotide analogues that increase affinity, such as 1-10 nucleotide analogues 5' and 3' to a continuous stretch of nucleotides that is able to recruit RNase - these regions are called regions A (A) and C (C), respectively .

In some embodiments, the gapmer is an interleaved gapmer, examples of which are discussed below. In some embodiments, the interleaved gapmer exhibits less off-target binding than the traditional gapmer. In some embodiments, the interleaved gapmer has better long-term tolerance than the traditional gapmer.

The alternating flanked gapmer may comprise a (poly)nucleotide sequence of the formula (5' to 3') A-B-C wherein: the A (A) region (5'-region or first wing sequence) contains at least one a nucleotide analog, such as at least one LNA unit, such as 1-10 nucleotide analogs, such as LNA units, and; region B (B) contains at least six consecutive nucleotides that are capable of recruiting an RNase (when duplexed with a complementary RNA molecule, such as a pre-mRNA or target mRNA), such as DNA nucleotides, and; region C (C) (3'-region or sequence of the second wing) contains at least one nucleotide analog, such as at least one LNA unit, such as 1-10 nucleotide analogs, such as LNA units; where regions A and C may include at any position in A and C 1-3 insertion regions of DNA nucleotides (eg, DNA inserts) in which each given DNA insert may be 1-6 DNA units in length.

In some other embodiments, the gapmer, e.g., the interleaved flanked gapmer, comprises a (poly)nucleotide sequence of the formula (5' to 3') A-B-C or possibly A-B-C-D or D-A-B-C in which: region A (A) the (5'-region) contains at least one nucleotide analog, such as at least one LNA unit, such as 1-10 nucleotide analogs, such as LNA units, and; region B (B) contains at least five consecutive nucleotides that are capable of recruiting an RNase (when duplexed with a complementary RNA molecule, such as a target mRNA), such as DNA nucleotides, and; region C (C) (3'-region) contains at least one nucleotide analog, such as at least one LNA unit, such as 1-10 nucleotide analogs, such as LNA units, and; the D region (D), if present, contains 1, 2, or 3 nucleotide units, such as DNA nucleotides.

In some embodiments, region A contains 1,2,3, 4, 5, 6, 7, 8, 9, or 10 nucleotide analogs, such as LNA units, such as 2-5 nucleotide analogs, such as 2-5 LNA units, such as 2-5 nucleotide analogs, such as 3-5 LNA units; and/or the C region consists of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotide analogs, such as LNA units, such as 2-5 nucleotide analogs, such as 2- 5 LNA units, such as 2-5 nucleotide analogs, such as 3-5 LNA units.

In some embodiments, B contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleotides that are capable of recruiting an RNase, or 6-14, 7-14, 8-14 or 7-10, or 7-9, such as 8, such as 9, such as 10, or such as 14 consecutive nucleotides which are capable of recruit RNase. In some embodiments, region B contains at least five DNA nucleotide units, such as 5-23 DNA units, such as 5-20 DNA units, such as 5-18 DNA units, such as 6- 14 DNA units, such as 8-14 DNA units, such as 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 DNA units.

In some embodiments, region A contains 3, 4, or 5 nucleotide analogs such as LNA, region B consists of 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 DNA units, and region C consists of 3 , 4 or 5 nucleotide analogs such as LNA. Such constructs include (A-B-C) 5-10-5, 3-14-3, 3-10-3, 3-10-4, 4-10-3, 3-9-3, 3-9- 4, 4-9-3, 3-8-3, 3-8-4, 4-8-3, 3-7-3, 3-7-4, and 4-7-3, and may further include region D , which can have one to 3 nucleotide units, such as DNA units.

In some embodiments, the ASO of this disclosure, for example, an interleaved gapmer, contains the formula 5'-A-B-C-3' in which

(i) region B is a contiguous sequence of at least 5, 6, 7 or 8, eg 5-18 DNA units that are capable of recruiting an RNase;

(ii) region A is a first wing sequence of 1-10 nucleotides, where the first wing sequence contains one or more nucleotide analogs and optionally one or more DNA units (e.g., a DNA insert), and where at least one of the nucleotide analogs is located at the 3' end of A; and

(iii) region C is a second wing sequence of 1-10 nucleotides, where the second wing sequence contains one or more nucleotide analogs and optionally one or more DNA units (e.g., a DNA insert), and where at least one of the nucleotide analogs is located at the 5' end of C.

In some embodiments, the first wing sequence (region A in the formula) contains a combination of nucleotide analogs and DNA units selected from (i) 1-9 nucleotide analogs and 1 DNA unit; (ii) 1-8 nucleotide analogs and 1-2 DNA units; (iii) 1-7 nucleotide analogs and 1-3 DNA units; (iv) 1-6 nucleotide analogs and 1-4 DNA units; (v) 1-5 nucleotide analogs and 1-5 DNA units; (vi) 1-4 nucleotide analogs and 1-6 DNA units; (vii) 1-3 nucleotide analogs and 1-7 DNA units; (viii) 1-2 nucleotide analogs and 1-8 DNA units; and (ix) 1 nucleotide analog and 1-9 DNA units.

In some embodiments, the second wing sequence (region C in this formula) contains a combination of nucleotide analogs and DNA units selected from (i) 1-9 nucleotide analogs and 1 DNA unit; (ii) 1-8 nucleotide analogs and 1-2 DNA units; (iii) 1-7 nucleotide analogs and 1-3 DNA units; (iv) 1-6 nucleotide analogs and 1-4 DNA units; (v) 1-5 nucleotide analogs and 1-5 DNA units; (vi) 1-4 nucleotide analogs and 1-6 DNA units; (vii) 1-3 nucleotide analogs and 1-7 DNA units; (viii) 1-2 nucleotide analogs and 1-8 DNA units; and (ix) 1 nucleotide analog and 1-9 DNA units.

In some embodiments, region A in the ASO formula has a subformula selected from the first wing design of any ASO in FIG. 1A-1C and 2 and/or region C in the ASO formula has a subformula selected from the second wing design of any ASO in FIG. 1A-1C and 2, where the upper letter represents a nucleotide analog (eg, a modified sugar analog, which can also be written as L), and the lower letter represents DNA (which can also be written as D).

In some embodiments, an ASO, e.g., a gapmer with alternating flanks, has the formula 5' A-B-C 3', where the B region is a contiguous sequence of 5-18 DNA units, the A region has the formula LLDLL, LDLLL, or LLLDL, and region C has the formula LLDLL or LDLDLL, and where L is an LNA unit and D is a DNA unit.

In some embodiments, the ASO has the formula 5' A-B-C 3', where the B region is a 10 DNA unit contiguous, the A region is LDL, and the C region is LLLL, where L is an LNA unit, and D is a DNA unit.

Other gapmer constructs are disclosed in WO 2004/046160, which is hereby incorporated by reference in its entirety. WO 2008/113832, hereby incorporated by reference in its entirety, refers to "short" gapmer ASOs. In some embodiments, the ASOs provided herein may be such short-term gapmers.

In some embodiments, an ASO, e.g., a striped flank gapmer, contains a contiguous nucleotide sequence of a total of 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotide units, where the contiguous nucleotide sequence has the formula (5 '-3') A-B-C or possibly A-B-C-D or D-A-B-C, where the A region consists of 1, 2, 3, 4 or 5 units of nucleotide analogs, such as LNA units; region B consists of 5, 6, 7, 8, 9, 10, 12, 13, 14, or 15 contiguous nucleotide units that are capable of recruiting an RNase when duplexed with a complementary RNA molecule (such as a target mRNA); and the C region consists of 1, 2, 3, 4, or 5 nucleotide analog units, such as LNA units. Region D, if present, consists of a single DNA unit.

In some embodiments, A contains 1 LNA unit. In some embodiments, region A contains 2 LNA units. In some embodiments, region A contains 3 LNA units. In some embodiments, region A contains 4 LNA units. In some embodiments, region A contains 5 LNA units. In some embodiments, region C contains 1 LNA unit. In some embodiments, C contains 2 LNA units. In some embodiments, region C contains 3 LNA units. In some embodiments, region C contains 4 LNA units. In some embodiments, region C contains 5 LNA units. In some embodiments, region B contains 6 nucleotide units. In some embodiments, region B contains 7 nucleotide units. In some embodiments, region B contains 8 nucleotide units. In some embodiments, region B contains 9 nucleotide units. In some embodiments, region B contains 10 nucleoside units. In some embodiments, region B contains 11 nucleoside units. In some embodiments, region B contains 12 nucleoside units. In some embodiments, region B contains 13 nucleoside units. In some embodiments, the B region contains 14 nucleoside units, the B region contains 15 nucleoside units. In some embodiments, region B contains 7-23 DNA monomers or 5-18 DNA monomers. In some embodiments, region B contains 6-23 DNA units, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 DNA links. In some embodiments, region B consists of DNA units. In some embodiments, the B region contains at least one LNA unit that is in the alpha-L configuration, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 LNA units in alpha-L configuration. In some embodiments, region B contains at least one alpha-L-oxy LNA unit, or in which all LNA units in the alpha-L configuration are alpha-L-oxy LNA units.

In some embodiments, the number of nucleotides represented in A-B-C is selected from (nucleotide analog units - region B - nucleotide analog units): 1-8-1, 1-8-2, 2-8-1, 2-8 -2, 3-8-3, 2-8-3, 3-8-2, 4-8-1, 4-8-2, 1-8-4, 2-8-4 or 1-9-1 , 1-9-2, 2-9-1, 2-9-2, 2-9-3, 3-9-2, 1-9-3, 3-9-1, 4-9-1, 1 -9-4, 4-9-4, or 1-10-1, 1-10-2, 2-10-1, 2-10-2, 1-10-3, 3-10-1 and 4- 10-4 or 3-11-4 or 4-11-3 and 4-11-4 or 3-12-4 and 4-12-4 or 3-13-3 and 3-13-4 or 1-14-4, or 1-15-4 and 2-15-3. In some embodiments, the number of nucleotides in A-B-C is selected from: 2-7-1, 1-7-2, 2-7-2, 3-7-3, 2-7-3, 3-7-2, 3-7-4 and 4-7-3.

In other embodiments, ASO contains 10 DNA units in B, LDLLL in A (first wing) and LLDLL in C (second wing). In other embodiments, ASO contains 9 DNA units in B, LDDLL in A, and LDLDLL in C. In other embodiments, ASO contains 10 DNA units in B, LLDLL in A, and LLDLL in C. In other embodiments, ASO contains 9 DNA units in B, LLLLL in A and LDDLL in C. In some embodiments, regions A and C each contain three LNA monomers, and region B consists of 7, 8, 9, 10, 11, 12, 13, 14, or 15 nucleoside monomers, e.g., DNA monomers . In some embodiments, both A and C each consist of two LNA units, and B consists of 7, 8 or 9 nucleotide units, such as DNA units. In various embodiments, other gapmer constructs include gapmers where the A and/or C regions consist of 3, 4, 5, or 6 nucleoside analogues, such as monomers containing the sugar 2'-O-methoxyethylribose (2'-MOE), or monomers, containing the sugar 2'-fluoro-deoxyribose, and region B consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleosides, such as DNA monomers, where the A-B-C regions have 3-8-3, 3-9-3, 3-10-3, 5-10-5 or 4-12-4 monomers. Additional gapmer constructs are disclosed in WO 2007/146511A2, hereby incorporated by reference in its entirety.

In some embodiments, an alternating-flanked ASO has at least 10 contiguous nucleotides containing an A region, a B region, and a C region (A-B-C), where the B region contains at least 5 contiguous nucleoside units and is flanked by a 5' region A of 1-8 contiguous nucleoside units and 3' region C of 1-8 contiguous nucleoside units, wherein region B, when duplexed with complementary RNA, is capable of recruiting RNase H, and where region A and region C are selected from the group consisting of from the following:

(i) region A contains a 5' LNA nucleoside unit and a 3' LNA nucleoside unit, and at least one DNA nucleoside unit between the 5' LNA nucleoside unit and the 3' LNA nucleoside unit, and region C contains at least two 3' nucleosides LNA;

(ii) region A contains at least one LNA 5' nucleoside and region C contains an LNA 5' nucleoside unit, at least two terminal 3' LNA nucleoside units, and at least one DNA nucleoside unit between the 5' LNA nucleoside unit and 3 ' LNA nucleoside units, and

(iii) region A contains a 5' LNA nucleoside unit and a 3' LNA nucleoside unit, and at least one DNA nucleoside unit between the 5' LNA nucleoside unit and the 3' LNA nucleoside unit; and region C contains a 5' LNA nucleoside unit, at least two terminal 3' LNA nucleoside units, and at least one DNA nucleoside unit between the 5' LNA nucleoside unit and the 3' LNA nucleoside units.

In some embodiments, region A or region C contains 1, 2, or 3 nucleoside DNA units. In other embodiments, region A and region C contain 1, 2, or 3 nucleoside DNA units. In other embodiments, region B contains at least five consecutive nucleoside DNA units. In some embodiments, region B contains 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive nucleoside DNA units. In some embodiments, the B region is 8, 9, 10, 11, or 12 nucleotides in length. In other embodiments, region A contains two 5' LNA nucleoside units. In some embodiments, region A has the formula 5'[LNA] _1-3 [DNA] _1-3 [LNA] _1-3 or 5'[LNA] _1-2 [DNA] _1-2 [LNA] _1-2 [DNA ] _1-2 [LNA] _1-2 . In other embodiments, region C has the formula [LNA] _1-3 [DNA] _1-3 [LNA] _2-3 3' or [LNA] _1-2 [DNA] _1-2 [LNA] _1-2 [DNA] _{1 -2} [LNA] _2-3 3'. In other embodiments, region A has the formula 5'[LNA] _1-3 [DNA] _1-3 [LNA] _1-3 or 5'[LNA] _1-2 [DNA] _1-2 [LNA] _1-2 [DNA ] _1-2 [LNA] _1-2 and region C contains 2, 3, 4 or 5 consecutive LNA nucleoside units. In some embodiments, region C has the formula [LNA] _1-3 [DNA] _1-3 [LNA] _2-3 3' or [LNA] _1-2 [DNA] _1-2 [LNA] _1-2 [DNA] _{1 -2} [LNA] _2-3 3', and region A contains 1, 2, 3, 4 or 5 consecutive LNA nucleoside units. In other embodiments, region A has a sequence of LNA and DNA nucleosides, 5'-3', selected from the group consisting of L, LL, LDL, LLL, LLDL, LDLL, LDDL, LLLL, LLLLL, LLLDL, LLDLL, LDLLL, LLDDL , LDDLL, LLDLD, LDLLD, LDDDL, LLLLLL, LLLLDL, LLLDLL, LLDLLL, LDLLLL, LLLDDL, LLDLDL, LLDDLL, LDDLLL, LDLLDL, LDLDLL, LDDDLL, LLDDDL, and LDLDLD, where L is an LNA nucleoside and D is a DNA nucleoside. In other embodiments, the C region has a sequence of LNA nucleosides and DNA, 5'-3', selected from the group consisting of LL, LLL, LLLL, LDLL, LLLLL, LLDLL, LDLLL, LDDLL, LDDLLL, LLDDLL, LDLDLL, LDDDLL, LDLDDLL , LDDLDLL, LDDDLLL and LLDLDLL. In another embodiment, region A has a sequence of LNA and DNA nucleosides, 5'-3', selected from the group consisting of LDL, LLDL, LDLL, LDDL, LLLDL, LLDLL, LDLLL, LLDDL, LDDLL, LLDLD, LDLLD, LDDDL, LLLLDL, LLLDLL, LLDLLL, LDLLLL, LLLDDL, LLDLDL, LLDDLL, LDDLLL, LDLLDL, LDLDLL, LDDDLL, LLDDDL and LDLDLD, and region C has a sequence of LNA nucleosides and DNA, 5'-3', selected from the group consisting of LDLL, LLDL , LLLLL, LLDLL, LDLLL, LDDLL, LDDLLL, LLDDLL, LDLDLL, LDDDLL, LDLDDLL, LDDLDLL, LDDDLLL and LLDLDLL.

In some embodiments, the alternating-flanked ASO has contiguous nucleotides containing a 5-3' nucleoside sequence selected from the group consisting of

;

;

где L представляет нуклеозид LNA, и D представляет нуклеозид ДНК. В других воплощениях нуклеозид LNA представляет собой бета-D-окси LNA.

where L is an LNA nucleoside and D is a DNA nucleoside. In other embodiments, the LNA nucleoside is beta-D-oxy LNA.

In other embodiments, the flanked ASO has contiguous nucleotides containing an LNA and DNA nucleoside alternating sequence, 5'-3', selected from the group consisting of: 2-3-2-8-2, 1-1-2 -1-1- 9-2, 3-10-1-1-2, 3-9-1-2-2, 3-8-1-3-2, 3-8-1-1-1-1 -2, 3-1-1-9-3, 3-1-1-8-1-1-2, 4-9-1-1-2, 4-8-1-2-2, 3-3 -1-8-2, 3-2-1-9-2, 3-2-2-8-2, 3-2-2-7-3, 5-7-1-2-2, 1-1 -3-10-2, 1-1-3-7-1-2-2, 1-1-4-9-2, 2-1-3-9-2, 3-1-1-10-2 , 3-1-1-7-1-2-2, 3-1-2-9-2, 4-7-1-3-2, 5-9-1-1-2, 4-10-1 -1-3-11-1-1-2, 2-1-1-10-1-1-2, 1-1-3-9-1-1-2, 3-10-1-2-2 , 3-9-1-3-2, 3-8-1-1-1-2-2, 4-9-1-2-2, 4-9-1-1-3, 4-8-1 -3-2, 4-8-1-2-3, 4-8-1-1-1-1-2, 4-7-1-2-1-1-2, 4-7-1-1 -1-2-2, 2-1-2- 11-2, 2-1-3-8-1-1-2, 3-1-1-11-2, 3-1-1-9-1 -1-2, 3-1-1-8-1-2-2, 3-1-1-7-1-1-1-1-2, 4-9-2-1-2, 4-7 -1-3-3.5-9-1-1-3, 5-9-1-2-2, 4-10-2-1-2, 4-10-1-1-3, 4-10 -1-2-2, 3-11-2-1-2, 3-11-1-1-3, 5-9-2-1-2, 3-11-1-2-2, 2-1 -2-9-1-2-2, 3-1-1-10-1-1-2, 3-1-1-9-1-2-2, 4-9-1-1-1-1 -2, 4- 8-2-1-1-1-2, 1-1-3-10-2-1-2, 2-1-2-10-2-1-2, 2-1-1 -12-4, 2-2-1-11-4, 3-1-1-11-4, 2-1-1-13-2-1-2-11-4, 2-2-1-12-3, 3- 11-1-2-3, 3-1-1-12-3, 2-1-2-12-3, 4-11-2-1-2, 4-10-2-2-2, 3- 2-1-9-1-1-3, 2-2-1-1-1-9-4, 2-2-2-9-1-1-3, 3-1-1-9-1- 1-1-1-2, 2-1-2-9-1-2-3, 3-1-1-10-1-1-3, 2-1-1-2-1-9-4, 4-9-1-1-1-2-2, 3-1-1-9-1-2-3, 2-1-1-1-1-10-4, 2-1-2-10- 1-1-3, 2-1-1-1-1-9-2-1-2, 2-2-2-9-2-1-2, 4-9-1-2-1-1- 2, 3-2-1-9-2-1-2, 2-1-2-9-2-2-2, 2-1-1-1-1-9-1-1-3, 3- 1-1-9-2-2-2, 2-2-2-10-4, 2-1-2-9-1-1-1-1-2, 4-10-1-2-3, 3-2-1-10-4, 3-1-1-10-2-1-2, 4-10- 1-1-1-1-2, 4-11-1-1-3, 3- 12-4, 1-2-2-10-1-1-3 and 2-2-2-10-1-1-2; where the first number represents the number of LNA units, the next is the number of DNA units, and then the regions with alternating LNA and DNA.

In other embodiments, the ASOs of this disclosure are represented as any one of the ASO numbers selected from FIG. 1A-1C and 2.

II.N. Internucleotide bonds

The monomers of the ASOs described herein are linked to each other via linking groups. Suitably, each monomer is linked to the 3' adjacent monomer via a linking group.

One of ordinary skill in the art would understand that, in the context of the present disclosure, the 5' monomer at the end of the ASO does not contain a 5' linking group, although it may or may not contain a 5' end group.

The terms "linking group" and "internucleotide bond" are meant to mean a group capable of covalently linking two nucleotides to each other. Specific and preferred examples include phosphate groups and phosphorothioate groups.

The ASO nucleotides of this disclosure, or a contiguous nucleotide sequence thereof, are linked to each other via linking groups. Suitably, each nucleotide is linked to the 3' adjacent nucleotide via a linking group.

Suitable internucleotide bonds include the bonds listed in WO 2007/031091, for example, the internucleotide bonds listed in the first paragraph of page 34 of WO 2007/031091 (hereby incorporated by reference in its entirety).

Examples of suitable internucleotide linkages that can be used with this disclosure include a phosphodiester bond (PO or subscript o), a phosphotriester bond, a methylphosphonate bond, a phosphoramidate bond, a phosphorothioate bond (PS or subscript s), and combinations thereof.

In some embodiments, it is preferable to modify the internucleotide bond from a normal phosphodiester bond to a bond that is more resistant to nuclease attack, such as phosphorothioate or boranophosphate—these two bonds, being cleavable by RNase H, also provide an antisense inhibition pathway to reduce target gene expression.

Suitable sero(S) containing internucleotide linkages may be preferred as provided herein. Phosphorothioate internucleotide linkages are also preferred, especially for the gap (B) region of gapmers. Phosphorothioate bonds can also be used for flanking regions (A and C, and for linking A or C to D, and within region D, as appropriate).

Regions A, B and C, however, may contain internucleotide bonds other than phosphorothioate, such as phosphodiester bonds, in particular, for example, when the use of nucleotide analogs protects internucleotide bonds within regions A and C from endonuclease degradation - as, for example, when regions A and C contain LNA nucleotides.

Internucleotide bonds in ASO can be phosphodiester, phosphorothioate, or boranophosphate so as to allow RNase H to cleave the target RNA. Phosphorothioate is preferred due to improved nuclease stability and other reasons such as ease of preparation.

In some embodiments, the internucleotide bonds comprise one or more stereo-defined internucleotide bonds (eg, such as stereo-defined modified phosphate bonds, eg, phosphodiester, phosphorothioate, or boranophosphate bonds with a defined stereochemical structure). The term "stereo-defined internucleotide bond" is used interchangeably with "chirally controlled internucleotide bond" and refers to an internucleotide bond in which the stereochemical designation of the phosphorus atom is controlled such that a specific amount of R _p or S _p internucleotide bond is present within the ASO strand. The stereochemical designation of a chiral bond can be determined (controlled), for example, by asymmetric synthesis. An ASO having at least one stereodetermined internucleotide bond may be referred to as a stereodetermined ASO, which includes both fully stereodetermined ASO and partially stereodetermined ASO.

In some embodiments, the ASO is fully stereodetermined. The term "fully stereospecific ASO" refers to an ASO sequence having a defined chiral center (R _p or S _p ) at each internucleotide bond in that ASO. In some embodiments, the ASO is partially stereodetermined. The term "partially stereodetermined ASO" refers to an ASO sequence having a defined chiral center (R _p or S _p ) in at least one internucleotide bond, but not all internucleotide bonds. Therefore, a partially stereo-defined ASO may include bonds that are achiral or stereo-indefinite, in addition to at least one stereo-defined bond. When the internucleotide bond in ASO is stereodetermined, the desired configuration - either R _p or S _p - is present in at least 10%, at least 20%, at least 30%, at least 40%, 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 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or essentially 100% ASO.

In one aspect of the ASO of this disclosure, nucleotides and/or nucleotide analogs are linked to each other via phosphorothioate groups. It is useful to use phosphorothioate internucleoside linkages with the oligonucleotides of this invention.

Phosphorothioate internucleoside linkages are particularly useful due to nuclease stability, beneficial pharmacokinetics, and ease of preparation. In some embodiments, at least 50% of the internucleoside bonds in the oligonucleotide or its contiguous nucleotide sequence is phosphorothioate, such as at least 60%, such as at least 70%, such as at least 75% as, for example, at least 80% or as, for example, at least 90% of the internucleoside bonds in the oligonucleotide or its continuous nucleotide sequence are phosphorothioate. In some embodiments, all internucleoside bonds of the oligonucleotide or its continuous nucleotide sequence are phosphorothioate.

It is recognized that the incorporation of phosphodiester linkages, such as one or two linkages, of an otherwise phosphorothioate ASO, especially between or adjacent to nucleotide analog units (typically in the A and/or C region) may modify the bioavailability and/or biodistribution of ASO - see WO 2008/113832, hereby incorporated by reference.

In some embodiments, such as those referenced above, where appropriate and not specifically indicated, all other linking groups are either phosphodiester or phosphorothioate, or a mixture thereof.

In some embodiments, the oligonucleotide of the invention contains both phosphorothioate internucleoside bonds and at least one phosphodiester bond, such as 2, 3 or 4 phosphodiester bonds, in addition to the phosphorothioate(s) bond(s). In gapmer oligonucleotide e, phosphodiester bonds, if present, are not appropriately located between adjacent DNA nucleosides in the gap-G region.

In some embodiments, all internucleotide linking groups are phosphorothioate.

When referring to specific gapmer oligonucleotide sequences, such as those provided herein, it will be understood that, in various embodiments, when the bonds are phosphorothioate bonds, alternative bonds can be used, such as the bonds disclosed herein, for example, phosphate (phosphodiester) linkages can be used, in particular for linkages between nucleotide analogs such as LNA units. Similarly, when referring to specific gapmer oligonucleotide sequences, such as those provided herein, when C residues are annotated as 5'-methyl modified cytosine, in various embodiments, one or more Cs present in ASO may be unmodified residues FROM.

U.S. Publication No. 2011/0130441, which was published on June 2, 2011 and is incorporated herein by reference in its entirety, refers to ASO compounds having at least one bicyclic nucleoside attached to the 3' or 5' ends. neutral internucleoside bond. The ASOs of this disclosure may therefore have at least one bicyclic nucleoside attached to the 3' or 5' ends by a neutral internucleoside bond, such as one or more phosphotriester, methylphosphonate, MMI (3'-CH ₂ -N (CH ₃ )-O-5'), amide-3 (3'-CH ₂ -C(=O)-N(H)-5'), formacetal (3'-O-CH ₂ -O-5' ) or thioformacetal (3'-S-CH ₂ -O-5'). The remaining bonds may be phosphorothioate.

In some embodiments, the ASOs of this disclosure have the internucleotide linkages described in FIG. 1A-1C and 2. As used herein, for example in FIG. 1A-1C and 2, phosphorothioate bonds are indicated by "s" and phosphodiester bonds are indicated by the absence of "s".

II.I. Conjugates

The term "conjugate" as used herein refers to an oligonucleotide that is covalently linked to a non-nucleotide moiety (conjugate moiety or C region or third region).

Conjugation of an oligonucleotide of this disclosure to one or more non-nucleotide moieties may improve the pharmacology of the oligonucleotide, for example by affecting the activity, cellular distribution, cellular uptake, or stability of the oligonucleotide. In some embodiments, the conjugate moiety modifies or improves the pharmacokinetic properties of the oligonucleotide by improving the cellular distribution, bioavailability, metabolism, excretion, permeability, and/or cellular uptake of the oligonucleotide. In particular, a given conjugate can target an oligonucleotide to a particular organ, tissue, or cell type and thereby increase the effectiveness of the oligonucleotide in that organ, tissue, or cell type. At the same time, the conjugate may serve to reduce the activity of the oligonucleotide in non-target cell types, tissues, or organs, eg, off-target activity or activity in non-target cell types, tissues, or organs. WO 93/07883 and WO 2013/033230 propose suitable conjugate moieties. Other suitable conjugate moieties are moieties capable of binding to the asialoglycoprotein receptor (ASGPr). In particular, trivalent N-acetylgalactosamine conjugate moieties are suitable for binding to ASGPr, see for example WO 2014/076196, WO 2014/207232 and WO 2014/179620.

Oligonucleotide conjugates and their synthesis have also been described in Manoharan's comprehensive reviews in Antisense Drug Technology, Principles, Strategies, and Applications, ST. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103.

In one embodiment, the non-nucleotide moiety (conjugate moiety) is selected from the group consisting of carbohydrates (e.g. GalNAc), cell surface receptor ligands, drugs, hormones, lipophilic substances, polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins , viral proteins (eg capsids) and combinations thereof.

In some embodiments, the conjugate is an antibody or antibody fragment that has specific affinity for the transferrin receptor, for example as disclosed in WO 2012/143379, hereby incorporated by reference. In some embodiments, the non-nucleotide moiety is an antibody or antibody fragment, such as an antibody or antibody fragment that facilitates delivery across the blood-brain barrier, in particular an antibody or antibody fragment that targets the transferrin receptor.

II.J. Activated ASOs

The term "activated ASO" as used herein refers to an ASO of this disclosure that is covalently linked (i.e., functionalized) to at least one functional moiety that provides a covalent bond of the ASO to one or more than one conjugate moiety, i. e. groups that are not themselves nucleic acids or monomers to form the conjugates described herein. Typically, the functional moiety will contain a chemical group that is capable of covalently bonding to ASO, such as through the 3'-hydroxyl group or the exocyclic NH2 group of the adenine base, a spacer that may be hydrophilic, and an end group that is capable of bonding to the conjugate moiety ( e.g. amino, sulfhydryl or hydroxyl group). In some embodiments, this end group is unprotected, for example, is an NH2 group. In other embodiments, the end group is protected, for example, with any suitable protecting group, such as those described in "Protective Groups in Organic Synthesis" by Theodora W Greene and Peter GM ^Wuts , 3rd edition (John Wiley & Sons, 1999).

In some embodiments, the ASOs of this disclosure are functionalized at the 5' end to allow the conjugate moiety to be covalently attached to the 5' end of the ASO. In other embodiments, the ASOs of this disclosure may be functionalized at the 3' end. In other embodiments, the ASOs of this disclosure may be functionalized along the backbone or on the heterocyclic base moiety. In other embodiments, the ASOs of this disclosure may be functionalized at more than one position independently selected from the 5' end, 3' end, backbone, and base.

In some embodiments, the activated ASOs of this disclosure are synthesized by incorporating, during synthesis, one or more monomers that are covalently attached to the functional moiety. In other embodiments, the activated ASOs of this disclosure are synthesized with monomers that have not been functionalized, and these ASOs are functionalized at the completion of the synthesis.

III. Pharmaceutical compositions and routes of administration

The ASOs of this disclosure may be used in pharmaceutical preparations and compositions. Suitably, such compositions contain a pharmaceutically acceptable diluent, carrier, salt or adjuvant.

The ASOs of this disclosure may be incorporated into a single preparation, such as in a pharmaceutically acceptable carrier or diluent, in a sufficient amount to deliver a therapeutically effective amount to a patient without causing serious side effects in the patient being treated. However, with some therapies, serious side effects may be acceptable in terms of ensuring a positive outcome of therapeutic treatment.

The drug obtained in dosage form may contain pharmaceutically acceptable binding agents and adjuvants. Capsules, tablets or pills may contain, for example, the following compounds: microcrystalline cellulose, gum or gelatin as binding agents; starch or lactose as excipients; stearates as lubricants; various sweeteners or flavors. For capsules, the dosage unit may contain a liquid carrier like fatty oils. Similarly, sugar or enteric coatings may be part of the dosage unit. Oligonucleotide preparations can also be emulsions of the active pharmaceutical ingredients and lipid forming a micellar emulsion.

The pharmaceutical compositions of the present disclosure may be administered in a variety of ways, depending on whether topical or systemic treatment is desired and the area to be treated. Administration can be (a) oral, (b) pulmonary, for example, by inhalation or inhalation of powders or aerosols, including by nebulizer, intratracheal, intranasal, (c) topical, including epidermal, transdermal, ocular and mucous membranes, including vaginal and rectal delivery; (d) parenteral, including intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, for example, intrathecal, intracerebroventricular, intravitreal or intraventricular administration. In one embodiment, ASO is administered i.v. (intravenously), v.b. (intraperitoneally), orally, topically or as a bolus injection, or injected directly into the target organ. In another embodiment, ASO is administered intrathecally or intracerebroventricularly as a bolus injection.

Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, sprays, suppositories, liquids and powders.

Conventional pharmaceutical carriers, aqueous, powder or oil bases may be necessary or desirable. Examples of topical formulations include formulations in which the ASOs of this disclosure are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelators, and surfactants. Compositions and preparations for oral administration include, but are not limited to, powders or granules, microparticles, nanoparticles, suspensions or solutions in water or non-aqueous vehicles, capsules, gel capsules, sachets, tablets or minitablets. Compositions and formulations for parenteral, intrathecal, intracerebroventricular, or intraventricular administration may include, but are not limited to, sterile aqueous solutions, which may also contain buffers, diluents, and other suitable additives such as penetration enhancers, carrier compounds, and other pharmaceutically acceptable carriers or excipients. .

Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, and preparations containing liposomes. These compositions can be made from a variety of ingredients and include, but are not limited to, pre-formulated liquids, self-emulsifying solids, and self-emulsifying semi-solids. Drug delivery to the target tissue can be enhanced by carrier-mediated delivery, including cationic liposomes, cyclodextrins, porphyrin derivatives, branched chain dendrimers, polyethyleneimine polymers, nanoparticles and microspheres (Dass CR. J Pharm Pharmacol 2002; 54(1):3- 27).

The pharmaceutical preparations of the present disclosure, 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 bringing into association the active ingredients with the pharmaceutical(s) carrier(s) or excipient(s). In general, these formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

For parenteral, subcutaneous, intradermal, or topical administration, this formulation may include a sterile diluent, buffers, tonicity regulators, or antibacterials. Active ASOs can be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties. For intravenous administration, carriers may be saline or phosphate buffered saline. International Publication No. WO 2007/031091 (A2), published March 22, 2007, further proposes suitable pharmaceutically acceptable diluent, carrier and adjuvants, which are hereby incorporated by reference.

The invention also provides the use of an oligonucleotide or an oligonucleotide conjugate of the invention as described for the manufacture of a medicament, wherein the medicament is in an intrathecal or intracerebroventricular dosage form.

IV. Diagnostics

This disclosure further provides a useful diagnostic tool during the diagnosis of SNCA-associated diseases, such as synucleinopathy. Non-limiting examples of synucleinopathy include, but are not limited to, Parkinson's disease, Parkinson's disease dementia (PDD), Lewy body dementia, and multiple system atrophy.

The ASOs of this disclosure can be used to measure the expression of an SNCA transcript in a tissue or body fluid from an individual and compare the measured level of expression to a standard level of expression of the SNCA transcript in normal tissue or body fluid, wherein an increase in expression level over the standard indicates a disorder susceptible to the ASO treatment of this disclosure.

The ASO of this disclosure can be used to analyze SNCA transcript levels in a biological sample using any of the methods known to those of ordinary skill in the art. (Touboul et al., Anticancer Res. (2002) 22 (6A): 3349-56; Verjout et al., Mutat. Res. (2000) 640: 127-38); Stowe et al., J. Virol. Methods (1998) 75 (1): 93-91).

By "biological sample" is meant any biological sample obtained from an individual, cell line, tissue culture, or other source of cells potentially expressing an SNCA transcript. Methods for obtaining tissue and body fluid biopsies from mammals are well known in the art.

V. Kits containing ASO

This disclosure further provides kits that contain the ASO of this disclosure described herein and which can be used to carry out the methods described herein. In some embodiments, this kit contains at least one ASO in one or more than one container. In some embodiments, these kits contain all necessary and/or sufficient components to perform a detection assay, including all controls, guidelines for performing assays, and any necessary program for analyzing and presenting results. One of ordinary skill in the art will readily recognize that the disclosed ASO can easily be included in one of the established kit formats that are well known in the art.

VI. Application methods

The ASOs of this disclosure may be used for therapy and prophylaxis.

SNCA is a 140 amino acid protein preferentially expressed in neurons at presynaptic terminals, where it is believed to play a role in the regulation of synaptic transmission. It is thought to exist in nature both as an unfolded monomer and as a stable α-helix tetramer, and has been shown to undergo several post-translational modifications. One modification that has been widely studied is the phosphorylation of SNCA on the amino acid serine 129 (S129). Typically, only a small percentage of SNCA is constitutively phosphorylated at S129 (pS129), while the vast majority of SNCA found in abnormal intracellular inclusions is SNCA pS129. These pathological inclusions consist of aggregated, insoluble accumulations of misfolded SNCA proteins and are a characteristic feature of a group of neurodegenerative diseases known collectively as synucleinopathies.

In synucleinopathies, SNCA can form abnormal neuronal aggregates known as Lewy bodies, which are characteristic of both Parkinson's disease (PD), Parkinson's disease dementia (PDD), and Lewy body dementia (DLB). The present ASOs can therefore reduce the number of pathological SNCA aggregates or prevent the formation of pathological SNCA aggregates. In addition, abnormal SNCA-enriched lesions referred to as glial cytoplasmic inclusions (GCI) are found in oligodendrocytes and represent the hallmark of a rapidly progressive, fatal synucleopathy known as multiple system atrophy (MSA). In some embodiments, the ASOs of this disclosure reduce the number of GCIs or prevent the formation of GCIs. Reports of either undetectable or low levels of SNCA mRNA expression in oligodendrocytes suggest that some pathological form of SNCA is spreading from neurons, where it is highly expressed, into oligodendrocytes. In some embodiments, the ASOs of this disclosure reduce or prevent the spread of SNCA, eg, an abnormal form of SNCA, from neurons.

ASO data can be used in research, for example, to specifically inhibit SNCA protein synthesis (typically by degrading or inhibiting mRNA and thereby preventing protein formation) in cells and experimental animals, thereby facilitating functional analysis of the target or evaluation of its usefulness in as a target for therapeutic intervention. Further provided are methods for down-regulating SNCA mRNA and/or SNCA protein expression in cells or tissues, comprising bringing the cells or tissues into contact, in vitro or in vivo, with an effective amount of one or more ASO, conjugate or composition of this disclosure.

For therapy, an animal or human suspected of having a disease or disorder that can be treated by modulating SNCA transcript and/or SNCA protein expression is treated with the administration of the ASO compounds of this disclosure. Further provided are methods of treating a mammal, such as treating a human suspected of having or prone to a disease or condition associated with expression of an SNCA transcript and/or SNCA protein, by administering a therapeutically or prophylactically effective amount of one or more ASOs or compositions of this disclosure. The ASO, conjugate, or pharmaceutical composition of this disclosure is typically administered in an effective amount. In some embodiments, the ASO or conjugate of this disclosure is used in therapy.

The disclosure further provides the ASOs of the disclosure for use in the treatment of one or more of the diseases referred to herein, such as a disease selected from the group consisting of Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, multiple system atrophy, and any combination thereof.

This disclosure further provides a method for treating α-synucleinopathies comprising administering an effective amount of one or more ASOs, conjugates thereof, or pharmaceutical compositions to an animal in need thereof (such as a patient in need thereof).

In some embodiments, the disease, disorder, or condition is associated with overexpression of an SNCA gene transcript and/or an SNCA protein.

The disclosure also provides methods for inhibiting (e.g., reducing) expression of an SNCA gene transcript and/or SNCA protein in a cell or tissue, comprising contacting the cell or tissue in vitro or in vivo with an effective amount of one or more ASOs, their conjugates. or the pharmaceutical compositions of this disclosure to affect the degradation of SNCA gene transcript expression, thereby reducing the level of SNCA protein.

In some embodiments, ASOs are used to reduce SNCA mRNA expression in one or more brain slices, such as the hippocampus, brainstem, striatum, or any combination thereof. In other embodiments, ASOs reduce SNCA mRNA expression, e.g., in the brainstem and/or striatum, to less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10% or less than 5% compared to SNCA mRNA expression after administration or vehicle exposure (without ASO) on day 3, day 5, day 7, day 10, day 14, day 15, day 20, day 21 or day 25. In some embodiments, SNCA mRNA expression is maintained at less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% compared to SNCA mRNA expression after administration. or exposure to vehicle (without ASO) up to Day 28, Day 30, Day 32, Day 35, Day 40, Day 42, Day 45, Day 49, Day 50, Day 56, Day 60, Day 63, Day 70, or Day 75 .

In other embodiments, the ASOs of the present disclosure reduce SNCA mRNA and/or SNCA protein expression in the medulla, dorsal striatum, pons, lumbar spinal cord, frontal cortex, and/or any combination thereof.

This disclosure also provides the use of the ASO or conjugate of this disclosure as described for the manufacture of a medicament. The disclosure also provides a composition containing ASO or a conjugate thereof for use in the treatment of a disorder referred to herein or for a method of treating a disorder referred to herein. The present disclosure also provides ASOs or conjugates for use in therapy. The present disclosure further provides ASOs or conjugates for use in the treatment of synucleinopathy.

The disclosure further provides a method for inhibiting an SNCA protein in a cell that expresses SNCA, comprising administering an ASO or a conjugate of this disclosure to the cell so as to effect inhibition of the SNCA protein in the cell.

This disclosure includes a method of reducing, ameliorating, preventing, or treating neuronal hyperexcitability in a subject in need thereof, comprising administering an ASO or a conjugate according to this disclosure.

The disclosure also provides a method of treating a disorder referred to herein, comprising administering an ASO or a conjugate of this disclosure as described herein and/or a pharmaceutical composition of this disclosure to a patient in need thereof.

ASO and other compositions according to this disclosure can be used to treat conditions associated with overexpression or expression of a mutated version of the SNCA protein.

This disclosure provides an ASO or a conjugate of this disclosure for use as a drug, such as for the treatment of α-synucleinopathies. In some embodiments, α-synucleinopathy is a disease selected from the group consisting of Parkinson's disease, Parkinson's disease dementia (PDD), Lewy body dementia, multiple system atrophy, and any combinations thereof.

This disclosure further provides the use of the ASO of this disclosure in the manufacture of a medicament for the treatment of the disease, disorder, or condition referred to herein. In some embodiments, the ASO or conjugate of this disclosure is used in the manufacture of a medicament for the treatment of α-synucleinopathy, a seizure disorder, or a combination thereof.

Generally speaking, one aspect of this disclosure is directed to a method of treating a mammal suffering from or susceptible to conditions associated with abnormal levels of SNCA, i. α-synucleinopathy, comprising administering to the mammal a therapeutically effective amount of ASO targeted to an SNCA transcript that contains one or more LNA units. A given ASO, conjugate or pharmaceutical composition according to this disclosure is typically administered in an effective amount.

In some embodiments, the oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition of this invention is administered at a dose of 0.1-15 mg/kg, such as 0.2-10 mg/kg, such as 0.25-5 mg/kg . Administration can be once a week, every 2nd week, every third week, or even once a month.

The disease or disorder, as referred to herein, in some embodiments, may be associated with a mutation in the SNCA gene or a gene whose protein product is associated with or interacts with the SNCA protein. Therefore, in some embodiments, the target mRNA is a mutated form of the SNCA sequence.

An interesting aspect of this disclosure is directed to the use of an ASO (compound), as defined herein, or a conjugate, as defined herein, for the manufacture of a medicament for the treatment of the disease, disorder, or condition referred to herein.

The methods of this disclosure can be used to treat or prevent diseases caused by abnormal levels of SNCA protein. In some embodiments, the diseases caused by abnormal levels of SNCA protein are α-synucleinopathies. In some embodiments, α-synucleinopathies include Parkinson's disease, Parkinson's disease dementia (PDD), Lewy body dementia, and multiple system atrophy.

Expressed alternatively, in some embodiments, this disclosure is further directed to a method of treating abnormal SNCA protein levels, comprising administering an ASO of this disclosure, or a conjugate of this disclosure, or a pharmaceutical composition of this disclosure, to a patient in need thereof.

This disclosure also relates to an ASO, composition or conjugate, as defined herein, for use as a drug.

This disclosure further relates to the use of a compound, composition, or conjugate as defined herein for the manufacture of a medicament for the treatment of abnormal SNCA protein levels or the expression of SNCA protein mutants (such as allelic variants, such as allelic variants associated with one of the diseases referred to in this document).

A patient in need of treatment is a patient suffering from or likely to suffer from a given disease or disorder.

The practice of this disclosure will use, unless otherwise indicated, conventional cell biology, cell culture, molecular biology, transgenic biology, microbiology, genetic engineering, and immunology techniques that are within the skill of the art. Such techniques are fully explained in the literature. See, for example, Sambrook et al., ed. (1989) Molecular Cloning A Laboratory Manual (2nd ed ^.; Cold Spring Harbor Laboratory Press); Sambrook et al., ed. (1992) Molecular Cloning: A Laboratory Manual, (Cold Springs Harbor Laboratory, NY); D.N. Glover ed., (1985) DNA Cloning, Volumes I and II; Gait, ed. (1984) Oligonucleotide Synthesis; Mullis et al. US patent No. 4683195; Hames and Higgins, eds. (1984) Nucleic Acid Hybridization; Hames and Higgins, eds. (1984) Transcription And Translation; Freshney (1987) Culture Of Animal Cells (Alan R. Liss, Inc.); Immobilized Cells And Enzymes (IRL Press) (1986); Perbal (1984) A Practical Guide to Molecular Cloning; monograph, Methods In Enzymology (Academic Press, Inc., NY); Miller and Calos eds. (1987) Gene Transfer Vectors For Mammalian Cells, (Cold Spring Harbor Laboratory); Wu et al., eds., Methods In Enzymology, Vols. 154 and 155; Mayer and Walker, eds. (1987) Immunochemical Methods In Cell And Molecular Biology (Academic Press, London); Weir and Blackwell, eds., (1986) Handbook Of Experimental Immunology, Volumes I-IV; Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, (1986); Crooke, Antisense drug Technology: Principles, Strategies and Applications, 2nd ^Ed . CRC Press (2007) and Ausubel et al. (1989) Current Protocols in Molecular Biology (John Wiley and Sons, Baltimore, Md.).

All references cited above, as well as all references cited herein, are incorporated herein by reference in their entirety.

INcarnations

1. An antisense oligonucleotide comprising a contiguous nucleotide sequence of 10-30 nucleotides in length that is complementary to a nucleic acid sequence within an alpha-synuclein transcript (SNCA), wherein the nucleic acid sequence is selected from the group consisting of (i) nucleotides 4942 - 5343 SEQ ID NO: 1; (ii) nucleotides 6326 - 7041 of SEQ ID NO: 1; (iia) nucleotides 6336 - 7041 of SEQ ID NO: 1; (iii) nucleotides 7329 - 7600 of SEQ ID NO: 1; (iv) nucleotides 7630 - 7783 of SEQ ID NO: 1; (iva) nucleotides 7750 - 7783 SEQ ID NO: 1; (v) nucleotides 8277 - 8501 of SEQ ID NO: 1; (vi) nucleotides 9034 - 9526 of SEQ ID NO: 1; (vii) nucleotides 9982 - 14279 SEQ ID NO: 1; (viii) nucleotides 15204 - 19041 SEQ ID NO: 1; (ix) nucleotides 20351 - 29654 SEQ ID NO: 1; (ixa) nucleotides 20351 - 20908 SEQ ID NO: 1; (ixb) nucleotides 21052 - 29654 SEQ ID NO: 1; (x) nucleotides 30931 - 33938 SEQ ID NO: 1; (xi) nucleotides 34932 - 37077 SEQ ID NO: 1; (xii) nucleotides 38081 - 42869 SEQ ID NO: 1; (xiii) nucleotides 44640 - 44861 SEQ ID NO: 1; (xiv) nucleotides 46173 - 46920 SEQ ID NO: 1; (xv) nucleotides 47924 - 58752 SEQ ID NO: 1; (xvi) nucleotides 60678 - 60905 SEQ ID NO: 1; (xvii) nucleotides 62066 - 62397 SEQ ID NO: 1; (xviii) nucleotides 67759 - 71625 SEQ ID NO: 1; (xix) nucleotides 72926 - 86991 SEQ ID NO: 1; (xx) nucleotides 88168 - 93783 SEQ ID NO: 1; (xxi) nucleotides 94976 - 102573 SEQ ID NO: 1; (xxii) nucleotides 104920 - 107438 SEQ ID NO: 1; (xxiii) nucleotides 108948 - 119285 SEQ ID NO: 1; (xxiiia) nucleotides 108948 - 114019 SEQ ID NO: 1; (xxiib) nucleotides 114292 - 116636 SEQ ID NO: 1; (xxiv) nucleotides 131 - 678 of SEQ ID NO: 5; (xxv) nucleotides 131 - 348 of SEQ ID NO: 3; (xxvi) nucleotides 1 - 162 of SEQ ID NO: 4; (xxvii) nucleotides 126-352 of SEQ ID NO: 2; (xxviii) nucleotides 276 - 537 of SEQ ID NO: 2; (xxix) nucleotides 461 - 681 SEQ ID NO: 2 and (xxx) nucleotides 541 - 766 SEQ ID NO: 2.

2. Antisense oligonucleotide according to embodiment 1, in which the nucleic acid sequence is selected from the group consisting of (i) nucleotides 4992 - 5109 of SEQ ID NO: 1; (ii) nucleotides 6376 - 6991 of SEQ ID NO: 1; (iii) nucleotides 7379 - 7600 of SEQ ID NO: 1; (iv) nucleotides 7630 - 7733 of SEQ ID NO: 1; (v) nucleotides 8327 - 8451 of SEQ ID NO: 1; (vi) nucleotides 9084 - 9476 of SEQ ID NO: 1; (vii) nucleotides 10032 - 14229 SEQ ID NO: 1; (viii) nucleotides 15254 - 18991 SEQ ID NO: 1; (ix) nucleotides 20401 - 29604 SEQ ID NO: 1; (x) nucleotides 30981 - 33888 SEQ ID NO: 1; (xi) nucleotides 34982 - 37027 SEQ ID NO: 1; (xii) nucleotides 38131 - 42819 of SEQ ID NO: 1; (xiii) nucleotides 44690 - 44811 SEQ ID NO: 1; (xiv) nucleotides 46223 - 46870 SEQ ID NO: 1; (xv) nucleotides 47974 - 58702 SEQ ID NO: 1; (xvi) nucleotides 60728 - 608555 SEQ ID NO: 1; (xvii) nucleotides 62116 - 62347 SEQ ID NO: 1; (xviii) nucleotides 67809 - 71575 SEQ ID NO: 1; (xix) nucleotides 72976 - 86941 SEQ ID NO: 1; (xx) nucleotides 88218 - 93733 SEQ ID NO: 1; (xxi) nucleotides 95026 - 102523 SEQ ID NO: 1; (xxii) nucleotides 104970 - 107388 SEQ ID NO: 1; (xxiii) nucleotides 108998 - 119235 SEQ ID NO: 1; (xxiv) nucleotides 181 - 628 of SEQ ID NO: 5; (xxv) nucleotides 181 - 298 of SEQ ID NO: 3; (xxvi) nucleotides 15-112 of SEQ ID NO: 4; (xxvii) nucleotides 176 - 302 of SEQ ID NO: 2; (xxviii) nucleotides 326-487 of SEQ ID NO: 2; (xxix) nucleotides 511 - 631 SEQ ID NO: 2 and (xxx) nucleotides 591 - 716 SEQ ID NO: 2.

3. Antisense oligonucleotide according to embodiment 1, in which the nucleic acid sequence is selected from the group consisting of (i) nucleotides 5042 - 5243 of SEQ ID NO: 1; (ii) nucleotides 6426 - 6941 of SEQ ID NO: 1; (iii) nucleotides 7429 - 7600 of SEQ ID NO: 1; (iv) nucleotides 7630 - 7683 of SEQ ID NO: 1; (v) nucleotides 8377 - 8401 of SEQ ID NO: 1; (vi) nucleotides 9134 - 9426 of SEQ ID NO: 1; (vii) nucleotides 10082 - 14179 SEQ ID NO: 1; (viii) nucleotides 15304 - 18941 SEQ ID NO: 1; (ix) nucleotides 20451 - 29554 SEQ ID NO: 1; (x) nucleotides 31031 - 33838 SEQ ID NO: 1; (xi) nucleotides 35032 - 36977 SEQ ID NO: 1; (xii) nucleotides 38181 - 42769 SEQ ID NO: 1; (xiii) nucleotides 44740 - 44761 SEQ ID NO: 1; (xiv) nucleotides 46273 - 46820 SEQ ID NO: 1; (xv) nucleotides 48024 - 58752 SEQ ID NO: 1; (xvi) nucleotides 60778 - 60805 SEQ ID NO: 1; (xvii) nucleotides 62166 - 62297 SEQ ID NO: 1; (xviii) nucleotides 67859 - 71525 SEQ ID NO: 1; (xix) nucleotides 73026 - 86891 SEQ ID NO: 1; (xx) nucleotides 88268 - 93683 SEQ ID NO: 1; (xxi) nucleotides 95076 - 102473 SEQ ID NO: 1; (xxii) nucleotides 105020 - 107338 SEQ ID NO: 1; (xxiii) nucleotides 109048 - 119185 SEQ ID NO: 1; (xxiv) nucleotides 231-248 or 563-578 of SEQ ID NO: 5; (xxv) nucleotides 231 - 248 of SEQ ID NO: 3; (xxvi) nucleotides 38-62 of SEQ ID NO: 4; (xxvii) nucleotides 226-252 of SEQ ID NO: 2; (xxviii) nucleotides 376-437 of SEQ ID NO: 2; (xxix) nucleotides 561 - 581 SEQ ID NO: 2 and (xxx) nucleotides 641 - 666 SEQ ID NO: 2.

4. Antisense oligonucleotide according to embodiment 1, in which the nucleic acid sequence corresponds to nucleotides 21052 - 29654 SEQ ID NO: 1; nucleotides 30931 - 33938 SEQ ID NO: 1; nucleotides 44640 - 44861 of SEQ ID NO: 1 or nucleotides 47924 - 58752 of SEQ ID NO: 1.

5. Antisense oligonucleotide according to embodiment 1 or 4, in which the nucleic acid sequence corresponds to nucleotides 24483 - 28791 SEQ ID NO: 1; nucleotides 32225 - 32245 SEQ ID NO: 1; nucleotides 44740 - 44760 of SEQ ID NO: 1 or nucleotides 48640 - 48660 of SEQ ID NO: 1.

6. Antisense oligonucleotide according to embodiment 1, in which the nucleic acid sequence corresponds to (i) nucleotides 7502 - 7600 of SEQ ID NO: 1; (ii) nucleotides 7630 - 7719 of SEQ ID NO: 1; (iii) nucleotides 116881 - 117312 of SEQ ID NO: 1 or (iv) nucleotides 118606 - 118825 of SEQ ID NO: 1.

7. Antisense oligonucleotide according to embodiment 1 or 6, in which the nucleic acid sequence is nucleotides 116881 - 117119 SEQ ID NO: 1; nucleotides 116968 - 117198 SEQ ID NO: 1 or nucleotides 117085 - 117312 SEQ ID NO: 1.

8. Antisense oligonucleotide according to embodiment 1, 6 or 7, in which the nucleic acid sequence is (i) nucleotides 7552 - 7600 of SEQ ID NO: 1; (ii) nucleotides 7630 - 7669 of SEQ ID NO: 1; (iii) nucleotides 116931 - 117262 of SEQ ID NO: 1 or (iv) nucleotides 118656 - 118775 of SEQ ID NO: 1.

9. Antisense oligonucleotide according to embodiment 8, in which the nucleic acid sequence is nucleotides 116931 - 117069 SEQ ID NO: 1; nucleotides 117018 - 117148 SEQ ID NO: 1 or nucleotides 117135 - 117262 SEQ ID NO: 1.

10. An antisense oligonucleotide according to embodiment 1, wherein the nucleic acid sequence is (i) nucleotides 116981 - 117212 of SEQ ID NO: 1 or (ii) nucleotides 118706 - 118725 of SEQ ID NO: 1.

11. Antisense oligonucleotide according to embodiment 10, in which the nucleic acid sequence is nucleotides 116981 - 117019 SEQ ID NO: 1; nucleotides 117068 - 117098 SEQ ID NO: 1 or nucleotides 117185 - 117212 SEQ ID NO: 1.

12. An antisense oligonucleotide according to any one of embodiments 1-11, which is 10 to 24 nucleotides in length or 14 to 21 nucleotides in length.

13. An antisense oligonucleotide according to any one of embodiments 1-12, which is 14, 15, 16, 17, 18, 19, 20, or 21 nucleotides in length.

14. An antisense oligonucleotide according to any one of embodiments 1-13, wherein the SNCA transcript contains SEQ ID NO: 1.

15. An antisense oligonucleotide according to any one of embodiments 1-14, wherein the contiguous nucleotide sequence comprises SEQ ID NO: 7 - SEQ ID NO: 1878 with one, two, three, or four mismatches.

16. An antisense oligonucleotide according to any of embodiments 1-15, wherein the contiguous nucleotide sequence comprises SEQ ID NO: 7 - SEQ ID NO: 1878.

17. An antisense oligonucleotide according to embodiment 1 or 4, wherein the contiguous nucleotide sequence contains a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353 with no more than 2 mismatches.

18. An antisense oligonucleotide according to embodiment 1 or 17, wherein the contiguous nucleotide sequence consists of a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302 or SEQ ID NO: 1309-1353.

19. Antisense oligonucleotide according to any of embodiments 1, 4, 5, 11-18, in which the continuous nucleotide sequence contains a sequence selected from the group consisting of SEQ ID NO: 276; 278; 296; 295; 325; 328; 326; 329; 330; 327; 332; 333; 331; 339; 341; 390; 522 and 559.

20. The antisense oligonucleotide of any one of embodiments 1-19, wherein the antisense oligonucleotide is capable of inhibiting the expression of a human SNCA transcript in a cell that expresses a human SNCA transcript.

21. An antisense oligonucleotide according to any one of embodiments 1-20, wherein the contiguous nucleotide sequence contains at least one nucleotide analog.

22. The antisense oligonucleotide of embodiment 21 wherein the nucleotide analog is a 2'-sugar modified nucleoside.

23. The method of embodiment 22, wherein the 2'-sugar-modified nucleoside is an affinity-enhancing sugar-modified nucleoside.

24. An antisense oligonucleotide according to any one of embodiments 1-23, which is a gapmer.

25. The antisense oligonucleotide of embodiment 24, which is a gapmer with interleaved flanks.

26. Antisense oligonucleotide according to embodiment 24 or 25, which contains the formula 5'-A-B-C-3', in which:

a) region B is a contiguous sequence of at least 6 DNA units that is capable of recruiting an RNase;

b) region A is a first wing sequence of 1-10 nucleotides, where this first wing sequence contains one or more nucleotide analogs and optionally one or more DNA units, and where at least one of the nucleotide analogs is located at the 3' end of A; and

c) region C is a second wing sequence of 1-10 nucleotides, where this second wing sequence contains one or more nucleotide analogs and possibly one or more DNA units, and where at least one of the nucleotide analogs is located at the 5' end of C.

27. The antisense oligonucleotide of embodiment 26, wherein region A contains 1-4 nucleotide analogs, region B consists of 8-15 DNA units, and region C contains 2-4 nucleotide analogs.

28. The antisense oligonucleotide of embodiment 26 or 27, wherein region A contains a combination of nucleotide analogs and DNA units selected from (i) 1-9 nucleotide analogs and 1 DNA unit; (ii) 1-8 nucleotide analogs and 1-2 DNA units; (iii) 1-7 nucleotide analogs and 1-3 DNA units; (iv) 1-6 nucleotide analogs and 1-4 DNA units; (v) 1-5 nucleotide analogs and 1-5 DNA units; (vi) 1-4 nucleotide analogs and 1-6 DNA units; (vii) 1-3 nucleotide analogs and 1-7 DNA units; (viii) 1-2 nucleotide analogs and 1-8 DNA units; and (ix) 1 nucleotide analog and 1-9 DNA units.

29. An antisense oligonucleotide according to embodiment 26 or 27, wherein region C contains a combination of nucleotide analogs and DNA units selected from (i) 1-9 nucleotide analogs and 1 DNA unit; (ii) 1-8 nucleotide analogs and 1-2 DNA units; (iii) 1-7 nucleotide analogs and 1-3 DNA units; (iv) 1-6 nucleotide analogs and 1-4 DNA units; (v) 1-5 nucleotide analogs and 1-5 DNA units; (vi) 1-4 nucleotide analogs and 1-6 DNA units; (vii) 1-3 nucleotide analogs and 1-7 DNA units; (viii) 1-2 nucleotide analogs and 1-8 DNA units; and (ix) 1 nucleotide analog and 1-9 DNA units.

30. An antisense oligonucleotide according to any one of embodiments 26-29, wherein region A is the first wing construct selected from any of the ASOs in FIG. 1A-1C and 2 and/or region C is a second wing structure selected from any of the ASOs in FIG. 1A-1C and 2, where the upper letter is the nucleoside analog and the lower letter is DNA.

31. An antisense oligonucleotide according to any one of embodiments 1-30, which contains at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten nucleotide analogs.

32. The antisense oligonucleotide of any one of embodiments 21-31, wherein the nucleotide analog or analogs are independently selected from one or more 2'-sugar modified nucleosides selected from the group consisting of a locked nucleic acid (LNA); 2'-O-alkyl-RNA; 2'-amino-DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'-fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), hindered ethyl nucleoside (cEt), 2'-O-methyl nucleic acid (2'-OMe), 2'-O-methoxyethyl nucleic acid (2 '-MOE) and any combination of them.

33. The antisense oligonucleotide of any one of embodiments 1-32, wherein the nucleotide analog or analogs contain a bicyclic sugar.

34. The antisense oligonucleotide of embodiment 33 wherein the bicyclic sugar comprises cEt, 2'-O-hindered 2'-O-methoxyethyl (cMOE), α-L-LNA, β-D-LNA, 2'-O,4' -C-ethylene-bridged nucleic acids (ENA), amino-LNA, oxy-LNA or thio-LNA.

35. The antisense oligonucleotide of any one of embodiments 21-34, wherein the nucleotide analog or analogs comprise β-d-oxy-lna.

36. The antisense oligonucleotide of any one of embodiments 21-35, wherein the antisense oligonucleotide comprises one or more 5'-methylcytosine nucleobases.

37. An antisense oligonucleotide according to any of embodiments 24-36, which contains two to five LNAs on the 5' region of the antisense oligonucleotide.

38. An antisense oligonucleotide according to any one of embodiments 24-37, which contains two to five LNAs on the 3' region of the antisense oligonucleotide.

39. An antisense oligonucleotide according to any one of embodiments 1-38, which contains an internucleoside bond selected from: a phosphodiester bond, a phosphotriester bond, a methylphosphonate bond, a phosphoramidate bond, a phosphorothioate bond, and combinations thereof.

40. The antisense oligonucleotide of any one of embodiments 1-39, wherein 50% of the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages.

41. The antisense oligonucleotide of any one of embodiments 1-40, wherein the internucleoside bond comprises one or more stereospecific, modified phosphate bonds.

42. The antisense oligonucleotide of any one of embodiments 1-40, wherein all internucleoside bonds in the contiguous nucleotide sequence are phosphorothioate.

43. The antisense oligonucleotide of any one of embodiments 1-42, wherein the antisense oligonucleotide has an in vivo tolerability less than or equal to a total score of 4, where the total score is the sum of the single scores of the five categories, which are 1) hyperactivity; 2) reduced activity and activation; 3) motor dysfunction and/or ataxia; 4) abnormal position and breathing; and 5) tremor and/or seizures, and where a single score for each category is measured on a scale of 0-4.

44. The antisense oligonucleotide of embodiment 43, wherein the in vivo tolerability is less than or equal to a total score of 3, a total score of 2, a total score of 1, or a total score of 0.

45. An antisense oligonucleotide according to any one of embodiments 1-44, which reduces SNCA mRNA expression in a cell by at least about 20%, at least about 30%, at least about 40%, at least about 50% , at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% compared to a cell not exposed to the antisense oligonucleotide.

46. An antisense oligonucleotide according to any one of embodiments 1-45, which reduces SNCA protein expression in a cell by at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% compared to a cell not exposed to the antisense oligonucleotide.

47. An antisense oligonucleotide according to any one of embodiments 1-46, which contains nucleotides A, T, C and G, at least one analogue of nucleotides A, T, C and G, and has a sequence score greater than or equal to 0.2, where sequence score is calculated by formula I:

48. The antisense oligonucleotide of embodiment 1-47, wherein the nucleotide sequence comprises, essentially consists of, or consists of a sequence selected from the group consisting of SEQ ID NOs: 7-1878 with a construct selected from the group consisting of the constructs in FIG. 1A-1C and 2, where the capital letter is the sugar-modified nucleoside and the lowercase letter is DNA.

49. The antisense oligonucleotide of embodiment 37, wherein the nucleotide sequence comprises, essentially consists of, or consists of SEQ ID NO: 1436 with construct ASO-003092 and SEQ ID NO: 1547 with construct ASO-003179, wherein the capital letter is a nucleoside analogue, and lowercase represents DNA.

50. The antisense oligonucleotide of embodiment 1-48, wherein the nucleotide sequence comprises, essentially consists of, or consists of a sequence selected from the group wherein the contiguous nucleotide sequence consists of a sequence selected from SEQ ID NO: 7 - SEQ ID NO: 1302, or SEQ ID NO: 1309-1353 with a construct selected from the group consisting of the constructs in FIG. 1A-1C, where the capital letter is the sugar-modified nucleoside and the lowercase letter is DNA.

51. The antisense oligonucleotide of embodiment 50, wherein the contiguous nucleotide sequence comprises a sequence selected from the group consisting of a construct selected from the group consisting of:

и

and

where capital letters indicate the sugar-modified nucleoside analog and lowercase letters indicate DNA.

52. An antisense oligonucleotide according to any one of embodiments 1-48, wherein the nucleotide sequence comprises, essentially consists of, or consists of a sequence selected from the group consisting of SEQ ID NOs: 7-1878 with the corresponding chemical structure in FIG. 1A-1C and 2.

53. An antisense oligonucleotide according to any one of embodiments 1-52, wherein the contiguous nucleotide sequence has the chemical structure ASO-003092 or ASO-003179.

54. Antisense oligonucleotide according to any one of embodiments 1-52, in which the continuous nucleotide sequence has a chemical structure selected from the group consisting of: ASO-008387; ASO-008388; ASO-008501; ASO-008502; ASO-008529; ASO-008530; ASO-008531; ASO-008532; ASO-008533; ASO-008534; ASO-008535; ASO-008536; ASO-008537; ASO-008543; ASO-008545; ASO-008584; ASO-008226 and ASO-008261.

55. A conjugate comprising an antisense oligonucleotide according to any of embodiments 1-53, wherein the antisense oligonucleotide is covalently attached to at least one non-nucleotide or non-polynucleotide moiety.

56. The conjugate of embodiment 55 wherein the non-nucleotide or non-polynucleotide moiety comprises a protein, a fatty acid chain, a sugar moiety, a glycoprotein, a polymer, or any combination thereof.

57. The conjugate of embodiment 55, wherein the conjugate is an antibody fragment that has specific affinity for the transferrin receptor.

58. A pharmaceutical composition comprising an antisense oligonucleotide according to any one of embodiments 1-57 or a conjugate according to embodiment 55-57 and a pharmaceutically acceptable carrier.

59. The composition of embodiment 58, which further comprises a therapeutic agent.

60. The composition of embodiment 59 wherein the therapeutic agent is an alpha-synuclein antagonist.

61. The composition of embodiment 60 wherein the alpha-synuclein antagonist is an anti-alpha-synuclein antibody or a fragment thereof.

62. A kit containing an antisense oligonucleotide according to any of embodiments 1-57 or a conjugate according to embodiment 55-57 or a composition according to any of embodiments 58-61 and instructions for use.

63. A diagnostic kit containing an antisense oligonucleotide according to any of embodiments 1-57 or a conjugate according to embodiment 55-57 or a composition according to any of embodiments 58-61 and instructions for use.

64. A method of inhibiting or reducing the expression of an SNCA protein in a cell, comprising introducing an antisense oligonucleotide according to any one of embodiments 1-57 or a conjugate according to embodiment 55-57, or a composition according to any one of embodiments 58-61 into a cell expressing the SNCA protein, where the expression of the protein SNCA in the cell is inhibited or reduced after administration.

65. The method of embodiment 64, wherein the antisense oligonucleotide inhibits or reduces the expression of SNCA mRNA in the cell after administration.

66. The method of embodiment 64 or 65, wherein SNCA mRNA expression is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% after administration compared to a cell not exposed to the antisense oligonucleotide.

67. The method of any one of embodiments 64-66, wherein the antisense oligonucleotide reduces the expression of the SNCA protein in the cell after administration by at least about 60%, at least about 70%, at least about 80%, or at least approximately 90% compared to a cell not exposed to the antisense oligonucleotide.

68. The method of any one of embodiments 64-67 wherein the cell is a neuron.

69. A method of treating synucleinopathy in a subject in need thereof, comprising administering to the subject an effective amount of an antisense oligonucleotide according to any one of embodiments 1-57, or a conjugate according to embodiment 55-57, or a composition according to any one of embodiments 58-61.

70. The use of an antisense oligonucleotide according to any of embodiments 1-57 or a conjugate according to embodiment 55-57 or a composition according to any of embodiments 58-61 for the manufacture of a medicament.

71. Use of an antisense oligonucleotide according to any of embodiments 1-57 or a conjugate according to embodiments 55-57 or a composition according to any of embodiments 58-61 for the manufacture of a medicament for the treatment of synucleinopathy in a subject in need thereof.

72. An antisense oligonucleotide according to any one of embodiments 1-57 or a conjugate according to embodiment 55-57 or a composition according to any one of embodiments 58-61 for use in therapy.

73. An antisense oligonucleotide according to any one of embodiments 1-57 or a conjugate according to embodiment 55-57 or a composition according to any one of embodiments 58-61 for use in the treatment of synucleinopathy in a subject in need thereof.

74. The method of embodiment 64-69, the use of embodiment 70 or 71, or the antisense oligonucleotide for use of embodiment 72 or 73, wherein the synucleinopathy is selected from the group consisting of Parkinson's disease, Parkinson's disease dementia (PDD), multiple system atrophy, dementia with Lewy bodies and any combination of them.

75. The method of embodiment 64-69, the use of embodiment 70 or 71, or the antisense oligonucleotide for use of embodiment 72 or 73, wherein the subject is a human.

76. The method of any of embodiments 64-69, the use of embodiment 70 or 71, or the antisense oligonucleotide for use of embodiment 72 or 73, wherein the antisense oligonucleotide, conjugate, or composition is administered orally, parenterally, intrathecally, intracerebroventricularly, pulmonary, topically, or intraventricularly .

77. An antisense oligonucleotide according to any one of embodiments 1-57 or a conjugate according to embodiment 55-57, or a composition according to any one of embodiments 58-61, a kit according to embodiment 62 or 63, a method according to any one of embodiments 64-69, a use according to embodiment 70, or 71, or an antisense oligonucleotide for use according to embodiment 72 or 73, wherein the nucleotide analog comprises a sugar-modified nucleoside.

78. The method of embodiment 64 wherein the sugar-modified nucleoside is an affinity-enhancing sugar-modified nucleoside.

EXAMPLES

The following examples are offered by way of illustration and not by way of limitation.

Example 1: ASO Construction

The antisense oligonucleotides described herein were designed to target different regions in SNCA pre-mRNA as shown in SEQ ID NO: 1 (genomic SNCA sequence) or in SNCA cDNA as shown in SEQ ID NO: 2, 3, 4 and 5. For example, the ASO data was designed to target regions designated using the pre-mRNA start site and pre-mRNA end site NG_011851.1 (SEQ ID NO: 1) and/or the mRNA start site and end site of its mRNA. Typical ASO data sequences (eg, SEQ ID NO) are described in FIG. 1A-1C and 2. In some embodiments, these ASOs were designed as gapmers or gapmers with interleaved flanks. See DES numbers.

FIG. 1A-1C and 2 show non-limiting examples of the ASO construct for selected sequences. The same methods can be applied to any other sequences disclosed in this document. These gapmers were designed to contain locked nucleic acids - LNA (capital letters). For example, a gapmer may have a beta-O-oxy LNA at the 5' end and 3' end, and have a phosphorothioate backbone. But these LNAs can also be replaced by any other nucleotide analogs, and the backbone can be other types of backbones (eg, a phosphodiester bond, a phosphotriester bond, a methylphosphonate bond, a phosphoramidate bond, or combinations thereof).

ASO was synthesized using methods well known in the art. Typical methods for preparing such ASOs are described in Barciszewski et al., Chapter 10 - "Locked Nucleic Acid Aptamers" in Nucleic Acid and Peptide Aptamers: Methods and Protocols, vol. 535, Gunter Mayer (ed.) (2009), the entire contents of which are hereby expressly incorporated herein by reference.

Example 2A: High content assay to measure reduction in SNCA protein level in primary neurons

SNCA-targeting ASOs were tested for their ability to reduce SNCA protein expression in primary mouse neurons. Primary cultures of neurons were created from the forebrain of mice PAC-Tg(SNCA ^A53T ) ^+/+ ; SNCA ^-/- ("PAC-A53T") carrying the complete human SNCA gene with the A53T mutation in an SNCA-knockout mouse. See Kuo Y et al., Hum Mol Genet., 19:1633-50 (2010). All procedures involving mice were performed according to Animal Analysis Methods (ATM) approved by the Bristol-Myers Squibb Animal Care and Use Committee (ACUC). Primary neurons were prepared by papain digestion according to the manufacturer's protocol (Worthington Biochemical Corporation, LK0031050). The isolated neurons were washed and resuspended in neurobasal medium (NBM, Invitrogen) supplemented with B27 (Gibco), 1.25 µM Glutamax (Gibco), 100 U/ml penicillin, 100 µg/ml streptomycin, and 25 µg/ml amphotericin B.

Cells were seeded in multi-well plates coated with poly-O-lysine at a density of 5400 cells/cm ² (eg 384-well plates, 6000 cells/well in 25 μl NBM). ASO was diluted in water and added to cells in DIV01 (ie 1 day after planting). ASO was added at 2x the final concentration in the medium, then manually delivered to the cells. Alternatively, ASO in water was dosed using a Labcyte ECHO acoustic dispenser. For ECHO dosing, 250 nl of ASO in water was added to the cells in media, followed by the addition of an equal volume aliquot of a fresh aliquot of NBM. For primary screening, ASO was added at final concentrations of 5 μM, 3.3 μM, 1 μM, 200 nM, or 40 nM. To determine efficacy, 8-10 point titrations of ASO were prepared from a 0.75 mM stock solution, then delivered to cultured cells for a final concentration range of 2.7-4000 nM or 4.5-10000 nM. ASO-000010 (TCTgtcttggctTTG, SEQ ID NO: 1879) and ASO-000838 (AGAaataagtggtAGT, SEQ ID NO: 1404) (5 μM) were included per plate as reference control inhibitors for tubulin and SNCA, respectively. Cells were incubated with ASO for 14 days to achieve steady-state mRNA reduction.

After a 14-day incubation, cells were fixed by adding fixative to the wells to final concentrations of 4% formaldehyde (J.T. Baker) and 4% sucrose (Sigma). The cells were fixed for 15 minutes and then the fixative was aspirated from the wells. Cells were then permeabilized for 20 minutes with phosphate buffered saline (PBS) containing 0.3% Triton-X 100 and 3% bovine serum albumin (BSA) or 3% normal goat serum. The permeabilization buffer was then aspirated from the wells and the cells were washed once with PBS. The primary antibodies were then diluted in PBS containing 0.1% Triton-X 100 and 3% BSA. 1:1000 dilutions of rabbit anti-SNCA antibody (Abcam) and 1:500 chicken anti-tubulin antibody (Abcam) were used. Cells were incubated with primary antibodies from 2 hours to overnight. After incubation, the staining solution of primary antibodies was aspirated and the cells were washed 2 times with PBS. A secondary stain solution was added to the wells containing a 1:500 dilution of goat anti-chicken antibody conjugated to Alexa 567, goat anti-rabbit antibody conjugated to Alexa 488, and Hoechst (10 μg/ml) in PBS containing 0.1% Triton-X 100 with 3% BSA and the plates were incubated for 1 hour. The secondary staining solution was then aspirated from the wells and the cells were washed 3 times with PBS. After washing the cells, 60 μl of PBS was added to each well. The plates were then stored in PBS until imaging.

For imaging, plates were scanned on a Thermo-Fisher (Cellomics) CX5 Imager using the Spot Detector (Cellomics) bioapplication to quantify nuclei (Hoechst stain, channel 1), tubulin extensions (Alexa 567, channel 2) and SNCA (Alexa 488, channel 3 ). Object (nucleus) counts were tracked but not published to the database. The total area covered with tubulin was quantified as a characteristic of SpotTotalAreaCh2, and the total staining intensity of SNCA was quantified as SpotTotalIntenCh3. Tubulin measurement was included to monitor toxicity. To determine the reduction in SNCA protein, the ratio of SNCA intensity to tubulin staining area was calculated and the results were normalized as median % inhibition using the median of vehicle-treated wells as whole and wells with ASO-000010 or ASO-000838 as maximum inhibited wells for tubulin or SNCA, respectively. The results are shown in Tables 1, 2 and 3 below.

Table 1 shows the percentage reduction in SNCA protein expression in both the human neuroblastoma cell line SK-N-BE(2) (“SK cells”) and in primary neurons isolated from A53T-PAC transgenic mice (“PAC neurons”), after in vitro culture with different ASOs from FIG. 1A-1C. Culture of PAC neurons is described in Example 2A and Example 2E describes culture of SK cells. For SK cells, these cells were treated with 25 μM ASO and SNCA mRNA expression (normalized to GAPDH) is shown as a percentage of control. For RAS neurons, cells were treated with either 40 nM or 5 μM ASO and SNCA protein expression (normalized to tubulin) is shown as percent inhibition. Where no value is given, the specific ASO was not analyzed under specific conditions.

Table 2 shows the effectiveness of different ASOs in reducing SNCA protein expression in primary neurons isolated from A53T-PAC transgenic mice in vitro. PAC neurons were cultured in vitro using a 10-point titration (shown above) of different ASOs, and the potency (IC ₅₀ ) of ASO is shown as the ratio of SNCA expression to tubulin (μM).

Table 3 shows the effect of additional exemplary ASOs from FIG. 1A-1C on SNCA protein expression in RAS neurons when cultured in vitro with 5 μM ASO. SNCA protein expression was normalized to tubulin expression and is shown as a percentage of control.

Example 2B: measurement of spontaneous fluctuations in calcium levels

Attenuated fluctuations in intracellular free calcium concentration (calcium fluctuations) are consistent with increased neurotoxicity and therefore may indicate reduced in vivo tolerability. To measure spontaneous fluctuations in the calcium level of primary cortical neurons, rat primary cortical neurons were obtained from Sprague-Dawley (E19) rat embryos. Briefly, the cerebral cortex was dissected and incubated at 37°C for 30-45 minutes in a solution of papain/DNase/Earl's balanced salt solution (EBSS). After trituration and centrifugation of the cell pellet, the reaction was stopped by incubation with EBSS containing protease inhibitors, bovine serum albumin (BSA) and DNase. Cells were then triturated and washed with Neurobasal (NB, Invitrogen) supplemented with 2% B-27, 100 μg/ml penicillin, 85 μg/ml streptomycin, and 0.5 mM glutamine.

Cells were seeded at 25,000 cells/well in 384-well poly-D-lysine-coated fluorescent imaging plates (BD Biosciences) in 25 μl/well supplemented neurobasal (NB) medium (containing B27 supplement and 2 mM glutamine). These cells were grown for 12 days at 37°C in 5% CO ₂ and fed with 25 μl of additional media in DIV04 (i.e. 4 days after planting) and DIV08 (i.e. 8 days after planting) for use in DIV12 (i.e. 12 days after planting).

On the day of the experiment, the NB media was removed from the plate and the cells were washed once with 50 μl/well of assay buffer at 37° C. (Hanks' balanced salt solution containing 2 mM CaCl ₂ and 10 mM Hopes, pH 7.4). Vibrations were analyzed both in the presence and absence of 1 mM MgCl ₂ . Cells were loaded with permanent fluorescent calcium cell dye, Fluo-4-AM (Invitrogen, Molecular Probes F14201). Fluo-4-AM was prepared at 2.5 mM in DMSO containing 10% Pluronic F-127 and then diluted 1:1000 in assay buffer to a final concentration of 2.5 μM. Cells were incubated for 1 h with 20 μl of 2.5 μm Fluo-4-AM at 37°C in 5% CO ₂ . After incubation, an additional 20 μl of room temperature assay buffer was added and the cells were allowed to equilibrate to room temperature in the dark for 10 minutes.

Plates were read on an FDSS 7000 fluorescent plate reader (Hamamatsu) at an excitation wavelength of 485 nm and an emission wavelength of 525 nm. Total fluorescence recording time was 600 seconds at a 1 Hz acquisition rate for all 384 wells. The baseline signal (measurement of intracellular calcium) was established within 99 seconds prior to the addition of ASO. ASO was added using a 384 well head in FLIPR in 20 μl of assay buffer at a concentration of 75 μM for a final concentration of 25 μM. In some cases, tau-targeting ASO such as ASO-000013 (OxyAs OxyTs OxyTs DNAts DNAcs DNAcs DNAas DNAas DNAas DNAts DNAts DNAcs DNAas OxyMCs OxyTs OxyT; ATTtccaaattcaCTT, SEQ ID NO: 1880) or ASO-000010 (TCTgtcttggctTTG , SEQ ID NO: 1879).

Fluorescence intensity measurements over time (described above) were exported from the Hamamatsu reader, and transferred to a proprietary application created in-house in the IDBS E-Workbook for data reduction and normalization. In each 384-well screening plate, up to a maximum of 48 individual ASOs were assayed per well in quadruple replication. 12 wells were exposed to a positive control (ASP-000010), which significantly inhibited calcium fluctuations counted over a 300 s data acquisition time frame, and 12 wells were exposed to an inactive ASO (ASO-000013) negative control, which did not inhibit the observation of fluctuations in levels calcium. Finally, 24 wells were assigned to a vehicle control consisting of RNase-DNase-free water used at the same concentration as used to dilute the test ASOs. The effects of individual well test ASOs on the frequency of calcium oscillations (over a period of 300 s) were expressed as % of the control of the median number of calcium oscillations counted in 24 vehicle control wells. Individual 384-well assay plates passed QC (quality control) standards if the positive and negative control ASOs (ASO-000010 and ASO-000013) exhibited well-characterized pharmacology with the Ca assay, and if the vehicle and pharmacological control wells produced a minimum of about 20 oscillations calcium levels over an experimental time period of 300 s.

Example 2C: QUANTIGENE® assay (96-well assay) to measure RNA reduction in human neurons

The ability of ASO to reduce the level of human SNCA mRNA and/or possible non-target human mRNAs was measured in vitro by the QUANTIGENE® assay. Human neurons (Cellular Dynamics Inc., "iNeurons") were thawed, plated and cultured according to the manufacturer's specifications. The iNeurons data is a highly pure population of human neurons derived from induced pluripotent stem (iPS) cells using proprietary differentiation and purification protocols from Cellular Dynamics.

Lysis: cells were planted in 96-well poly-L-ornithine/laminin-coated plates at 50,000 to 100,000 cells per well (depending on off-target expression studied) and maintained in neurobasal medium supplemented with B27, glutamax, and penicillin- streptomycin. ASO was diluted in water and added to cells in DIV01 (ie 1 day after planting). For single point measurements, a final ASO concentration of 0.5 μM was typically used. For IC ₅₀ determinations, neurons were treated using a 1:4 dilution giving a seven-point concentration response, with the highest concentration being 5 μM for IC ₅₀ determination. Cells were then incubated at 37° C. and 5% CO ₂ for 6 days to achieve steady state mRNA reduction.

After incubation, the medium was removed, the cells were washed 1 time in DPBS and lysed as follows. Measurement of messenger RNA lysate was performed using the QUANTIGENE® 2.0 reagent system (AFFYMETRIX®), which quantifies RNA using a branched DNA signal amplification method dependent on a specifically designed RNA capture probe set. Cell lysis buffer working solution was prepared by adding 50 μl of proteinase K to 5 ml of pre-warmed (37° C.) lysis mixture and diluted in dH ₂ O (distilled water) to a final dilution of 1:4. Working lysis buffer was added to the plates (from 100 to 150 μl/well, depending on the studied expression outside the target), triturated 10 times, sealed and incubated for 30 min at 55°C. After lysis, the wells were triturated 10 more times and the plates were stored at -80° C. or analyzed immediately.

Assay: Depending on the specific capture probe used (ie SNCA, PROS1 or tubulin) the lysates were diluted (or not diluted) in the lysis mixture. The lysates were then added to capture plates (96-well field and plate coated with capture probe) in a total volume of 80 µl/well. Working probe kit reagents were prepared by combining nuclease-free water (12.1 µl), lysis mix (6.6 µl), blocking reagent (1 µl), and specific probe kit 2.0 (0.3 µl) (human SNCA cat. no. SA-50528, human PROS1 cat. no. SA-10542 or human beta 3 tubulin cat. no. SA-15628) according to the manufacturer's instructions (QUANTIGENE® 2.0 AFFYMETRIX®). Then, 20 µl of working probe set reagents were added to 80 µl of lysate dilution (or 80 µl of lysis mix for background samples) on the capture plate. The plates were centrifuged at 240 g for 20 seconds and then incubated for 16-20 hours at 55° C. for hybridization (target RNA capture).

Signal amplification and target RNA detection was started by washing the plates with buffer 3 times (30 μl/well) to remove any unbound material. Then hybridization reagent 2.0 Pre-Amplifier (100 μl/well) was added, incubated at 55°C for 1 hour, then aspirated, added and aspirated washing buffer 3 times. Then hybridization reagent 2.0 Amplifier (100 μl/well) was added as described, incubated for 1 hour at 55°C, and the washing step was repeated as described previously. Then hybridization reagent 2.0 Label Probe (100 μl/well) was added, incubated for 1 hour at 50°C, and the washing step was repeated as described previously. The plates were again centrifuged at 240 g for 20 seconds to remove any excess wash buffer and then added to the plates 2.0 Substrate (100 μl/well). The plates were incubated for 5 minutes at room temperature and then the plates were scanned on a PerkinElmer Envision multi-label reader in luminometer mode for 15 minutes.

Data determination: For the gene of interest, the mean assay background signal was subtracted from the mean signal of each technical replicate. The background-subtracted mean signals for the gene of interest were then normalized to the background-subtracted mean signal for housekeeping tubulin RNA. The percent inhibition for the treated sample was calculated relative to the control treated sample lysate.

Example 2D: QUANTIGENE® assay (96-well assay) to measure mRNA reduction in Ramos cells

Ramos cells (human lymphocytic cell line) were used to measure the possible reduction in mRNA levels of non-target human IKZF3 (IKAROS zinc finger family 3). Because Ramos cells do not express SNCA, RB1 (RB1 transcriptional corepressor), which is expressed in Ramos cells, was used as a positive control to evaluate ASO-mediated knockdown of IKZF3 mRNA expression. Two ASOs were synthesized to bind to and knock down human RB1 mRNA expression. Beta-2 microglobulin (p2M) was used as a housekeeping control gene. Ramos cells were grown in suspension in RPMI media supplemented with FBS (fetal calf serum), glutamine and penicillin/streptomycin.

Lysis: Cells were planted in 96-well poly-L-ornithine/laminin-coated plates at 20,000 cells/well and maintained in neurobasal medium containing B27, glutamax, and penicillin-streptomycin.

ASO was diluted in water and added to cells 1 day after seeding (DIV01) to a final concentration of 1 μM. After treatment with ASO, cells were incubated at 37° C. for 4 days to achieve a steady state decrease in mRNA levels. After incubation, the medium was removed and the cells were lysed as follows. Measurement of messenger RNA lysate was performed using the QUANTIGENE® 2.0 reagent system (AFFYMETRIX®), which quantified RNA using a branched DNA signal amplification method dependent on a specifically designed RNA capture probe set. The lysis mixture (QuantiGene 2.0 Affymetrix) was preheated in an incubator at 37° C. for 30 minutes. To lyse the cells in suspension, 100 µl of 3x lysis buffer (with 10 µl/ml proteinase K) was added to 200 µl of the cells in suspension. The cells were then triturated 10 times for lysis, the plate was sealed and incubated for 30 min at 55°C. The lysates were then stored at -80° C. or analyzed immediately.

Assay: Depending on the specific capture probe used (ie, on IKZF3, RB1 and p2M), the lysates were diluted (or not diluted) in the lysis mixture. Lysates were then added to capture plates (96-well polystyrene plate coated with capture probe) in a total volume of 80 μl/well. Working probe set reagents were prepared by combining nuclease-free water (12.1 µl), lysis mix (6.6 µl), blocking reagent (1 µl), specific probe kit 2.0 (0.3 µl) (human IKZF3 cat. no. SA-17027, human RB1 cat. no. SA-10550 or human beta-2 microglobulin cat. no. SA-10012) according to the manufacturer's instructions (QUANTIGENE® 2.0 AFFYMETRIX®). Then, 20 µl of working probe kit reagents were added to 80 µl of the lysate dilution (or 80 µl of lysis mix for background samples) on the capture plate. The plates were then incubated for 16-20 hours at 55°C for hybridization (target RNA capture). Signal amplification and target RNA detection was started by washing the plates with buffer 3 times (300 μl/well) to remove any unbound material. Then hybridization reagent 2.0 Pre-Amplifier (100 μl/well) was added, incubated at 55°C for 1 hour, then aspirated, added and aspirated washing buffer 3 times. Then 2.0 Amplifier hybridization reagent was added as described (100 μl/well), incubated for 1 hour at 55° C., and the washing step was repeated as previously described. Then hybridization reagent 2.0 Label Probe (100 μl/well) was added, incubated for 1 hour at 50°C, and the washing step was repeated again as described previously. The plates were again centrifuged at 240 g for 20 seconds to remove any excess wash buffer and then added to the plates 2.0 Substrate (100 μl/well). The plates were incubated for 5 minutes at room temperature and then the plates were scanned on a PerkinElmer Envision multi-label reader in luminometer mode for 15 minutes.

Data determination: For the gene of interest, the mean assay background signal (ie, no lysate - just 1x lysis buffer) was subtracted from the mean signal of each technical replicate. The background-subtracted mean signals for the gene of interest were then normalized to the background-subtracted mean signal for housekeeping mRNA (for Ramos cells, this was beta-2-microglobulin). The percent inhibition for the treated sample was calculated relative to the average of the untreated sample lysate.

Example 2E: qPCR (quantitative polymerase chain reaction) assay to measure the reduction in SNCA mRNA in SK-N-BE(2) cells

SNCA-targeting ASOs were tested for their ability to reduce SNCA mRNA expression in human neuroblastoma cells SK-N-BE(2) purchased from ATCC (American Type Culture Collection) (CRL-2271).

SK-N-BE(2) cells were grown in cell culture medium (MEM [Sigma, cat. no. M2279] supplemented with 10% fetal calf serum [Sigma, cat. no. F7524], 1x glutamax TM [Sigma, cat. 3050-038], 1x solution of non-essential amino acids MEM [Sigma cat. no. M7145] and 0.025 mg/ml gentamicin [Sigma cat. no. G1397]). Cells were trypsinized every 5 days by washing with phosphate buffered saline (PBS), [Sigma, cat. No. 14190-094], followed by the addition of a solution of 0.25% trypsin-EDTA (ethylenediaminetetraacetic acid) (Sigma, T3924), 2-3-incubation at 37°C and trituration before cell seeding. Cells were maintained in culture for up to 15 passages.

For experimental use, 12,500 cells per well were seeded in 96-well plates (Nunc, cat. no. 167008) in 100 μl of growth medium. Oligonucleotides were prepared from a 750 μM stock solution. ASO dissolved in PBS was added approximately 24 hours after cell seeding to a final concentration of 25 μM for single point studies. Cells were incubated for 4 days without any medium change. To determine the effectiveness prepared 8 concentrations of ASO for a final concentration range of 16-50000 nm. ASO-004316 (CcAAAtcttataataACtAC, SEQ ID NO: 1881) and ASO-002816 (TTCctttacaccACAC, SEQ ID NO: 1882) were included as controls.

After incubation, cells were harvested by removing the medium, followed by the addition of 125 µl of PureLink©Pro 96 lysis buffer (Invitrogen 12173.001A) and 125 µl of 70% ethanol. RNA was purified according to the manufacturer's instructions and eluted in a final volume of 50 μl of water, resulting in an RNA concentration of 10-20 ng/μl. RNA was diluted 10-fold in water before the one-step qPCR reaction. For a one-step qPCR reaction, qPCR-mix (qScript TMXLE for 1-step qPCR-RT TOUGHMIX®Low ROX from QauntaBio, cat. #95134-500) was mixed with two Taqman probes at a ratio of 10:1:1 (qPCR mix: Probe 1 :probe 2) to obtain a master mix. Taqman probes were purchased from LifeTechnologies: SNCA: Hs01103383_m1; PROS1: Hs00165590_m1: TBP: 4325803; GAPDH 4325792. Master mix (6 µl) and RNA (4 µl, 1-2 ng/µl) were then mixed in a qPCR plate (MICROAMP® optical 384-well, 4309849). After seeding, the plate was rapidly centrifuged - 1000 g for 1 minute at RT (room temperature), transferred to a ViiaTM 7 system (Applied Biosystems, Thermo) and the following PCR conditions were used: 50° C. for 15 minutes; 95°C for 3 minutes; 40 cycles of: 95°C for 5 s, followed by a temperature decrease of 1.6°C/s, followed by 60°C for 45 s. Data were analyzed using the QuantStudioTM Real_time PCR software. The results are shown in Table 1 in Example 2A.

Example 3: In vitro assay of ASO-003092 and ASO-003179 for the effect of lowering human SNCA mRNA levels

ASO-: 1436003092 (20 bases, SEQ ID NO) and ASO-003179 (19 bases, SEQ ID NO:1547) are LNA modified ASOs that target the exon 6 region of human SNCA pre-mRNA (SEQ ID NO: 1 ).

Efficiency of ASO-003092 and ASO-003179 in mouse neurons

Using the methods described in Example 2A above, ASO-003092 and ASO-003179 were analyzed for their ability to reduce SNCA protein expression as a subsequent result of a decrease in SNCA mRNA levels. Briefly, primary neurons derived from PAC-A53T mice were treated with ASO-003092, ASO-003179 or control ASO for 14 days. The cells were then fixed and the levels of SNCA protein and tubulin protein were measured by high content imaging. Tubulin levels were measured to monitor toxicity and to normalize the decline in SNCA protein levels.

As shown in Table 4 below and Table 1 in Example 2A, incubation of cells with 40 nM ASO-003092 or ASO-003179 resulted in a 76% and 73% decrease in SNCA protein expression, respectively. In contrast, both ASOs had minimal to no effect on tubulin protein expression levels.

The above results demonstrate that ASO-003092 and ASO-003179 effectively reduce SNCA mRNA levels, which in turn mediate a decrease in SNCA protein levels. The ASO data were well tolerated in both mouse and human neurons. These data support the continued development of SNCA-specific ASOs (eg, ASO-003092 and ASO-003179) as a disease-modifying therapeutic agent for the treatment of synucleinopathies.

Example 4: in vivo tolerance and in vivo SNCA mRNA reduction

The in vivo tolerability of selected ASOs was analyzed to understand how these ASOs were tolerated when injected into different animal models (i.e. mice and cynomolgus monkeys):

Mice

Subjects: male and female (2-3 month old) PAC-Tg(SNCA ^A53T ) ^+/+ mice; SNCA ^-/- ("PAC-A53T") carrying the complete human A53T mutated SNCA gene in an SNCA knockout mouse were used for short-term, long-term, and in vivo PK/PD (pharmacokinetics/pharmacodynamics) efficacy studies. In some cases, wild-type (WT) C57B/6 mice were used for long-term (ie 4 weeks) health assessment. The mice were housed in groups of 4 or 5 in a temperature controlled housing room with food and water available ad libitum. All mouse procedures were performed according to the Animal Analysis Methods (ATM) approved by the Bristol-Myers Squibb Animal Care and Use Committee (ACUC).

Preparation of ASO Dosing Solution: Sterile saline syringes (1 ml) equipped with Whatman 0.2 µm filters and nuclease-free centrifuge tubes were used to prepare dosing solutions. The specified volume of water or saline was added to the ASO powder and shaken on a vibratory mixer (about 1 min) to dissolve the ASO powder. This solution was then allowed to settle for 10 minutes and again shaken on a vibratory mixer for about 1 minute. These tubes were briefly centrifuged to return all the liquid to the bottom of the tube, and then the solution was filtered through a 0.2 μm sterilizing filter into a 2nd RNase-free tube. A small aliquot of the primary stock solution was diluted to 1 mg/mL for concentration analysis using Nanodrop. The analytical sample was shaken three times using manual inversion to thoroughly mix. The UV absorbance of the sample was then measured twice at 260 nm using a Nanodrop (the base was washed and wiped three times before applying the sample). The prototype was discarded as soon as the analysis was completed. A sample was considered ready for dosing if the UV absorbance was between 90% and 110% of the sample. If the UV absorbance exceeded 110% of the sample, a second dilution was prepared; if the absorbance was less than 90%, the sample was prepared at a higher initial concentration and the same steps were followed as described above. Samples were stored at 4°C until use.

Manual intracerebroventricular (ICV) injection: ICV injections were performed using a Hamilton microsyringe fitted with a 27 or 30 gauge needle according to the method of Haley and McCormick. The needle was equipped with a polyethylene stop at a distance of 2.5-3 mm from the tip in order to limit its penetration into the brain. Mice were anesthetized using isoflurane anesthetic (1-4%). Once they were sufficiently anesthetized, the mice were held by the loose skin of the back of the neck with the thumb and forefinger of one hand. By applying gentle but steady pressure, the animal's head was then immobilized by pressing against a relatively firm, flat, leveled surface. Dosing was done using 10 µl Hamilton syringes equipped with a 27% gauge needle. The tip of the needle was then inserted through the scalp and skull approximately 1 mm lateral and 1 mm caudal to the bregma (i.e., to the right of the midline, approximately 3 mm posterior as measured from the line of the eyes). Immediately after insertion of the needle, ASO was given in a volume of 5 μl in saline vehicle and injected over about 30 seconds. The needle was left in place for 5-10 seconds before being removed. The mice were returned to their home cage and allowed to recover for about 2-4 minutes. Mice were observed continuously for 30 minutes immediately after dosing for adverse behavioral effects of the drug and/or dosing. During this time, any mouse that exhibited seizures more than 3 separate times was sacrificed immediately and given an automatic score of 20. Drug tolerance was scored 1 hour plus/minus 15 minutes after dosing. Animals dosed with non-tolerant compounds (tolerance score greater than 4) were sacrificed immediately after 1 hour of evaluation.

ASO tolerance assessment: Animals dosed with ASO were assessed immediately after dosing and monitored for 2 hours for any adverse events. For short-term tolerance (AT) studies, mice were assessed at the time of dosing and again at the time of release, ie. 3 days after ASO injection. For long-term health assessment, mice were weighed weekly and monitored for any health and behavioral problems until the end of the experiment. Mice that had a weight loss greater than 15% of their original body weight or showed tolerance problems were removed from the studies and sacrificed. Health and tolerance assessments were performed according to the following scheme:

Tissue Sampling: After final behavioral and health assessments, the mice were decapitated on a guillotine and the brains were quickly removed. Each brain was divided into hemispheres, and a) the hippocampus was dissected for mRNA measurements in 3-day short-term tolerance studies; b) the hippocampus, brainstem and striatum from one hemisphere were dissected for mRNA measurements, while the same regions from the second hemisphere were dissected for protein/PK measurements in PK/PD dynamic dose response studies.

In some studies, blood and cerebrospinal fluid (CSF) were also collected for PK (blood) and PK/protein (CSF) measurements. For blood and CSF collection, mice were deeply anesthetized using isoflurane (4%). Blood was collected by cardiac puncture using a 23 gauge needle. Immediately after removal, blood was transferred to 2 ml BD Microtainer tubes (K2EDTA BD #365974) and placed on ice until processed. For blood processing, these tubes were centrifuged at 4500g for 10 min at 4°C. The plasma was then removed, placed in 0.5 ml Eppendorf tubes and stored at -80°C until use. For CSF sampling, the chest cavity was opened to expose the heart and as much blood was drained as possible to avoid CSF contamination. CSF samples were taken through the posterior cerebellar cistern using micropipettes and placed in lo-bind protein Eppendorf tubes. Then these tubes were centrifuged at 4500g for 15 min at 4°C. The CSF was carefully transferred to clean 0.5 ml Eppendorf lo-bind tubes and stored at -80° C. until further use.

Data on cynomolgus macaques

Subject: Male cynomolgus monkeys weighing 3.5-10.0 kg at baseline were used. Each was implanted with an intrathecal cerebrospinal fluid (CSF) catheter entering at the level of the L3 or L4 vertebrae. The distal tip of the polyurethane catheter extended within the intrathecal space to approximately the L1 vertebra. The proximal end was connected to a subcutaneous access port located in the animal's lower back. Animals were allowed to heal wounds for at least two weeks before the start of the study. Care of laboratory animals was carried out in accordance with the Public Health Service Policy on the Care and Use of Laboratory Animals and the NRC Guidelines for the Care and Use of Laboratory Animals (2011) (National Research Council: Guide for the Care and Use of Laboratory Animals (The National Academies Collection:

Reports funded by the National Institutes of Health). National Academies Press (US), Washington (DC)). This protocol has been approved by the Wallingford Animal Care and Use Committee of the Bristol-Myers Squibb Company.

Blood and CSF Collection: The CSF port was accessed subcutaneously using aseptic techniques and CSF was collected from conscious animals sitting upright in a primate restraint chair. Approximately 0.1 ml of CSF was discarded at the start of collection to clear void space in the catheter and port. CSF was collected by gravity current to a maximum of 0.5 ml CSF per sample. CSF was centrifuged at 2000g at 4°C for 10 min. The supernatant was frozen on dry ice or in liquid nitrogen and kept at -90°C until analysis.

Blood was collected from an accessible vein, typically the saphenous vein. Blood samples were prepared by a variety of techniques, depending on the particular measurement under consideration. To obtain plasma, blood was collected in tubes treated with EDTA. To obtain serum, blood was drawn into serum separation tubes and allowed to clot for at least 30 minutes prior to centrifugation. For measurements of clotting and coagulation factors, blood was drawn into tubes treated with citrate, and for RNA analysis, blood was drawn into tubes containing RNAIater. After processing, the samples were frozen on dry ice or in liquid nitrogen and kept frozen until analysis.

Intrathecal dosing: Animals were trained to receive dosing in a conscious state and using modified commercially available restraint chairs, the animals were maintained in the prone position. SNCA-targeted antisense oligonucleotides (ASO) were dissolved in saline, sterilized by filtration, and injected at a rate of 0.33 ml/min in a volume of 1.0 ml, followed by rinsing with 0.5 ml of sterile water. The total infusion time was 4.5 minutes. Animals remained in the prone position for 30 min after infusion.

Necropsy: Cynomolgus monkeys were injected with an appropriate volume of a commercially available killing solution while anesthetized with ketamine and/or isoflurane.

Necropsy tissues were obtained immediately thereafter and the brain was transferred to wet ice for dissection. Regions of interest were prepared using 4-6 mm sections in the ASI Cyno Brain Matrix, as well as using manual techniques. Samples were placed fresh in the RNAIater or frozen on dry ice for later analysis. CNS (central nervous system) tissue was rapidly dissected from cynomolgus monkeys and pieces no longer than 4 mm in any axis were collected and placed in 5 ml RNAIater. Samples were stored at 4°C overnight, then transferred to -20°C for storage until analysis.

Brain regions analyzed included the medulla, pons, midbrain, cerebellum, dorsal striatum (left and right), hippocampus (left and right), frontal cortex (left and right), temporal cortex (left and right), parietal cortex (left and right), right), occipital cortex (left and right) and white matter of the cortex. Additionally, the spinal cord was sampled in the cervical, thoracic, and lumbar regions. Samples were also taken from the liver, kidney and heart. In some cases, trigeminal, tibial, and aortic nuclei were sampled to test off-target pharmacology in these areas.

Quantitative ELISA Measurement of ASO Concentration in Tissue, Plasma, and CSF from Mice or Monkeys

The tissue was homogenized with plasma and water in a ratio of 1:1. A standard curve was generated by 2-fold serial dilutions from 5000 to 4.9 nM in plasma (for plasma and CSF) and plasma:water (for tissue samples) and then further diluted a total of 5000-fold using a single 5×SSCT ( 750 mM NaCl and 75 mM sodium citrate, pH 7.0 containing 0.05% (v/v) Tween-20) and in 5×SSCT containing 35 nM capture and 35 nM detection reagents to obtain a standard range of 1 -1000 pM. The degree of dilution used varied depending on the expected concentration range of the sample. The capture probe was AAAGGAA with 3'-biotin (Exiqon) and the detection probe was 5" DigN-isopropyl 18 linker-CTCTCCT (Exiqon).

Experimental samples and standards were added to Clarity Lysis Buffer (Phenomenex, cat. no. AL0-8579) at a 1:1 ratio prior to dilution with capture and detection buffer and prior to transfer to the ELISA plate. CSF samples were diluted with plasma (2-fold) prior to addition of lysis buffer. Streptavidin (Thermo 15119) coated plate was washed 3 times with 5×SSCT buffer. 100 μl samples were added and incubated for 60 min at room temperature. A detection probe was added - 100 µl of an anti-Dig Fab fragment conjugated to AP (alkaline phosphatase) diluted 1:4000 in PBS containing 0.05% Tween-20 (Roche Applied Science, cat. no. 11093274910) and incubated for 60 min at room temperature. After washing the plate with 2×SSCT buffer, 100 µl of Tropix CDP-star Sapphire II substrate (Applied Biosystems) was added for 30 min at room temperature. Antisense oligonucleotide concentrations were measured by luminescence (Enspire-PerkinElmer).

Alpha synuclein protein measurements:

Brain tissue samples were homogenized at a ratio of 10 ml/g of tissue in RIPA buffer (50 mM Tris HCl, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxychalate, 0.1% sodium dodecyl sulfate) using a Qiagen Tissuelyser ball homogenizer II at 25 cycles/s using a 5 mm stainless steel ball for only 2 minutes. Homogenized samples were incubated for 30 min on ice. A 50µp aliquot of each sample was saved for PK analysis. The remaining samples were centrifuged at 20800 g for 60 min, 4°C. The supernatant was saved and used for analysis. Total protein was measured using the Pierce BCA Protein Assay Kit (23227).

Brain tissue extracts: SNCA protein was measured using ELISA MJFR1+4B12. Briefly, ELISA plates (Costar) were coated with 100 μl anti-SNCA MJFR1 antibody (Abeam) at 0.1 μg/ml diluted in VipH carbonate-bicarbonate buffer, pH 9.4 (Thermo Scientific), overnight (O/N ) at 4°C. The next day, the plates were washed 4 times with Dulbecco's PBS (Life Technologies) and blocked with 3% BSA (protease-free bovine serum albumin, Fraction V, Roche Diagnostic) in PBS for 2-3 hours at room temperature (RT) or for nights at 4°C. Both standards and brain samples were diluted with 1% BSA/0.05% Tween/PBS containing Roche protease inhibitor (Roche 11836145001, 1 pellet/25 ml) and phosphatase inhibitor 2&3 (Sigma, 1:100). Wild-type SNCA (rPeptide) was used as a standard. Samples were loaded in duplicate (50 microns/well) and incubated O/N at 4°C. Plates were then equilibrated to RT, 50 µl of B12 detection antibody 4 (Biolegend) (diluted 1:4000 in 1% BSA/0.1% Tween/DPBS) was added to each well and co-incubated with samples at RT for approximately 2 hours.

The detection antibody was pre-conjugated with alkaline phosphatase (AP kit from Novus Biologicals). The plates were then washed 4 times with 0.05% Tween/PBS and developed with 100 µl alkaline phosphatase substrate (Tropix CDP Star ready to use with Sapphire II, T-2214, Life Technologies) for 30 minutes. The luminescence count was measured using a Perkin Elmer EnVision (2102 multi-tag reader). During the assay, the plates were kept under constant shaking (titer plate shaker, speed 3). Data was analyzed using GraphPad Prism. Total protein in brain tissue was measured using the Micro Protein Assay Kit (Thermofisher #23235) according to the manufacturer's instructions.

Cerebrospinal Fluid (CSF): SNCA protein was measured using the U-PLEX Human SNCA Kit: (Cat. No. K151WKK-2, Meso Scale Discovery) according to the manufacturer's instructions. CSF samples were diluted 10 times. Hemoglobin was measured in CSF samples using the Abeam mouse hemoglobin ELISA kit (ab157715). For hemoglobin measurements, CSF samples were diluted 40 times.

mRNA measurements by qPCR-RT

Regions of the brain were sampled and placed in 1.5 ml RNAIater tissue protection tubes (Qiagen, Cat. No. 76514) that had been pre-filled with RNAIater, an RNA stabilization solution. Tissue in RNAIater solution can be stored at 4°C for 1 month or at -20°C or -80°C indefinitely.

RNA isolation: RNeasy Plus Mini kit: RNA from mouse hippocampus and cortex was isolated using the RNeasy Plus Mini kit (Qiagen cat#74134). Tissue samples were homogenized in a volume of 600 μl or 1200 μl of RLT Plus buffer containing 10 μl/ml 2-mercaptoethanol and 0.5% Dx reagent. 600 µl of lysis buffer was used if the mass of the tissue sample was less than 20 mg, 1200 µl of lysis buffer was used for tissue samples greater than 20 mg. For homogenization, the tissue sample was transferred into a 2.0 ml Safe-Lock round bottom Eppendorf tube (Eppendorf, cat. no. 022600044) containing 600 µl RLT Plus buffer (plus 10 µl/ml 2-mercaptoethanol and 0.5% Dx reagent) and 5 mm stainless steel ball (Qiagen cat. no. 69989). Samples were homogenized using a TissueLyser II from Qiagen. The samples were treated for 2.0 min at 20 Hz, the samples were inverted 180° and treated for another 2.0 min at 20 Hz. The samples were then treated for 2.0 minutes at 30 Hz, the samples were inverted 180° and treated for another 2.0 minutes at 30 Hz. Longer homogenization and/or homogenization at a higher frequency is used if processing is not completed. 600 μl of tissue lysate was then transferred to a gDNA Eliminator spin column in a 2.0 ml collection tube and the samples were centrifuged for 30 s at 10,000 g. All centrifugation steps were performed at RT. The eluate was collected, an equal volume of 70% ethanol was added and mixed. 600 μl was transferred to an RNeasy centrifuge column in a 2.0 ml collection tube and the samples were centrifuged for 15 s at 10,000 g. The eluate was discarded and the remaining 600 μl of sample was added to the centrifuge column. The centrifugation columns were centrifuged and the eluate discarded. The columns were washed with 700 µl RW1 wash buffer, centrifuged for 15 s at 10,000 g, and the eluate was discarded. The columns were then washed 2 times with 500 μl of RPE buffer containing 4 volumes of ethanol as described in the kit protocol. The columns were first centrifuged for 15 s at 10,000 g for the first wash and then for 2.0 min at 10,000 g for the second wash. After the second wash, the columns were centrifuged once for 1.0 min at 10,000 g to dry the membranes. The columns were then transferred to a new 1.5 ml collection tube and 30 μl of RNase-free water was directly added to the center of the membrane. The membranes were allowed to incubate for 10 min at RT. The columns were then centrifuged for 1.0 min at 10,000 g to elute the RNA. The eluate containing RNA was collected and stored on ice until RNA concentrations could be determined by UV absorbance using a NanoDrop spectrophotometer (Thermo). RNA samples were stored at -80°C.

RNA Isolation: RNEASY® Plus Universal Mini Kit: RNA from all other cynomolgus, mouse and rat tissue samples was isolated using the RNEASY® Plus Universal Mini Kit (Qiagen cat#73404). For homogenization, 50 μg or less of the tissue sample was transferred to a 2.0 ml Safe-Lock round bottom Eppendorf tube (Eppendorf, cat. no. 022600044) containing 900 μl of QIAZOL® lyse reagent and a 5 mm stainless steel ball (Qiagen, cat. no. 69989 ). Samples were homogenized using a TissueLyser II from Qiagen. The samples were treated for 2.0 min at 20 Hz, the samples were inverted 180° and treated for another 2.0 min at 20 Hz. The samples were then treated for 2.0 minutes at 30 Hz, the samples were inverted 180° and treated for another 2.0 minutes at 30 Hz. Longer homogenization and/or homogenization at a higher frequency is used if processing is not completed. The homogenized tissue lysate was then transferred to a new 2.0 ml round bottom Eppendorf Safe-Lock tube and left at RT for 5.0 min. 100 µl of gDNA Eliminator solution was added to each tube and the tubes were shaken vigorously for 30 seconds. 180 µl of chloroform (Sigma cat #496189) was added to each tube and the tubes were shaken vigorously for 30 seconds. The tubes were left at RT for 3 min. The tubes were centrifuged at 12000g for 15 min at 4°C. After centrifugation, the upper aqueous phase was transferred to a new 2.0 ml round bottom Eppendorf Safe-Lock tube - about 500 μl. An equal volume of 70% ethanol was added and mixed. All future centrifugation steps were performed at RT. 500 μl was transferred to an RNeasy centrifugation column placed in a 2.0 ml collection tube, and the samples were centrifuged for 15 s at 10000g. The eluate was discarded and the remaining 500 μl of sample was added to the centrifuge column. The centrifugation columns were centrifuged, the eluate was discarded, and the columns were washed with 700 μl RWT wash buffer containing 2 volumes of ethanol. The columns were centrifuged for 15 s at 10,000 g and the eluate was discarded. The columns were then washed 2 times with 500 μl of RPE buffer containing 4 volumes of ethanol as described in the kit protocol. The columns were first centrifuged for 15 s at 10,000 g for the first wash and then for 2.0 min at 10,000 g for the second wash. After the second wash, the columns were centrifuged once for 1.0 min at 10,000 g to dry the membranes. The columns were then transferred to a new 1.5 ml collection tube and 30 μl of RNase-free water was directly added to the center of the membrane. The membranes were allowed to incubate for 10 min at RT. The columns were centrifuged for 1.0 min at 10,000 g to elute the RNA. The eluates containing RNA were collected and stored on ice until the RNA concentration was determined by UV absorbance using a NanoDrop spectrophotometer (Thermo). RNA samples were stored at -80°C.

Synthesis of cDNA via reverse transcription: 300 ng RNA was diluted to a final volume of 10.8 µl using nuclease-free water (Invitrogen, cat. no. 10977-015) in a PCR-96-AB-C microplate (Axygen, cat. no. 321-65-051). To each well was added 6.0 µl of reaction mix 1 containing the following: 2.0 µl of 50 µM random decamers (Ambion, cat. no. AM5722G) and 4.0 µl of 1× dNTP (deoxynucleotide triphosphates) mix (Invitrogen, cat. no. 10297 -018). This plate was sealed with an optical sealing tape (Applied Biosystems, cat. no. 4360954) and centrifuged for 1.0 min at 1000 g at RT. This plate was then heated for 3.0 min at 70° C. using a GeneAmp PCR 96-well thermal cycler system (Applied Biosystems). The tablet was then completely cooled on ice. Then, 3.25 µl of Reaction Mix 2 (containing 2 µl of 10× Complementary Strand DNA Synthesis Buffer, 1.0 µl of 200 U/µl MMLV-RT Reverse Transcriptase Enzyme (Ambion, cat. #2044) and 0 .25 µl 40 U/µl RNase inhibitor (Ambion cat. no. AM2682)). The plate was sealed with an optical sealing tape and centrifuged for 1.0 min at 1000 g at RT. Using a 96-well thermal cycler, the plate was heated at 42°C for 60 min, switched to 95°C for 10 min. The plates were then chilled on ice. The cDNA plates were stored at -20° C. until they were ready to be used for PCR analysis.

qPCR to amplify and quantify alpha-synuclein and GAPDH mRNA expression: cDNA was diluted 5-fold in nucpease-free water in a PCR-96-AB-C microplate. To each well of a 384-well optical PCR plate (Applied Biosystems, cat. no. 4483315) was added 16 µl of a master mix solution consisting of the following: 10 µl of 2x Taqman Gene Expression Master Mix (Applied Biosystems, cat. no. 4369016 ), 1.0 µl of a 20× Taqman primer-probe kit (Applied Biosystems) and 5.0 µl of nuclease-free water. 4.0 μl of diluted cDNA was added to each well of a 384-well optical PCR plate. The plate was sealed with an optical sealing tape and centrifuged for 1.0 min at 1000 g at RT. PCR was performed on an Applied Biosystems 700 HT Fast real-time PCR system using the following parameters in standard mode: 50°C for 2.0 min, 95°C for 10 min, followed by 40 cycles at 95°C for 15 s and 60°C for 1.0 min.

RT qPCR primer-probe kits: Applied Biosystems (Thermo Fisher) primer-probe kits included the following:

Human alpha synuclein (p/n Hs01103383_m1) labeled with FAM

Human PROS1 (p/n HS00165590_m1) labeled with FAM

Cynomolgus monkey alpha-synuclein (cat. no. Mf02793033_m1) labeled with FAM

GAPDH of the cynomolgus macaque (p/n Mf04392546_g1) tagged with FAM

GAPDH of the cynomolgus macaque (cat. no. Mf 04392 546_g1) labeled with VIC Primer Limited

Rat alpha-synuclein (cat. no. Rn01425141_m1) labeled with FAM

Rat GAPDH (p/n Rn01775763-g1) labeled with FAM

Rat GAPDH (cat. no. 4352338E) labeled with VIC Primer Limited

Mouse GAPDH (p/n Mm99999915-g1) labeled with FAM

Mouse GAPDH (p/n 4352339E) labeled with VIC Primer Limited.

Table 6 shows the tolerance score ("Tox score") and percentage reduction (or knockdown, "KD") in both SNCA mRNA and SNCA protein expression in ASO A53T-PAC-treated transgenic or WT (wild-type) mice. Tolerance scores are given for days 1 (1D) and 28 (28D) after ASO administration. Percentage reduction in SNCA mRNA and SNCA protein expression is shown for days 3 (3D) and 28 (28D) after ASO administration in the hippocampus (Hippo), brainstem (BS), and striatum (Str).

Example 5: In Vivo Activity and Tolerability Assay of Antisense Oligonucleotides (ASOs) Targeting SNCA in Cynomolgus Macaques

To evaluate the activity and tolerability of ASO in vivo, a cynomolgus macaque model with an intrathecal port (Cyno IT) was developed. This model provides an assessment of ASO-003092- or ASO-003179-mediated SNCA knockdown and SNCA alpha-synuclein protein.

As described above in Example 3, each animal was implanted with an intrathecal cerebrospinal fluid (CSF) catheter entering at the level of the L3 or L4 vertebra. ASO-003179 and ASO-003092 were dissolved in saline and administered to animals, infused for 4.5 minutes using the IT port (2 animals per dose group). Each of the animals received one of the following: (i) ASO-003179 (total 8 or 16 mg) and (ii) ASO-003092 (total 4 or 8 mg). Animals were then sacrificed at various time points after dosing, then tissues were collected for analysis of exposure and ASO activity. Brain regions analyzed included medulla (Med), pons (V-Pons), cerebellum (CBL), dorsal striatum (left and right) (CauP), hippocampus (left and right) (Hip), frontal cortex (left and right) (FrC), temporal cortex (left and right) (TeC), occipital cortex (left and right) (PaC), parietal cortex (left and right) (OCC), and cortical white matter (WM). Additionally, the spinal cord was sampled in the cervical (CSC), thoracic (TSC), and lumbar (LSC) regions. Liver, kidney, heart, trigeminal nuclei, tibial nerve, and aorta were also sampled to test off-target pharmacology in these areas.

The ASO data were well tolerated in cynomolgus macaques with no observed adverse events (data not shown). And as shown in Fig. 3 and 4, and in Table 7 below, administration of ASO-003179 resulted in a decrease in SNCA mRNA expression in all brain tissues analyzed at 2 weeks post dosing at both 8 mg and 16 mg (FIG. 3). For ASO-003092, a decrease was observed in the frontal cortex and lumbar spinal cord, but not in other tissues at 2 weeks post dosing (FIG. 4).

The results presented herein demonstrate that the SNCA-specific ASOs disclosed herein (eg, ASO-003092 and ASO-003179) effectively reduce SNCA mRNA and are well tolerated in neurons and in in vivo preclinical species studies. In addition, results from A53T-PAC neurons confirm that ASO-003092 and ASO-003179 mediated reductions in mRNA levels lead to decreases in SNCA protein levels in vitro and in vivo. Overall, these data support the ongoing development of SNCA-specific ASOs as a disease-modifying therapeutic agent for the treatment of synucleinopathies.

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SEQUENCE LIST

<110> Roche Innovation Center Copenhagen A/S

<120> ANTISENSE OLIGONUCLEOTIDES TO ALPHA-SYNUCLEIN AND THEIR APPLICATIONS

<130> P34685-WO

<150> US 62/616,944

<151> 2018-01-12

<160> 1882

<170>PatentIn version 3.5

<210> 1

<211> 121198

<212> DNA

<213> Homo sapiens

<400> 1

60

atggactcag aaaagaatca gtaagactta gtgaaggatc attgtctatt atagagaagt 120

180

tatagacaag cgttttattc ttggaagaca aaaagaagaa aaattgaatt caaccgatgt 240

atacgaaaat aaaaagtaac agtaaattaa aaatagataa ttaaataaat atatgataca 300

360

tttatactaa agtgttttc aaatagccat taagagataa cttctttgaa taatttgctt 420

tctaaatttc ttaactacat aaatttccag ctttatatgg aacaccaagt tttcaaacca 480

ttagtgatgt gctttttata tggtgttaaa aagtttcttt ctttcttttt tctttttccc 540

ccaagatgga gtcttgctct gtcgcccagg ctggagcgca gtagtgcgat ctcggctcag 600

tgcaacaacc acctcctggg tacaagcaat tctcctgcct cagcccccca agtagctggg 660

attacaggca cctgccacca cgtccagctg atttttgtat ttttagtaga gacggggttt 720

taccatcttg gccaggctgg tctctaactc ctgacctcag gtaatctgcc cacctcagcc 780

tcccaaagtg ctgagattac aggcgtgagc caccatgccc gacctaaaaa gtttcttaaa 840

cgtcacttta tactctcaaa ttatctagaa aggaaaacgt attagattcc tggatatttt 900

ggatattgta aggaacatac ttatttgctg tatatactct gtttgtaaca gtattgtaac 960

ttcagttcaa aacaatacac aaaacattac aagttcccgt gatattttaa aaattcattt 1020

1080

1140

aaagggtctg tcaaacttgg aacaccattt gttgtatcat tttatttttt tctcttggca 1200

aatccacata attcatacag gactatgcca gtgtcttttg aaagaaacaa ggtttaagaa 1260

tagtgaatgt taattctgtc attgttactg tatttcttca 1320

agctgtggct gcaaactgct ttgagtgatg ttattgtaac tcgcacatta gggagagaaa 1380

gagatgtttg gtagattttt aattaatgat ccctatcaat gctccttgag ctttcccact 1440

ctatctctcc acaacttcca tccctggttg gaaattttttt gcttacccat actaagtgag 1500

agttattgat gggaaggcat cagatatctc acgtgtgttg ctggtgggat gggagactgt 1560

ggaggatggg aacaggtgga aatctactgc aatggaaaaa aaaaaaaagc atgtcctagg 1620

acacccaaaa catggaggct agataataac aatagctact tgtactgaga gcttccactc 1680

tgcctggctc tttgctatga gccacattat tcattcctta caacaatcaa acaagacaag 1740

taaaatatca tgcccatttt ttaatgagaa aactagagat tagagaggtt atagatactt 1800

gctctgagtc actagtaatg agtagtagag ctttaataag tccctgaatt taggttgtat 1860

ctagtacatt tactcttaga agtctatcat gctcaccaga gttgcagagt tgcgtgtatt 1920

tcttgggctc attaatgtgt ttttttcttt ctaaaactaa agtcatttga acttgttaga 1980

ttttgaaata tttaaatatc ttttctatct ggctttaaca tctttaatct tggaatcttg 2040

catgccttca tattcttagg accacgaaac cacaggaata tttaaaatga tatctagtgg 2100

aaacaatatg aagttggcca tggggtcaaa ttagagaatc tgaatactat gcttctcctt 2160

gattgctctt cccatttctt cagagtaacc ctattccccc atctcatgct cacccccttt 2220

ccaaaatcat acataatgat ctcccaacag tatgcattag gctttctcta ctctacccac 2280

tatgaaatta cacaagaagc ctatcgcaat ctcactacct cgtctctctc acaggtttac 2340

agaaggtgag aggaaggtgc agatagagaa taagaagcag gtggctccag catcaacatt 2400

acatcacccc ttgtgttcac aacaaatacg gaatattatc caaagataat aaacgttgta 2460

ttttcttaac ttaaacacat taaatcagtc ctctctttaa tcaattgtta atgggcagca 2520

tctttatttt catgccattc tactctgctg tctttgctat agcacaagtt taccacatac 2580

catacctaaa aattcagttg ttctatgggg gtaaacaaag tctaggttaa gcatatattt 2640

catagaatgt taatctatag caaaattaat gaattaaatc cagataaaag aatcctatta 2700

tggtctggta aaatatttat atttcactta gcaaagagaa aacaaaacat gaatattgta 2760

gttatgaaca gaatatgcat gttagtaatg cttccaaata tgttattact tcataacttc 2820

atatttctta tgaggtacaa gccattcaat tagtttaacg ttatattcag agaggctaaa 2880

gatttactga agaccatgct gtccatcaat aatgaaaaga aaaattaaaa aaactttatt 2940

ttaacttcta gttcccttct ttgtacttga gcagctttcc ctccttaaga atacagacct 3000

agaacatatg caatatcact atcaatatta tgtgtaatta aaagttcatt ggatgtttac 3060

tagttgtaa ttcaaaatga 3120

3180

tgaggaatac caatatagaa aaggcaaaac tttaaatatg aatgaactgt ttcataataa 3240

cataagttct tcttgatttc cattgtcaca tccaaatttg aaggctattt ctaacacagc 3300

tgggttctac ctttttcctt ctcactcttt accacaccca atctgtgagg cttcagacac 3360

3420

ctctgccact taaaatagct aggtgatctc agcatatcac caaaactctt ggagctcagt 3480

ttctctgtct ataaaagtta cataaaatgt aattgatctg cttgttatga ctaaataaca 3540

tagtacatta gtcctttgcc aaaggactaa caaattacca aataaaagtt tggaatcatg 3600

ttaaacgttt ataagaagtg caactgtcca gaaataattc tctcacattg gtctgttgta 3660

atgagaccta aaatatctca ttttatttac ctctttgact taaagcacta ggtctcaagg 3720

aggtcatggt tatactataa atatgtcatg tgaaataata tattaaataa ttgttgtaat 3780

actctattga gatactagtt gtaaagaggc acaatggaaa acttatacta ttaacagtag 3840

taaaaagaaa caacaaaaag caataaaaaa caaaacaccc attcatgcaa cgacatgaac 3900

3960

ctacgtgatt agatctttat gacattctag aatatgcaca tgaaggtaca aggtaactgt 4020

ctggaatgat gaaaatgtcc tgtgtcttca aaatagtgtg ggttacacta atgcatggct 4080

ttttcaaaac tgatttaaag ggacacaaca tctgagcatt tccctaggtg taaattacac 4140

tgcaatttta aagaatcatc taatgatatt gtggttattt ttaaacagtc cttaaatttt 4200

gtggatgcat actgaatgtt tacagctgaa aagatatata taaagcttga atttggtaaa 4260

4320

tgatcagcca tgcattgaaa aaatgtaaaa gttggatgat cttcacatga gagtccttta 4380

ttctgtctac ttttgcatat gtttgaatat ttcccataac aaaaagttga aaatagagtg 4440

atcacatgag ttaatctcct aatttacaaa aaagaaaact ggaaacagaa ggagaacaaa 4500

acttgttcaa ggtctcaaag ccagacagca aactagctcc caagtccaac cttcttgctc 4560

tggtcctaag caaacaaaaa atattaatat gagctactgc attaaggaaa gtctgctttt 4620

ccaaagggca gaccaatagt tcaaggaaga gtttaaataa taaatatttg tgatcttact 4680

ttcatgcttt tctattttcc actgaacaca tatgcattat cttctatatg tcttttatgt 4740

ataatcattt gcttcctgtt ccttgtggtt ttaaagttgt tttgtatgtt taaatttgat 4800

4860

aatataaaaa caattaaaaa aaaaacatac agcaaaaacg agttgttgtt tcccccctcc 4920

tcttccagtg cttaactaat cttccgaatc caggcacaga aagcaaaggc tttctgctag 4980

tgggaggagc ttgcttctcc attctggtgt gatccaggaa cagctgtctt ccagctctga 5040

aagaggtgaa aatgtgttaa gcgatgcaaa aattgtcttg aagttcgcgt gtgtatgtct 5100

gtgtgcatgt gcgtgtggtg ggtgggggga gagaaaaggg ggtgtcaatt ctgagggcaa 5160

cgagaatcag aagtcagaaa ggtgagtggt gtgtagcatc tccctttcag aaggggctga 5220

agaagaaatt ggatatgatg gtccggtagg ctaaatcacg ctggatttgt ctcccagata 5280

aagggaggtc tgcaaagtaa gtcccatttc tagagcgaaa agccttagga ccgcttgttt 5340

tagacggctg gggaatattt attccttgtt ccactgatgg gaaaatcagc gtctggcagg 5400

cgctgattgg tggaaaggaa aatggtgata gtggcgtgga aagaggattt gctgagcctt 5460

ctcctgcctc ctcaacctgt gactcttcct tagtagtctc cctttcaccc tcaggaccct 5520

5580

cccctaacgt tgtaacctgt gaccgtgatt aaatttcagc gatgcgaggg caaagcgctc 5640

tcggcggtgc ggtgtgagcc acctcccggc gctgcctgtc tcctccagca gctccccaag 5700

ggataggctc tgcccttggt ggtcgaccct caggccctcg gctctcccag ggcgactctg 5760

acgaggggta gggggtggtc cccgggga cccagaggaa aggcggggac aagaagggag 5820

gggaagggga aagaggaaga ggcatcatcc ctagcccaac cgctcccgat ctccacaaga 5880

gtgctcgtga ccctaaactt aacgtgaggc gcaaaagcgc ccccactttc ccgccttgcg 5940

cggccaggca ggcggctgga gttgatggct caccccgcgc cccctgcccc atccccatcc 6000

6060

6120

taggaggagg aggacggcga cgaccagaag gggcccaaga gagggggcga gcgaccgagc 6180

gccgcgacgc ggaagtgagg tgcgtgcggg ctgcagcgca gaccccggcc cggcccctcc 6240

gagagcgtcc tgggcgctcc ctcacgcctt gccttcaagc cttctgcctt tccaccctcg 6300

tgagcggaga actgggagtg gccattcgac gacaggttag cgggtttgcc tcccactccc 6360

ccagcctcgc gtcgccggct cacagcggcc tcctctgggg acagtccccc cggggtgccg 6420

6480

ttgtttaaat ttttttttta aaaaaagaga gaggcgggga ggagtcggag ttgtggagaa 6540

gcagagggac tcaggtaagt acctgtggat ctaaacgggc gtctttggaa atcctggaga 6600

6660

ccgctgggcc aggtctctgg gaggtgagta cttgtccctt tggggagcct aaggaaagag 6720

acttgacctg gctttcgtcc tgcttctgat attcccttct ccacaagggc tgagagatta 6780

ggctgcttct ccgggatccg ctttttccccg ggaaacgcga ggatgctcca tggagcgtga 6840

gcatccaact tttctctcac ataaaatctg tctgcccgct ctcttggttt ttctctgtaa 6900

agtaagcaag ctgcgtttgg caaataatga aatggaagtg caaggaggcc aagtcaacag 6960

gtggtaacgg gttaacaagt gctggcgcgg ggtccgctag ggtggaggct gagaacgccc 7020

cctcgggtgg ctggcgcggg gttggagacg gcccgcgagt gtgagcggcg cctgctcagg 7080

gtagatagct gagggcgggg gtggatgttg gatggattag aaccatcaca cttgggcctg 7140

ctgtttgcct gagtttgaac cacaccccga gtgagcagtt agttctgttg cctacgcctt 7200

tccaccatca acctgttagc cttcttctgg gattcatgtt aaggataccc ctgaccctaa 7260

gcctccagct tccatgcttc taactcatac tgttaccctt tagaccccgg gaatttaaaa 7320

aaggggttaa tcttttcatg caactccact tctgaaatgc agtaataaca actcagagga 7380

ttcatcctaa tccgtggtta ggtggctaga cttttactag ccaagatgga tgggagatgc 7440

taaattttta atgccagagc taaaaatgtc tgctttgtcc aatggttaaa tgagtgtaca 7500

7560

tttccccgaa agttctcatt caaagtgtat tttatgtttt ccagtgtggt gtaaaggaat 7620

tcattagcca tggatgtatt catgaaagga ctttcaaagg ccaaggagggg agttgtggct 7680

gctgctgaga aaaccaaaca gggtgtggca gaagcagcag gaaagacaaa agagggtgtt 7740

ctctatgtag gtaggtaaac cccaaatgtc agtttggtgc ttgttcatga gtgatgggtt 7800

aggataatca atactctaaa tgctggtagt tctctctctt gattcatttt tgcatcattg 7860

cttgtcaaaa aggtggactg agtcagaggt atgtgtaggt aggtgaatgt gaacgtgtgt 7920

atttgagcta atagtaaaaa atgcgactgt ttgcttttcc agatttttaa ttttgcccta 7980

atatttatga ctttttaaaa atgaatgttt ctgtacctac ataattctat ttcagagaac 8040

agttttaaaa actcatagtc ttttaaaaaa taatcaagaa tattcttaag aatcaaaatc 8100

attgatggat ctgtgatttc ttttaccatc

ctgattttta aaatatgact ttgatatgcc cctgtgatgt gtataaagag acctatttgt 8220

ggccctaaaa tggaaagaac agattagtct ttgatagagt tacttcatgt gatcatttgg 8280

tctctgtgaa cactgaggac agagaaaagt gcttgagggc tgctactaat ctctcagaaa 8340

catttgtata gttcatccat caaatgacac acatactaaa agaataaaga aattgatgct 8400

tattacctac ttgttcctaa agttccacct tggggtatac acccaaactc tgactctctt 8460

ttctgtaact tgaactgtat tcaattgagt gttattttac aaaccacttt gaattccttg 8520

gaaaagaata gacacacact ctcatccaca ggcatagaca cacacactca acacagacac 8580

attgcccatt cttcctctct tctttctcct ctgagctttt tcacattctc tggtggcaac 8640

tatagcagta agagtcacag gatgaacagt caggtggagg atgaccacat tgagttgcct 8700

agctgaaaca tgtgctccgt ctatgtctgc aaagtgaaag aaagctacac tatctcttca 8760

acatagatca gtgggggaaa ttttatactt gggatgattt atatgaatgc atctcatcaa 8820

agttcacaac acattttttt ttcagttttt tattttcagt tttttagagtc agggccttgc 8880

tctgtcgcc aggctggact gcagtgatgc tatcatagct cactgcatcc ttgaattcct 8940

gggctcaagt catgccccca cctcagcctc ctgagtagcc aggattatag gcatgtgcca 9000

ctgcctcatt atttagactt ttcttatgtt gacttaatct tcccacaaat cttcaattaa 9060

attacttttt ttctacctta aaacatattt tcagaaagtc attgaaatag ggtgttacaa 9120

gaggaaaaaa ttgatgagtt aattttaaat attttatgaa gtgtgaatta taccttttta 9180

gatggaattt ggaatactga atcagtgaca tgcagtttat caatatcttt ccgtttgtcc 9240

tcagatttcc aagttctgca agcacaagtt tctttgactt agttaccttt taactgttca 9300

ttgaaatcat tttcaatgtc tctcatggca tttaacacat agcacattct ataaattttt 9360

tattggttac attctgagtt ctaattgaga gttgaactta cacacagaat ttaagataaa 9420

aaatgaccat gtgaagacac aatagtatag tccagggatt ggcaaaattt tgggtaagga 9480

atcagatagc acgtatttta agccatgaga tctatgtctt ggccaggtgc cgtggctcag 9540

gtctttaatc ccagcacttt gagagcccga ggctggtgga tcacttgagc ccaggggttt 9600

gagaccagcc tgggccacat ggtgaaaccc tgtgtctaca aacaacgcaa aaattagccg 9660

ggtatggtag catgcatgtg tattgccagc tacccaggag gctgaggtag gaggatggct 9720

tgagccatac agctcactgc agaggttgca gtgagctgag atcgagccac tgcactccag 9780

cctgggtggc agagtgatac cctgtctaaa aaaaagaaaa aaaaatctat gtctcaattc 9840

tgctgttgaa gtgtgaaggt agtcataaac aataactagt gtggctgtgt cccaataaaa 9900

cttcatttat caaaacaggt ggtgggctgg aattgtcttg tatgttgtag cttgctgact 9960

actgatagag tggaaagaac atgcactaat cacacaaacc aaagttttag ttgagactac 10020

atcacttatc acctttaggg tcttggggaa gcgtacttaa catctctgag catcacttcc 10080

ctgattagta aaaaatatga tttagaaaac tgcaactacc ttgcagtttt tgtgggaatg 10140

tcataataag acaggacata tgaataattg agcacacttt tatatatagg aaccatggtt 10200

attattatca aataaactct ccaacggaat aattactttg ccaacacgtt ttccatttat 10260

tctttttcc ttcattacat aactagtttg aaagattgga ggcgaccaaa gaccattttta 10320

taatttcact tatggctgaa gatgtttggt agaagcctca taagaaaagt aatctcattc 10380

ctttataaga atatactttt aacaactact ttttaactca ttgaagaact accttaatga 10440

10500

caatcaacat acttcaattt aatagacaaa aatttcttca aatgactcag aaattaatta 10560

10620

gcaataaata caagaaaatg atgatctttg agtgtcttcc aatgccactc tgctcaataa 10680

gcagcagtgg ccatcagtga aattgatagc aaattctcaa gtcaaaatgt gcttcacctc 10740

actaagctga caaagtcaac ataacatgca caacagggat aactgagttc tcaaaactct 10800

caggtattac ttctgacctt cttctccact ctgtgctctt ttgaggttgg gaagacaaga 10860

tagggtgtgt gtgggacacc tccgctcagg gaagccatca gctctggtgt ccctacagca 10920

tttatacctt gctagtcaca taaccacttg gcacctattt tgtaggtgta cgttatcaat 10980

tacagattac tcataaatta aaggctaacc atcaattaca gattattagt aaataattat 11040

gacctcaaag aacaactgat tggtttgata catggtaacc ttatgaggac tctcatttat 11100

ctcgtttttt taagttatat acctatctct ttggggttgc actacaaaaa tataaaatat 11160

gttgcataag atatttataa aaaataatta attataagtt ctaatggtgt ggtttagtgg 11220

cattcttttt tttttctttt tttctgagat agggtctcaa tctgtcattt cactccaggc 11280

11340 tgaagtgcag tggtgtgatc tcggctcact

ctcctgactc agcctcctga gtagctgaaa ttacaggcat gcaccaccat gcccggctaa 11400

tttttgtatt tttagtagag atggggtttc accatgttag ccaggatggt ctcgaactcc 11460

tgatctcatc atccccgacc tcggcctccc aaaatgctgg gattacaggc gtgagccatt 11520

gcacccggcc tagtggcatt cttttttaaa aataaattta attgtgtata tttagggtat 11580

gcaacatgat gctatcagat acattagaca ctaaaaaatt actatattga agcaaattaa 11640

tatattcata atctctcata gttacctttt ttgttgtttt tgtggcaagg gcagctaaaa 11700

11760

attagatctg tacacttttt catcttacac atctgctact tgcttggatc ctatggccta 11820

11880

11940

ttctgtgttt ggcttatttc acttagcata attttgtctg ggttcatcca tgttgtaaat 12000

ggtaggatct tgttttttta gggctgactg atattccatt gtatctatgt acccacaatct 12060

ttttatctac ctatctatca gtagacactt tagttgtggc tattatgttt ttcttttttt 12120

ctttttggga gacagggtct tgctgtcacc caggctgcaa tggagtggtg ttatcatagc 12180

tcactgtaac ctcaaacttc tgggctcaag agatcctcct gccttggcct cccaagtagc 12240

tgagactaca ggcatacatt accatgcctg gctaattttt aatatttttt gtagatatag 12300

catctcactc tgttgcccag actggtctca aactcctaat tcaaatttag aatagagtat 12360

gacaattctg taaaatataa aaaacatgtc cactccgtat aggaagttat acaatgagaa 12420

gaagacaaac actattaca ttactcttga taagtttttt acaaagaaat aaaacacttt 12480

12540

aaaattcctt atatagttat aagtgatctt cctgcctcag cctcccaaag cactgggatt 12600

ccaagcaaga gccactgtgt tggggccctt ggaaacagat atgctgaaat cttttcttgt 12660

ggatctacac ccagaagagg gattgctggg tcatatgcta ctctattttt aatttttctt 12720

tatttttag tgaatatgta ataattgtat ataattgtgg gatccagaat tatatttcca 12780

tacatgtata caatgtgtga taatcaaatt agggtaatta acatatccat tacctgaaac 12840

atttatcatt cctttgtggt gggaacagta aaaattaaaa attctctctt ctagattttt 12900

gaacatatgc aataaactat tgttaagtat atcaccctac agtactacag aatgctagaa 12960

ctcattcctc atatttggct ccaatttcat attctttaac caacctctcc atatcctccc 13020

ctccctctta ccgttgtcag cctctaataa tcataattct actctctact tctatctcat 13080

tgtctttgat ttagaatatg tttcataatt taaccaaagg tcaaattctt aggtactgct 13140

aaggcaaaga acaaagatcg cattccagct gttagacatt tcttactact agtcattttt 13200

13260

aatatcagct gttctcactc tgcatagttc cagcacaaac aaattccagg tactatggtt 13320

13380

aagtcattgc ataaagtaca aactttgctg ctaactcttc agccttcaaa tcattacata 13440

aataacagaa acccattata atcagtgaca aaaccacagc acttctttca aagctttttg 13500

gagattggtt gcttcacatc tgttatgcag ttcatacaga cagcaatgcc cggacttgtg 13560

tggccacatt gtctcccagt ggtgagccca tgtgatgttt cacgaaaatg cgcaatcaaa 13620

agaggaaact ggccagcaaa gatgaaagag tagcaaacaa aggaagtgaa acattctgga 13680

gtagctaccc tgaggatgtt 13740

gtcactgctg caattcagga gactctaaat atgcagtcag aggaacgtag tgaggtgaag 13800

13860

tgctgaaaaa tacaccttat gttaaataca ctgtcagtat atcatgacat taaagtgcaa 13920

13980

taaaaatcat gccgattcca taaattatac agtgtgaatt acactgaaaa atccaacatt 14040

agagaggata tgaatacaat tttttacaag cataatttta ataatacaca taataattat 14100

ttgtattcaa gtttagtaat gttcaaggtt tggaagaaat tctgatcctg tgtagagacc 14160

ctagtttgaa tgtgcttata gcctattatt acatgtgtaa tgttacataa attacttaac 14220

tcggattttt aatttcatca gctatttaaa atgggcataa tataactata ttaaatggct 14280

14340

ctgtttgttt ttttgagaca gagtcttgct ctgttaccca ggctggagtg cagtggcaca 14400

atcttggctc actgcaagtt ctgcctcccg agttcatgcc attctcctgc ctcagcccct 14460

accacgcctg gctaattttt tgtatttttg 14520

14580

gcccacctcg gcctcccaaa ttgctgggat tacaggcatg agccactgcg cccagcctaa 14640

aatgtttttt ttacataatg ggtgttcagc acatgttaaa gccttctctc catccttctt 14700

cccttttgtt tcatgggttg actgatctgt ctctagtgct gtacttttaa agcttctaca 14760

gttctgaatt caaaattatc ttctcactgg gccccggtgt tatctcattc ttttttctcc 14820

14880

tcgtaattgg agaggacctc ctgttagctg ggctttcttc tatttattgt ggtggttact 14940

ggagttcctt cttctagttt taggatatat atatatattt ttttctttcc ctgaagatat 15000

15060

atcagcaatt taaggctagc ttgagactta tgtcttgaat ttgttttttgt aggctccaaa 15120

accaaggagg gagtggtgca tggtgtggca acaggtaagc tccattgtgc ttatatccaa 15180

15240

tgtaaaacaa tcactgagca ttctaagaac atatcagtct tattgaaact gaattcttta 15300

taaagtattt ttaaataggt aaatattgat tataaataaa aaatatactt gccaagaata 15360

atgaggggctt tgaattgata agctatgttt aatttatagt aagtgggcat ttaaatttc 15420

tgaccaaaaa tgtattgaca aactgctgac aaaaataaaa tgtgaatatt gccataattt 15480

taaaaaaagt aaaatttctg ttgattacag taaaatattt tgaccttaaa ttatgttgat 15540

tacaatattc ctttgataat tcagagtgca tttcaggaaa cacccttgga cagtcagtaa 15600

15660

tgcaattatt acatttctga ttatattatt catttggcct aaatttaccg agaatttgaa 15720

15780

15840

aaaatttaac aaattaaaag cccacagact tgctgtaatt aagttttctg ttgtaagtac 15900

15960

16020

taaaatggaa atgaggacaa tgatatggga atcttaatac agtgttgtgg atatgactaa 16080

aaacacagga gtcagatctt cttggttcaa cttcctgctt actccttacc agctgtgtgt 16140

tttttgcaag attcttcacc tctgtgtgat ttagcttcct catctataaa ataattcagt 16200

16260

16320

16380

ttgaaactag ttctgttaga agttaattgt gcacctttaa tgggctctgt tgcaatccaa 16440

16500

attgtgaagc atgattataa taagaactag ataacagaca ggtggagact ccactatctg 16560

aagacggtca acctagatga atggtgttcc atttagtagt tgaggaagaa cccatgaggt 16620

ttagaaagca gacaagcatg tggcaagttc tggagtcagt ggtaaaaatt aaagaaccca 16680

actattactg tcacctgatg atctaatgga gactgtggag atgggctgca tttttttagt 16740

cttttccaga atgccaaaat gtaaacacat atctgtgtgt gtgtgtgtgt gtgtgtgtgt 16800

16860

16920

actttgtata ctttattttc tctttagcgt attaaggaat ctgagatgtc ctacagtaaa 16980

gaaatttgca ttacatagtt 17040

tcttcattag ttactagggt tgaatgaaac tagtgttcca cagaaaacta tgggaaatgt 17100

tgctagggcag taaggacatg gtgatttcag catgtgcaat atttacagcg attgcaccca 17160

tggaccaccc tggcagtagt gaaataacca aaaatgctgt cataactagt atggctatga 17220

gaaacacatt gggataaatc ggctgctatc ataatcattc ctctcccaca tcagataaat 17280

17340

aataagataa ttacacttca atggttaaag aggggagaa taatttgcat attatgcctg 17400

atgtaaaatg tttattatgg gtacatatta agtgctaact aattgttaat tgttcttgct 17460

acaagtctta atgcagggaa acaagaaatt attacatagt acctaatatt atcttctaat 17520

attaaagaaa caatttcccc taaattcatc ccattagctt ttttttttttc ggtggggcag 17580

gggagaaata cagacttcag taaacttggg ctgggaactt tctacctaca aagttcaaat 17640

aaaataaatt atcctagtta gataatatca atgaaaaatc caccaactta aatcctggct 17700

17760

gaaaatgtgt ttaattaaac ttactgaatg atatgttttt tcaggtactt taaaaataaa 17820

17880

gagattttct gaaggttttg attcttataa atttattaca tcataatgaa caaaactaat 17940

18000

tccatattta catatgtata tttaaatata catatttact tgtataacaa ttcaaaacca 18060

18120

18180

aacctattat ttatattaat gcagacatta gaggtagaca ctaaattcat tttagtatat 18240

tctaaattat ttattatcta ctatgaaata atataaagaa aaataaagca gaatccctga 18300

18360

18420

gagatagtgt gaaaggccct caaggggaaa aatagaggtt aaaggtcagc agagacccta 18480

ctagagaaat cagttctaca gaaatgtttt taaatgtgtc gattattgct acatgtacac 18540

tctgtcattt tgtaatgtag ccattttatt tatgattata ataataaaac aacaaaatta 18600

taataatgtg tagagtacat tttactgtgc agtgtattgc attaaaacta gattaaaatt 18660

18720

18780

18840

18900

tttcgctggc atttaaatcg aactttgaat tgtaaaatagc tcttgctctt aaggagacat 18960

cagccatatc cttagaagtg gcacggagtt gttaggtagt tgtacaaaat tctagcctaa 19020

19080

tcaggcttgc ccacattgcc tgtactaagg agaaagcctc ttgtccttac agaccccctt 19140

agcttacata gtctatttga aaacaaattg ctttgtccac accatttaaa tattggcttc 19200

aggccaggcg cggtggctca cgcctgttat cccagcactt tgggaggctg aggcgggcag 19260

atcacgaggt caggagatcg agaccatcct ggctaacacg gtgaaaccct gtctctacta 19320

aaaatataaa aaaattagcc gggtgtggtg gcgcgcacct gtagtcccag ctgctgggga 19380

ggctgaggca ggagaatggc ctgaacccgg gagtcggagt ttgcagtgag ccgacatcgt 19440

gccactgcac tccagcctgg gtgacagagc aagactccgt ctcaaaataa ataaataaat 19500

aaataaataa gtaaatattg gcttcttcaa ctggtgagat gaaacctata caatagtcat 19560

gtgaatagca ctaaacagct gacatggtgt aactcctctc agactgaggc ttatctgggg 19620

agtacaaagc atgtcaagaa aatgtgcctt catttcctta gatgagtgtc cccatcctcc 19680

actctcctcc actgttctcc tctctgcttc tatgatatca acttttcttt ttctttagat 19740

tccacatgag tgagatcatg tggttgtttg cctttctgtt tctggcttat ttaactgaac 19800

aagaaagttt ttgacatgaa attaaacttc tgcttgtaaa ctcaattcaa actatttaca 19860

ctgtcttctc aaaaatgtta acttatttta ataaatctac tgaatgaccg tatctcattt 19920

tgttttatga aaagaaattg taagggtgct caatagcctc ttcattttca tactgtctag 19980

20040

acctgaagtt ctataaaaag atccaagttc cttcacaacc gtttcttatg ctgttattcg 20100

tacatatgtg ataataccac gtctgaacac gtagataata agtagggggct gggtgcggtg 20160

gatcatgcct ataatcctag cactttggga ggctaaggcg ggtggatcac ctgaggttag 20220

gagttcgaga ccggcctggc caacatgatg aaaccctgtt tctactaaaa atacaaataa 20280

taataataat aataattagc caggtgtggt tgtgggcacc tgtaatccca gctactcggg 20340

agactgaggc aggagaatag cttgaactca ggaggcggag gttgctgtga gctgagattg 20400

tgccattgca ttccagcctg aacaacaaga atgaaactcc atctcaaata aataaataaa 20460

tagaagtatg tattgtgttg cttagaaggt gtggtggaaa ttaacttgct gagtgagatc 20520

aaaggattgg cactgaattg aaataaagaa atattcatgc tgagtctggt tcaaatataa 20580

ctgcacctgt aagaattgct ttctgtaaac tttccatagt ataaaccaaa tccaaatcac 20640

tcatggcttt acattcctga tcgttaaact tgaagcactt tttaatactg catgacttta 20700

gccaaaatat cttagccaag attcaatgtt tggttgaacc acactcactt ggacatcttg 20760

20820

20880

atctgttgtt gctctttatt tgtaccagtg gctgagaaga ccaaagagca agtgacaaat 20940

gttggaggag cagtggtgac gggtgtgaca gcagtagccc agaagacagt ggagggagca 21000

gggagcattg cagcagccac tggctttgtc aaaaaggacc agttgggcaa ggtatggctg 21060

tgtacgtttt gtgttacatt tataagctgg tgagattacg gttcattttc atgtgaggcc 21120

tggaggcagg agcaagatac ttactgtggg gaacggctac ctgaccctcc ccttgtgaaa 21180

aagtgctacc tttatattgg tcttgcttgt ttcaggcatt aacccagata aatgccatgc 21240

21300

gtagtaaaat gccaaaggaa cagtgacatt tcagaaagaa tgagggcttt catgttaatt 21360

gtaagtcttg gaatttctct tccttggagt aacaaatccc tttgtgccta atttcctaat 21420

ttccaaaata aagttctttt acttatttct ttatagtgac atcatctctt attaaatggc 21480

21540

taaaatacat accaaccaga gatatagttt tgaggtagat tttaaaattc tgagaagaat 21600

tttgactgaa tttttttgac aaacatggga cacgaataag attataccaa agatattata 21660

actttcattt taaatatgga actaatacag tatgaggtgt caacaacgtt gaagtttcac 21720

aaacatcacc actacaacag caaaataatt tttgcttttt ccctgccaca atgacctcct 21780

tgctatttct tgaataaatc aagcataccc ttgccctgac acgttcttgg ggaggcctgc 21840

cctaatctat ataaaattgg agccattctt ctcacctctg gtattcccag tctccctact 21900

ttttttcctt ctttctttct ttttcttttt ctttctttct ttccttcttt ctctctttcc 21960

tttctttctt ttcccttcct tccttccttt ctcccttcct tccttcctcc ctctctccct 22020

cccttccttc ctccctttct ttctttctct ttttctttc ttgcttcctt ccttccttct 22080

ttccttttct ttctttttcc tttctttgcc aaagtgttat tcacctttaa atataataca 22140

taatgtgctt actttaatgt atgattttta ttttatttct cccttctaga atgtaggcac 22200

catgagagtg aaatatattt attttgttca ttgatatttc acaagtgtct gggagagttt 22260

ccaacttaca gtagacaatt aacaaacatt tattaaatta aggagggaag gaagtgagta 22320

agcacaacaa ctttcatttc tgggtctttt ataatcatat gcttagtata agaacagtgc 22380

tattcagcta tccaaaagtt acaatcaaaa tgattttggga tgaatatctt gaaaattgtg 22440

agaaagaagt tttatttgct ggcaaactat tctgggttgt ttccacttca tgtaatccta 22500

agtagcagcc ttaccttgat agcccattaa aactctgata ataaaaaggc agaacaaaaa 22560

tatctgtgat atatttagat ttactacatg tacttacatg tctagtgtct ggtgcaatgg 22620

atgctaatga tggcaaatcc ttactgggct tctagtgaag ttcttcagct aatgtttgaa 22680

tgcatggttg gtcatggtgg tacccctttg tacaaaatat gcttttcaaa taatcttatt 22740

agggataata attatattaa ttcctggttt ccatctaaaa ttttaattct atttatagct 22800

tcgtaagatt tcacaagtta agagggacct cagattaaat tagtacacag gcaattaatc 22860

agttttgtgt ctccgaccct tttcacgggc taatagaagc tatagaccct cttagcttca 22920

22980

ctctgttcag atcaatcttc tgattgtaga gatgaggaaa cagaaatcta cagaggaagt 23040

gggtagtcca agattgcaca gtcatttgga atagactgga caccagtagt acttttccag 23100

ccactatatc acttccccaa gcacttcctc aaaacttacc ttcctttgggg tctttataca 23160

ttcagttatg gacaactaga tttaactaga ggattttatt gcttcagaat attaagcaac 23220

agggaaacat gtaccgtctt ttattcacct gcatttaagg catacaatat aaattgcaaa 23280

tggagcatga aagtgcttaa tcttttacaa aactgggttt gctttccacc catctaaaaa 23340

tacttctatt tattttaata tttaaagcag aaatctaagt gatgtgacaa aattaatcat 23400

ttggagatat ttcccttata ggtagtatag ttttcttactg atttctaata tgaaaatgaa 23460

gccatagaac ctagaaattg cagcatagtt gtggaaataa acattggact gagagtgaaa 23520

atggctagtc ttcctctctg ctcatacacc acctgactgg ataacctttc gcagatctcc 23580

23640

caataaagtt ctgagtttct ataataattc aaagaatact ctaataaatg tctgcaattg 23700

23760

tcattatgaa ctttgaaata atttatttca tttttttaaac tttgatcaaa atgaccctgg 23820

taaatagaaa taagcaaact ctttttgctt gaaatgctta ttaatgactg cattgagaca 23880

ctcattcatc attcaagaaa gaatgtttgc tcacactgtg ccagaaactt ggaggaagag 23940

ggatgtgaca agtaggggta ctggatgtct agcttgtaga agtggattaa tggctctgct 24000

tttaagatca ggaacactga aagggagtaa tggcaccggt tttcacctttt catgcccttt 24060

gagggtatct ggtccatcac cctctagttg atgagggagg gaaagttccc tctcccttca 24120

24180

agcagatacc tgttttgtta atttgatcat atgaatgtag ctgcccttag taataatttc 24240

24300

agaacaatat taactcttgt gtttagtaca ttagaataat agatcttttg atccatattt 24360

ttactcatgt gcacataaga agttatcagt catacaattc atttcttgaa gttcatacct 24420

ttcattggca gagtagaaac aggttaaaag tgcacaggca gaaattttaa gtgcaaagca 24480

24540

24600

24660

gtcttgcttg tggctggtgc tcaaataaat ccttgctgaa ctaatgagca tctctttcat 24720

gccacatgga atgctctaaa agagttggat cctgaagttt ttatattttt gtaattttct 24780

ggagttttag agagcaaaag tcctgaataa actgtgaagc cactgcctga caaataatac 24840

24900

gttttcacgc aagaaataag cttgaaatgt ctgttgcctt ggatacttaa aacatccagg 24960

25020

tggaaaaatt acatcaatat attatgaaca acttttttta aatcttgatt tcaaatggat 25080

tgacacgtgt atattctgta ataatcctga cttaattcat aaaaggatag ctagccagtt 25140

25200

taatatctaa gtatcctttt actcatttcc tttgacttac tatggctgtc atgttgggct 25260

tcatgaaaat ttatttttaa acacttgagt gttatggacc ctctgattaa atgattaatc 25320

agatgatgta tgttgccatc agctgaatca tttaatgttg atttcacaaa caagcacagg 25380

tcacaggcaa catttcagat ttctttgaag aagcacacac aggtcacagg cataatctta 25440

25500

atagtaagct ttccccttaa gtgtctaata attgttaata taatacattg cctcaaataa 25560

ttaaaagttt ggttcttgtc cttgtgcttg acttcagaag ataaccagat gactattagg 25620

25680

tttcgagtgg catatactat tactggcact ataatcttag attaaagcat actgtgatta 25740

ttaaagaaaa atttaagatt gatttgtttc taaaggtatg taacagtgac attttgcaat 25800

gtggtatgta aaagttggta tttctcactc atatgagagc ccactaatgg tacataaact 25860

gtccccactt agaaacacaa ttattatggc ctttctttgt atctgacaaa atttcactgg 25920

gttcaagatg gatgaatagt gaattctaat gacccttaat cctgtaaggt tctaggtggg 25980

aaagtactct gtaattatgt ataaaattat aaggaaaata ggcttactgc tatgttttca 26040

ttaaaaatca ttaactgagt acttaatatg tgccagacac tcagctgggc accatgagaa 26100

atacaaaact gagtaacata tgggtggctc ctgccttcaa gaaatggggca gttcaggccg 26160

ggagactgac atatttaccc tgggaaaaag ggagcagctg tggtctctga gaacaatatg 26220

gtttgttaca agtatatatc catcatggaa aaaaagagat ttatcttaga aatgagagag 26280

gctgatgctc tcaataaata tcatacatta aattgtgttt ttgtcagtag actgaaatta 26340

cctcacatac acgcacagat agtagccatg atattttagc tgcttagata tagagacaaa 26400

tacttccacc caaatcttag gatcagtggt taatagtctg taagcattac aatcccacaa 26460

catatgcatg actatacatc caattttaat attcaaagaa ctgattgcga tgatagtttt 26520

gtttgtcaaa gaaatgtatt ataggatgag tgggatagaa ctgcatcacg ttacaccaac 26580

aaataggttt aaatcatatt tgtgcacttc ccttgttcct tcataaatgt ttaacatagc 26640

ttaaaattct gtggactgca acgtgagagc aatgaccaca cttctgtgaa cccattttta 26700

ctgtgcatgt gctaacgtct attgttagta ttccttcact tgcaaagatg gcatgataat 26760

tttgctggtt tcattaatga gatactgtta aatgtaggat gacttcaaac ttagttgtat 26820

26880

atctttattt atatatata ataatataca cacgtatata aaagtgattc ctacattgaa 26940

gcaaattaac atacccatca tcatatggtt atctttgctt ttttactatc agtgcctaaa 27000

atctactttc ttgaaaaatt accagtatgc actacaatat tattaacaat aatcttcatg 27060

ttgtacatta gatctttaga cttactcatc ttacatgact taggtttgtt tttacctcta 27120

ctaccatctg agccatattt ccactttgta atttgataat aaacttggaa aaatagcact 27180

27240

cttgtctcca actacaatga taaacaacct gtttgtccct aaaaagtaag aaataacttg 27300

acttttctgc cccttcaagc ataggctgtt agcttttaag ttttagggag acattgatga 27360

tgctatttgc tttatcaaga ggaaattgtc aaaagaggtc ttttggttct caaactattc 27420

27480

27540

atgatacatc tcatcaattt aattgttctt ctacaaggag aaaatgaaca atttgtcaac 27600

27660

ttaagttgca atttaaatat ccccttctac caggtgattc tggaatcact aagcagttac 27720

ttgtgaaaat tccaaagtag catttaattc ttattaatgt catagtgaat actaatgcaa 27780

agaatactga gccagaaatt atgcttgttg aataaataga ttattttattg aacaagtaag 27840

tgaaaaaatg gaaataaaga acggatatat attttatctt cctgcttaga tgtgggactg 27900

27960

taggaatgaa ttcagttaca ttatggattg tgatgaataa tgtacacttt taatttaatg 28020

aaatcaaata gattttaact atctatgctt acaatggggt gacataagtc tgacaatcct 28080

taatatcaag tcatctccaa ttcacatgta tacacacttt ttttctattt ggctattgggg 28140

aatcctcaca aaaatcgaaa attgcccttt cagtgtacgt tacggtattt catgccacac 28200

agattttctg aggttgtaca tacagctttg ccttgaggtt ccaatttttg ctcagtggat 28260

tgagtatata ttatttgcta tatatcagaa gaggcatgtg cttcctactt atgtcaggta 28320

actttgggat taatataatt gtcctacaaa gcatagatag atagaaatac ttcatcctta 28380

28440

ctaatgactg cttatagtgg caattcatct ttcatggtag tcctcctaca aaggtatact 28500

28560

ctgctgtttg atccagcatg atggccagct ggccctcctg tgcatgacgg ctcgtggttt 28620

aactgcacca ttttgtttgg tcatatacag ggaaaacatg gcatggtgtg gagggcatgg 28680

gcttgaattc agggaacaga gagttggtct tctctctctc actctactgg atgatgtcat 28740

ctcccctctc taagcatgag ttttcttatc tgtgaaataa aaatgttgaa ttaaatgagt 28800

tcaaaatgct ttcagtctgt gtttaatagc ttgaatctta agacaatgta ttcaattatg 28860

cgttgccaga tccctggcaa ctcatgtaac ctttctaaac catagctact catctgtaac 28920

tggccagcca actgcccagg gttggagtgt gaatgaaata agataatgca gacaaaagat 28980

ttttaaaaat tgtagtgcat tatacagttg taatattttg ccaagaactt acattttctc 29040

taagaagtgt gtcgatacat gatcacagaa aatcttttcc atattccttt gtagtttgat 29100

gatattaagt aagtaaattg tataacacaa agagggaaaa gcatcactga acatgccgtt 29160

ttatttagct aaataaaatg taatcactat tagttttcct ctgatttccc caaagtcatg 29220

tgattccatt gagtattatg cacatggtat aattagaatg gattctctgc tcaaataatt 29280

ttgggaaaca tttaaattaa caaagtttaa aagtatctct gttaagctga agcaaatctc 29340

aaaggcctta atattgtatg taagggaat agttaccatc tttcctaatg cctctttgac 29400

gccaaaccca tggagaatag ttctaggtgt tcagtaaaac acagatttgg gatgccacag 29460

gttaattgga actgtcccct gcaatccttt tctctttttc ttaataatgg ctgattgcag 29520

gtcctagatg aaagacattt agagagatta tcaggactca gcatcccata tcagaatcca 29580

ttcttttata gtcattttct gttacatttc ttgggacaac accaaagaaa tgaccatctt 29640

cattcacata ggctttgtac caaatgctga caaagatcct tggtgaccta gatgggggca 29700

ggtctaagta gattgcagct gtaaaattgg ctgatgaatg atctcagccc cttttactca 29760

cactcaaagg caggacagtc cattaagggg aaggagggca gagtttttcc ttaggccaat 29820

tccctatgcc agaacttttt agaatggaag catttccaga ggagaaacaa ccccaagcac 29880

agttcaaagc cccctcctcc caagttcatt tgaaagtggg atggtttatc tgcaaagggg 29940

gaaaagatga gggataggga cgggaatatc cctacccttc agagagtctg gtttcatcct 30000

30060

ggtctaaacg tgcctggctg atcctctcta atacttcagg ggtctaaaag ggataacatg 30120

ctctcctgtt actcaccgac tctgtccgcc atatttcacc cagccagcca ctgccttcac 30180

ttccgtccga ggcctaatct gagcccatgg gaaacctaag aacccctacc acaactgcct 30240

30300

30360

cctcaggctg catcctacca gggagtaaga cccaagtcct tcctgctttc agacaacacc 30420

aagcctcatg agtccccact cagaggaagg accagagaca aactctaatg ttccactaat 30480

acttcccttc ttattacttt ccttgaaaat cccttctccc tctttctttt tatacttcgc 30540

30600

cccgcggacg tattccacaa taacccttgc atcttctact aagatgtggg ctaggaaggg 30660

accagccagt tcccagggtc acagtgcctc agctgatgtt tcatattttc agcaacttta 30720

tgttagagat gtccatcaat cagaacaata tggttagaga ataaactaat aaaagtcatt 30780

tttgaggaca tgttggaagt ctatcaaaag cattgaaatt atgcatgctc tgaccagtcg 30840

catgtctaag aatttaaata tgatcataag tttaaatatg aagatgttta tcacagaatt 30900

gattataaaa caaaattgaa aaaaatagtg ctagaagttt gatcataggg acctcattaa 30960

atgcattatg gttgatccat gcagtggttt gctgaacagc cattaaaatg ttgtagaata 31020

31080

31140

aaagacgtgg aataaatgca caaggtactc agtttttctc agtgaagccc attttgcatt 31200

ttgggctggg taattcttcg ctgtggagaa ctctcattca ttgtaggatg tttacaagcc 31260

ctgggcctta cctctttaac gccagtaggc acccccagca tggcaacaag cacaaaatgg 31320

tctctctcat attgcccttg aggaaatttt gcaactaagt aactattact gggtcctaga 31380

ttacagtctg gattattgcg ttcctttctt atttttattt tctccaattc cctttaataa 31440

gcatgtactg gattcataaa aaaacaacat aaatggtaat tacaatattc cgcactggtt 31500

aaaacttatg taaataagca ttctgctgct ttagccacaa ttgcaattta tgctccttct 31560

ctttcttaag ttcccagttc ccacgtacat tcattcgact gattcaaaag tcattttagc 31620

31680

ttgtccaccc atccatctga tccattttgt tgatgcatgc tgtgtataaa atactacacc 31740

agcctggtgc ggtggctcac gcctgtaatt ccaggacttt gggaggccaa ggcgggtgga 31800

tcacctgaag tcaggtgttt gagaccagcc tggccaacgt ggaaaaaccc tgtctctact 31860

aaaaatacaa aaattagcca ggcatggtgg cagacgactc taatcccagc tacttaggag 31920

gctgaaccag gagaatcgct cgaacccagg agatggagtt tgcagtgagc tgagatcatg 31980

ccaatacact ccagcctggg tgacagagca agactccgtc tcaaaaacaa acaaaaaaaa 32040

tacaatgcca agcatcataa aaaatatagt gatatataag acctatttgt tgtgctctag 32100

gcattgacat ctagctgtca accattaata tgtgtaggag tctatctatc aatattatgg 32160

actgtgcttg aagacttctt ccccaatctt tttctcttcc cattaagttt gaagtgaggt 32220

tttctgagtg aagtatcata gtacatacag tctcattatt tttcaaaaat ctctggttat 32280

agtacatttc ttttcctttat cccctttgtt cccaactatc aaaccatttt ggatatccag 32340

tattggtatc cagtattatt aaaaagcaaa acagagaact attaacaaaa aaatttgtag 32400

gagtaattgg ttgtatggta tccagtacta ttagatagta aatcagaaaa ttattaacaa 32460

32520

32580

32640

32700

tctggaggct gggaactcca agatcaaggc atttgtcttc aggttcagta tctggcgagg 32760

gccggttctc tactcccaag atggtgtctt gtcactgtat cctccagagg gccaaatgct 32820

gtgttctcac atggtagaga gatagaaagg gccaactcac tccctcaagg cctttcataa 32880

tgttaccaat tccacttgtc agggctctgc ccccgtgact ttattacctc tgcaaggccc 32940

caccacttaa tactatcacg ttggttatta cgatttatca catgaatttc gaccatacta 33000

gttgccatcc tttcattttc atatatcctt aaaactttgc ctttctcatt ttaatgtact 33060

33120

actgtaaaag tgcagttttt gatacactct ttagctgccc gtttacttct actgtcgtta 33180

33240

ttttgggtcat ttttattcat tagtgcttcc cttataatct ctgaatacca ttttattagt 33300

acatactgct attcttaata gtaactagca tgcctgatca tcccaaatgt ctaggttcac 33360

33420

tcatagttgt atgtttttgg aagtagaatt caactgtaaa tagaaattgg ttgtttagat 33480

ctcactatat atgaaaaaat gaaggcttta ggagaaaatc tccccaaagt acccattttt 33540

catgtgataa atatcatgaa atgatttgag aaaaaaatgt atatttgtta cagctaacaa 33600

atatttgtgt tttttattct tcatggagag aatgaaattt cttctcttct ttacacattt 33660

ctttttctta ttagaaacta attggtgcct ttataaaaat taactgcaga gcactaacgt 33720

gtatatataa gtattatgta gggtgtaggg tatgttcagg gtatggtgtg tgtgtgtgtg 33780

33840

ttcagaaatc tgcttggtct tcccagagtt cattcatctt ataaattcat ctacattgat 33900

ctctattttt ggaatccatg aaatgttttt tggcagtact tcctttaata tagtgtgctg 33960

gaaatctgga aatttctagc cagattagtt acaaaaaatt agccagtggt tttgcactct 34020

ctatagaatc aaggcccaag gcctactctt gttactcagg gccttgtttt atctggcctc 34080

tttcttttca gccatatagc tctcaaatac tcaacaaaat tcttcattct aggtagacaa 34140

gtatcttcaa aatacttccc aattatctaa taactgtctt accactaaga aggcttttat 34200

gtctcctgtc tgaattttat ccatgcaaaa aagtccagcc caagcctcca gaactccaaa 34260

aagttatccc taactgctga aacacagtaa tttcactatg tgaaatttca ctttggtctc 34320

34380

ctaaccctta agctaataat tttacctaca ctgtaattca aaatgtatcc ccagtcttac 34440

catgtctccc ttctctactg ttaccaccct aggctaggcc ttcatcattt ctcacctgga 34500

ctccttccct aacctctgaa ctgatctgcc tgcttccact tagacaccca acctagtcca 34560

ttcttgagca gtcggaataa ttcttttaag aaagaaacca gatcacatcc ccctctgctc 34620

ccaaccatcc agtgacctct tatcatacat agaatgaaat gcaaatcttt actgtgtttt 34680

aaaggcccta cattatctgg acctcagtaa cttcttactt cctatccctt ttctccttgt 34740

atgccaccct ccaactacac tctaactaca ctgtcttttt ccctgttctt cagacctgcc 34800

aaccatattt tcactgctca attaatatgt agaaaatgaa ttgtttgtta aatgtagact 34860

34920

ttcctgattt taattttaaa aagacaaact gcaagaatgt gttaaacagt aaggaaacaa 34980

35040

atatgagggt attctaataa acttaactct atgctgtata cttatcatga tagctcattt 35100

tcttatatgt ttataacagc actacttatt gtacatggat acgtgggaaa taaattaatt 35160

35220

tacttataat taattataca ttattcatat aatgttaagt

35340

gtgagcataa gatgccagaa agaagattag gaatatcaag gcagggagct tccgatcgct 35400

cttgaaaaca ttgacccttc actcctcact ctccacgatg catttccttt gaaaagtaat 35460

gccttccaaa acaaagttct ctgttttata tctaaactta ctcaatagtt tctcatggtt 35520

attgatatat aaaaaataaa gtaaaatgtt taggcagacc aaaagaagaa tttccccctc 35580

cctctgcctt ttatgccaag gtgacagcta tgaaatgtac agtacgtttc ctctgcaagg 35640

aatgtagcag tgttccattg caagaagatg aggggagag aaaggttgca cgctgaggaa 35700

tatagtgtca tttgtcactg cctagactca tcagctgtgt ggaactctga gaggcaccag 35760

35820

aatgtgaaaa acgaattagc ttttgtgatg gggagtagtc atctctgaat attgatcaag 35880

attaagaggg ttgtcttcgt aacttctttt atccatagtc tatactgatt taactagaaa 35940

actaatttca ggtggtattt cgggtgtggc agatctttat agtaaatgaa gaatctagtc 36000

aaatctactg aaaaactctg cttactttaa tgtttgatct ggttgaaacc attttagctt 36060

acagcaaaat tatgtggaag 36120

ggccattagc ttcacatcca atgcaaattt tgcctgtgtt tactcttccc caatccaaaa 36180

36240

tttttcattt cctgttctca gacccttat aattgataga ataaaatcag aagagcccta 36300

gagctgtccc acctattctg cctcacaaaa gtagaagtaa tggcaaccac tatcataggg 36360

atcatgctca cctttttctt accagacaaa tttggatatt agcttgaaat taataccttc 36420

36480

tatggaatta tttttgccct atattttcac ttaagtgttc tctacccaag attttaattg 36540

36600

aaatttgcat tcgtctagtg 36660

tttgttatgt atttccccct tttgtttgat tatatgtcta tatttttctt gtagaaattg 36720

atttttaacc tgctttttat gttagctttt atgagcttct gtctgaattc tgaatatgtc 36780

tttcttaatg tcttctaaat gtttctttct ggattattaa aagatttatt aggcttttaa 36840

36900

aacacagcat tgaacttttt cttgttagag atacattgtt ttctaggcat tttattggga 36960

tgtctttggc tgatattaac tcttctaaga tgcattgttt 37020

ctgagaacac cattgtctga tttcattcag ggaaatttca cacaagccag tagagtcaat 37080

acttttttca agacctgtta attgatatat ataaaaactt gccattgttt acatgcccat 37140

ttcagatcct ttatgtgacc taagctagaa atgcatttta acagcatttg tttttccaaa 37200

aatatttatt tatttattta ttatagagat agcgtctctc tatgttgccc aggctggcct 37260

cgaactcctg ggctcaagca attctcctgc ctcggcctcc caacagtgct gggatacagg 37320

37380

37440 gtttgaaggt gatccctaga tagcaaccag taatgattcg agcagcaaaa

agtaatttta taagaaaatg cagaacataa atgagcccat aaaaaattat attaggttct 37500

37560

cagtgccata taccattatg aattctagga tagaagaatg agtgagaaat gttcttaggc 37620

cttaggaaga aggaacaagc atctctgtgt aatagttatt tcaactcttc ttttacacct 37680

cattcccata ttaaatctca gaaaagctaa agtaatagct atcccagatc tatttagac 37740

tccagacact tacttcaatg tcttgttctc cttatcagac tggaatcatt ccaaacctct 37800

taacttctgg gcaaccatga taatgcgaca gaaaggacac taaatctgtc gcaaatttat 37860

cttgatattc tatccagtct tacttggtac tgaaggtcac aagtaaaata aggtggttgt 37920

tttttgtttg tttttttttt tttgacagaa gagaaaagaa cactgtgagc acagagtgaa 37980

tgtctaacat tgattcttga gtagcaggaa ttctctatgc gagaggatct ctatgcaaaa 38040

38100

ttatcaataa gctatggggt aatatattgt atgtggtgtg gcttgaattc tagaaatttg 38160

atttctagaa atggtccctg tagttaagga tatataatgt ggccgtctcc agttttctat 38220

gaggaatagg aaaatactat cattattagc tgtgtgacca tggacaactt gcttcgttct 38280

tcagttgcat catctgtata aaataagaat aagaaaattt acatctgcaa ggtgtgatgg 38340

agatcacatg ggataattgt ggtcccagag cctggcacaa aagggcttaa tattatataat 38400

cctccccatt tctccgtata ctctaaagga agtttattgc ttatcaaatt gtgccgtggt 38460

tagttgtaca gcttccctgc caaattgtaa actccaacac taatgtgacg ttacatttta 38520

38580

attagtataa ttattgctat tgtcaatatt attattacaa cagcttcaca gtaagatggg 38640

cagaaaaaaa tttaatttcc attttacaaa tgcacttttg aggctcacag aagtcaaata 38700

gaccaaagtc acagggctag tgagggaccc agaagaaaca aattgtaatt cactgattcc 38760

aagttcagtg gttgccttac tgcatcataa aggctattac acaatccagg tgtatcatat 38820

38880

tcaacagata ctgatagtca ttagtactta aatctttatc aaatgaaata ttaataccca 38940

39000

39060

ttctcaacat atttccttcg gtagaaaagc aaacctccag ttctctgttc tttgcttgga 39120

39180

39240

39300 ttcattcatt cactaatgct ggcaatacaa aatggtacag

39360

39420

cagctcagca tggctgagga ggcctcagaa agcttataat catggtggaa ggagaagggg 39480

aagcaaggca cctacttcac aaggtgacag gaaggagaat gaatgcagga ggaactacca 39540

aacacataaa accattagct ctcgtgagaa ctcactcgct atcatgagaa cagcatgggg 39600

gaaacagctc tcatgatcta gttacctcca cctggtctct cccttgacat gtggggatta 39660

tggggattat aattcaagat gagatttgggg tggggacaca aagcctaacc atatcaccat 39720

atgatccaaa atcatgctac atgatattca cccaaaggaa atgtaaactg tgtccacacc 39780

39840

ccaagatgtt cctcaatagg tgaatgaaca aaaagactgg cacatgtact caatggaata 39900

ttattcagtg ataaaaagaa atgagctatc aagccacaaa aacacatgga gaaaacttag 39960

gtacgtaagc cagtttgaaa ggttgcattc tatatgattc caatatatga cattctgaaa 40020

gagacaaaat tctggagaca gtaaaaagat cagtgattgc ctggggctct gagaaagtgc 40080

agagggatga atgggtgaag cacatggcat gtttaggaca gtgaaactat tctctatgat 40140

actgtcatgg tggatacatg accttatacc tttgttaaaa ctcagaattt tacaatacag 40200

agtgaattct aatataaact atggacttta gttgtaataa ggtatcaatg ttatttcata 40260

agttttaata atgtaccaca ctaatgcaaa attataataa taggggaatt gggggaaggg 40320

taatggagta tatgggaatg cactgtaatc tcagtacaat tattccacaa acctaaaact 40380

tctttcaaaa atacaagcta ttggtcaggt gtgatggctt ataccagtaa tctcagcact 40440

ttgggaagtc aagaccctca gatcacttga ggccaggagt tcgagaccag cctggccaac 40500

atggtgaaat cctgtctcta ctaaaaatac aaaaaaaaaa aaagaaagaa agaaaagaaa 40560

gaaagaacag aagaaataaa agaaagaaag gaaagaaaga aagaagaaaa gaaagaaaga 40620

40680

gaaagaaaga aagaaagaaa gaaaagaaag acagatgcgg ttgctcatgc ttgtaatcac 40740

aactactcgg gagactgagg catgagaatc gcctgaactc agaaggtgga ggttgcagta 40800

gggtgagatt acgccactgc actccagcct gggtgacaga gcaaggctct gtctcaaaaa 40860

aaaaaaaaaa aagctattaa aaatatgtaa agctcagtct agatacagta ccagaatagt 40920

aggaacttta tttcacctgt cctacaaatt atggttgtgt gccacttggg taaaactcag 40980

aatccaaata tgtgaatgta agatttatgg ggaaattatt tgtatttcaa aataatcctt 41040

aatgaatgca ctccttctaa agtagccatt aataaagcag ttaatgtttc atttaattat 41100

agattaatgt acataagata tgccaggaat gcaattagga actgggaagg gggtgtttatt 41160

ctaataactt ccacatagca ttgtgagaca ttttctgctt tcttcaaatt tcatttaatt 41220

acattttaaa caaatatttt tgtgagccta ttatatagtc cttcgctagc actgaggaga 41280

catgctttgt gaccttggtg atttcacatt caaatttccc tttcacctac actcttcctt 41340

gttttttcat gcctgtgtag attgtaaatt cttcctcaga ttaagacatt ttattcacct 41400

ttgtaacatc cacagtatct agcacaatca gtgccttcaa aaacaattgg cctcaagaat 41460

tgattgactc aatgagtgac tgaaagacta aattaataag tacacatcta tttgtacttc 41520

cctgcttact tataaggtat gacaatgaaa tactgagaca gttatacatt acttacggac 41580

tcaatctcat ttctttacaa tctctattct tcttttttga gtataatgtt attttacaat 41640

tcactaact tgtcactctt tattataaat tcatatctcc atttcacctg agaataataa 41700

aggcaaggaa gtattttaaa tgatcttgtt ttttataact agcattcatt gagcaaatca 41760

aagtatgaaa ataatatagg tgtcagtgat tattataaag ttgtatgcac aaaacattcc 41820

aatgattggg gccaatacag agaaaacatc tcaatatttg gaattttgct tttctgtaaa 41880

tactttgata tgtacttaca tcatatcaat tataactcct gctgaaaaca aacagtgcac 41940

42000

42060

accactaggc caaaatgaac taaatgaaca gggagattac catttatcag aaaaagaggg 42120

agaaaggaag gagagatgac caagcaagtc ctatgtgaag acggctgcct gacttgagct 42180

gtgtgatctt tggactgata ccacctgcct gcactggcct agcaggggcga gaatagtcaa 42240

tatctggaaa atggatcacc tgaccttact ttcctccctc cctgtttcct ctttgtggtg 42300

tttccactgg ccaaactcac agcgtagaca aaaggagtgc attgatgtag cagtggttct 42360

aatccagggc caattgtgct cccagggaac attagtggtt atcacagctc aggggaggaa 42420

gggagaggag tggagtgcta ctatgattca ctgagggatt tttttaaaca tctacaatgc 42480

acaggacatc cttccacaac aaagtatcca gttaaaaaat gtcattactg ccaaggttga 42540

aaaaccgtgg tgtagtcagt acaattcatc ttctccaggc acagtgcagg agtggggtgg 42600

agtgtctgaa ggggaagaag gaagaaacca gcacacccca caaaagtaac caatgcaaat 42660

accaaatagg aaaagacagc acttaaaata caaaagtctc aggaatatat ctgatagtgt 42720

tttatggaat ttattaaaat ttagcctgga gtgagtaata tttagcaagc caggtttgtc 42780

tttagagaaa tccttgtggg gtttatacaa ggatttatta acaaagggca cacacaatac 42840

tcatattaca gtcagtctgg ttatgtaaaa catgggcaag aatgtaatag gacaatgtga 42900

tgtattcaca aggatttta ggactacaca gataatcctc taatgctttc acttacgtac 42960

43020

tgcagctata catgtttgca cacaccagga tgcatgccct ttctacctgg ttgatttttt 43080

43140

cttaaatctt taatctattg tgtggatttc tgactcattc tccaagcttt tcctcttccc 43200

tccgcaatgc cttatagtct tatgactatt tatccctttg cctacatttc tagccagatc 43260

tcttgcctga tacacactct catatttctc tttgcacgct acacattttt atttagatat 43320

cacactacta ctttgatttc aacaggtctc agtttaactt aatttttcct tcaagcaagg 43380

agtcccttca tatcagttat caccattggc accagaattt ttcttatgac ttcccatgac 43440

ctacaatata aaccatataa atcactgatg cctccatagt tccctccctc tcaaatttag 43500

ccataagatg attttaggat ccttgttttt tccaatctct ctttcattct ctcccccatc 43560

tcttccatta tgaaggtttg gataggacac aactcatgcc tagattagtg caatagatgc 43620

tgagcctgtg cagcggtagt ttagctttct ctcctggtta actttaactg ccacatatat 43680

cacttcacac gtcatttttc attcaaacgt atttaactgg ctcttcattc ataagaagct 43740

ggaatttgtc gtttgactga tattttaaag attttatatt ttttctccat cctcgttcta 43800

atgttgtatc ttgtgtcatt tgttcattca taaacttaag acttagctaa ccactgagca 43860

tccaggaaat tcagtatcta tcatgtgaat tctctaatac tggttgatcc attgtcacca 43920

gagcatagca ggcttctcct gcctttatgt atgtttgtca tatagttcat gcctaaaatt 43980

ctttcttaaa tcttaaattc ctaagataca cacttttgcc caagatcaca gtaatctctg 44040

ccataatctc tgctggaatc tgttcactgt gttgctcctg ctaaacttct tacagatgac 44100

tttttttctt tttggtttcc ctggtatcta gtataatttc ttatataggt actcaataaa 44160

tgtttcctgt tgatctctac acctactctg tacaatacca tagtgactag acacatgttg 44220

ctatcaagca tttcaaaagt agctagcctg agttgagata taggggtaaa atacacaaca 44280

gatttcaaga catattatga aaaaaaccca taaaatttct cagtaatttt tttatagatt 44340

acatgtagaa actataacat tttgaataag ttgtatcaaa taaaatataa aattcacccg 44400

gttcttttta atttgttaaa tgtggtggct agaaaattta aaattacata attggctcac 44460

agaataatta taatggatgg tattgcttta gatcaagttt gtctaacccg tggcccatgg 44520

gccacaagcg gcccaggatg gttttgaatg agatccaaca caaatgtgtg aacttcctta 44580

44640

gttagtgtat tttatgcatg gctcaagaca attaattctt cttcaaatat ggcccaggga 44700

agccaaaaga ctggacaacc ctgctttaga tagtaaagca tatgagtagt taatgtgtac 44760

tataagcagt gtgatctgat agactattta atgttgtttg atggtacatt attcaagtcg 44820

attatattatgt ctacctatgc agtttaacga cggtaatgag aggggcagc ttgattacag 44880

gtcttatctt ttgactaact tgctaggcca cctgagaagg acccaaatta tctgaatgct 44940

taactcaact aatttgtatt cacttgaaga atttcaagga tgtttatatg ccatcaactt 45000

gctttaaatt ttttctctca gtgaaaattt ttcttaaaat gagtatgtgg tattcaaatt 45060

45120

tttgagatgc attctacatg taactattgc acagtttgca tgtagtaagg ttcattattc 45180

ttctactttt ccaaacacct ggcatgttta cttgaggttg gtacaccttg tatcccagat 45240

tttgctgttt ttaacttaaa tattgaatat tttgattaaa cattatggaa agtttaaatg 45300

ggtcaagaaa aatagctttt cttcccatga agaacaatac ggcataggag ttaagagcat 45360

agatttaaag tcagaaaacc tgtgctgcct acttgtgcaa agtcacttac atgctgtact 45420

tctgtttctt catctgtaag ttctacccct aggtatttac ttaagattaa tggaagcata 45480

tgttcataca atgacttgta cagaattatt cacgatagca ttactcttaa tagctctaac 45540

tggtaacaac acaataatca atcaacaatt gtgctgtatt catacagcag aatactactt 45600

45660

tcatgctgtg tgatgccagg cacaaatcag tacatactat aattccagaa aagacaaatg 45720

tcatccatgg taacaacaag atccatgctt gctggaggta gaggcatcag ttcagtcatt 45780

caggaagctg attccaagat ggtgttagaa ttacaaccat ccacaagaga tttattgcag 45840

gcaatagcta tgaaaggtag aaagagaaca ggagaaaaac caggcaagga aaaaccacaa 45900

tgtagttgtg atatcacttc aaagggaggc agaagggaagg agaattgggt aggaatagcc 45960

acagattaca gtgcagttac aagaaagtct tggcttccaa caaaggttac ttgttgagga 46020

gtcatgcatt aggcagacat gtctgggctg tagtttcctt gctgctccca gtcattggct 46080

ggaggccagt ctgggttcct gtgctgtggt ggatcccatt gctgctgcag caggaggcca 46140

atagcactcc tggcagctaa ttggagagaa aagatccaag aggtgtacct tcatggctac 46200

ccccatgggg ctggggtgga ggtggaggag aaggagaagg aattaactag aaaaaggcac 46260

46320

tgggtttatt aatgcatcaa aactcaagaa atgtacattt aaaatgagtg catatgattg 46380

taagtgaatt atacctcaat atagttaatt ttttaaaaat catagatttc tttatattta 46440

atgcatgaac ataaacctaa gacactcctc cactccaaaa cttaattacc ttgtgatcag 46500

gacatttaac 46560

aagggacagg aaaatggacc ttgtcctaag ttaccaaact gcaaaaatat cacctacaaa 46620

ggctattcat aacatacatt ttcaaggggg ttacaatatt tgcctactat aaaattttgg 46680

atctgtaaag gggttaaatt atttgtgcag gggaataaac atcaaagaaa cattaagagg 46740

46800

tgtggaatta agttgtattg attatgatct gatcttcttc cccctaaatt tgatcctctt 46860

cctgtaatct attgtttcca tcatcttcaa ctcttccctt tccctctccc ttgtccctca 46920

gttctagtca atcacaaagt cctacagttt cactttctgt ataccttatt tctggaattc 46980

atctctagac ttcaaaatat atatatatat attttttttt ttgagatgga gtctcgctct 47040

gttgcccagg ctggagtgcc gtggtgcaat ctcagctcac agcagcctct gccacccagg 47100

ttcaagcgat tctcctagtt cagcctcctg agtagctggg attacaggca tctgccacca 47160

cgcctggtta atttttgtat tttcagtaga gatggggttt cgccatgttg gccaggctga 47220

tctcgaactc ctgacctcag gtgatccacc cgcgtcagcc tcccaaagtg ctggaattac 47280

aggtgtgagc cactgcttcc agcccaaaat atcttaagta gataattgca cgactaatct 47340

ctgcttttct ctcccagcag ccttccaaat tcatgtctca cagctgacag agttgttcct 47400

gccttcagat tcatgacctg gctctgtgtt ctagctcagg ctttctctct catatcacct 47460

cttgcctctc tgttgccccc atattttccc ctctggttgg ttggtgctcc tttggaaccc 47520

tctgcatatc ttttcaagaa tattatgact tattatgcct ataaactttg tttaattatt 47580

tatttctaaa atttgacagg gaactttccg aaggcaggta ttgtgtcttt ctcatttaaa 47640

agcaaattct cgcctggcat ggtggctcat gcctgtaatc cccacactttg ggaggctaag 47700

gtggacagat cacttgagcc taggagttca tgaccagcct gggcaacaca gttagaccaa 47760

aaaaaaaata tatacgaaaa ttagcctggc atggtggcac acccccgtag tctcagctag 47820

tctggtagct gaggtgagag gatcacttga gcctggatgg ttgaggttgc agtgagctgt 47880

gattgtatca ctgcactcca gcctgggcaa aaaagtaaga tcctgtctca aaaaaaaaaa 47940

aaaaaaaaat tagtgaatcc tcagtgttta aaaagtccat aaacatacta aacatagaag 48000

acctccaaat gaaattaatc aattattatt tagtgggttg cttctctttt gttttaatat 48060

agttttaaca aagagtaaaa gttatgatct ttttatatgt aaaataaata atgccggggtt 48120

tgacataaat tttaggaaaa ctagagacgc tacttcctaa aaattttctt tctataatct 48180

tcctaaatat ttttccataa agtacaaaat aatagaaaaa aattaagaga ttgagtatcc 48240

tttcaggaag tgatatgaca aatagggttc gagaactatt tgaattctca ccacttttca 48300

taagggcaga tctcaagtta aatttttcta ttcgaattta aatgactttc actggaatac 48360

cattacagaa aagcttctgt gtttagatgg caatatggag tttcttttct tggaatatta 48420

attgaaggag aagtcttaat tttttaagtc tatatctccg tatatatttg aacctatttt 48480

atatgttagt ccttctcttt agtaaccttc atccacagtg aacaagattt acccttacct 48540

ttaagcagta gcggctactt tatgtgaagt gaacagctgc tttttttatc tgcatctaga 48600

catcaagtag tccagagtcc tttctaacac cctagcaata gaagtaagaa tattttgacc 48660

attccatgac ttgatgatac ttctagtaat aatactgtat tattaaaaac aaacaaacct 48720

ttgtgcagtg gtaattgaag cagttccttg ggaacatgta ttaagtactt tttagcagtt 48780

aagtccactc tctgtaggtt aaggaatatt taaataaaat aatgtggcaa atgagttcaa 48840

gatgataaat gcgatgagaa ctaaaacagc tttaatttta tgtgggaaat aaatagaggga 48900

aaagtacatt acagggctcc tggacttatt tctttcttca aagtgtttct cctagcgaat 48960

attattacta ttttttctct taagtaaaaa atacacaaag tatgaatcta cacaggataa 49020

taatattgaa gttaaggatg atgtctcctc cttcactctc caaaatacta tttacttggc 49080

ttcatggaaa tctctctcac tccaattcca ccgtgtcaac tgaggtcttc tgttctttct 49140

ctccctatag catattcctg ttacataaat cctaaactgt gtcgtgttag tcacacactg 49200

taacctctag ataagcgcct gtccagaggt tctcaatcag agccttgcaa atatgtatta 49260

aatcaatggg tcatcttcag tgtctcagtg ggcccttgga tatgttttgc agactgctgt 49320

gagtatgtag ggatgtccag tatcgaggga agtgtggatg gctttcattg gttcttatag 49380

ggctgaagaa cacatagagc agtaagcact tctactgtag ggagagatcg agcttctccc 49440

atccccactg ctggcaccac caccaccta caccccattt tgagttctga aagtgaatcc 49500

ttgagaaaga acacacaaaa caaccatcat aatagtgggc acagctgtgg gtggtagaat 49560

aacattccca agcttctttt cctacacatg attaatatta attcagcaaa catttattca 49620

gctcctactt ttaaacaggc actattctag gtactaaaga catagaggca aagcatacaa 49680

gactctgcct ttgtgaaaca attaagaaat aagtaaaaag aaaagaaaca gaaaaggcaa 49740

tttggatagt gtcaggtgct ataaagaaaa caaaatgcca ttttaataaa taataataat 49800

acaatgtttt catactatgt gctagacact atgctagtag gtatttatag acataacctc 49860

aattaatcct caaaatggca tgttgatatc aataccccaa gtttacatat gagacttaag 49920

atgtctgagt atattcccc aggtaacaat taatatgcac aataaaactt tttgctcatt 49980

catttattaa cctatgttga ttgagtacct attttgtgtc aggcatcatt ttaaggcacc 50040

tggatatagt tatgaacaaa caaataaaaa tctctgccct caaataatta atatctcaca 50100

gaggttaggc aaaatataat cagaaaataa gtataacgta taggatgcca gatcatgaaa 50160

gaagctatga atggcatcaa gaagctggaa aaggcaagga gacagatttt ctcctagagt 50220

ctccaaaaca gaacacagtc ctgccgacac cttaacttta ggctagtgag acccctattg 50280

gacttcagac ttacaatccc acaatgtaat aaatttgtgg taattcagta ggggaacaat 50340

agaaaactaa tatcatagaa caagaaaatg taattgtgac 50400

aaataatacc tacaaaaatg ttgtaaatgc taggcaaata atgtgtttaa agcacttagg 50460

ccaatgttca acgtaaagta attcatgcta taatatcatc atcatcatta ccaatattta 50520

ggggctctaa caaatgatgt acgtgtaagc agatgtaaga aaatttcctt gctgaagagg 50580

50640

tttattggat taaatttaat tttaaaaact acaagaggcc gggcgcggtg gctcacgcct 50700

ataatcccag cactttggaa ggctgaggtg ggtggatcac gaggtcagga gatcgagacc 50760

atcctggcca acatggtgaa acgctgtctc tactaaaaat acaaaaatta gctgggcctg 50820

gtggcgcgtg cctgtaatct cagctatttg ggaggctgag gcaagagaat cacttgaaca 50880

accaaggagt cggaggttgc agtgagccaa gattgtgcca ctgcactcca gcctggcaac 50940

agagtgagat cccgtctcaa caacaacaac aacaacaaca acaacaacaa caacaacaac 51000

51060

agactctgag tactgcatgt gtaaaaataa aggcatgatg aaaagatcaa gagattagag 51120

tgatactttt tatctactag tgtcagagtc atgaccaggg gattggctat gagaatacat 51180

aagctgtgcc aggagtaatc caaggagatt gtttcaattt ggaagagtgt ccacagaatg 51240

attctcatac tagacgttgg gctattgtaa agaaagttgg taggtactcc atcgctagga 51300

tcatatcagg gagaaattga acaggatggc cctaatgacc ctgttgtacc cctagcttat 51360

ggattaggca agtcacttct actcgtatac cctgtttccc catttgtaaa taagaggatg 51420

tgttactcta aggatctcta agattctttg cagttgttaa attgcatagc tctccactga 51480

ttccatggtg gaaatttgct attctattac aaatattcta aatgtatgag atatcagaca 51540

tactcattta aaaaacaaaa tacaaaaaat aagtattcta caaataaaca cagataatgt 51600

51660

gcaagaaaat gtcgtgatgt tcctagtgca agttaaaaag atttgctttc ctcaagtcgg 51720

51780

gaggagtcaa tatccatctt taaaggtagc caggtcacat gtatacatat gtaactaacc 51840

tgcacaatgt gcacatgtac cctaaaactt aaagtataat ttaaaaaaaa agaatttaaa 51900

taaaaaaaga aaatcagaga gaaaaaaaaa aagatgcatg tgcaccctga tactaccatc 51960

catagtgata cggtttggct ttgtgtcccc acccaaatct catcttgaat tgtaaccccc 52020

atgtgttgag ggagggacct tatgggaggt gattggatca tgggggtagt ttctccatgc 52080

tgttctcatg atagtgaatg agttctcata agatctaatg gtttaaaatc atggcacttc 52140

cttttgctct ctctttctcc tgccatgtga ggtgtgcctt gcttcccctt ccccttctgc 52200

52260

ctttctttat aaaaaaaaaa aaaaaaaaaa aggtagccag gtaaaaatta cttgtttcca 52320

ggacattttc acctgaaaga agcattgtca tataacatag aagcaagaaa tccagtagtg 52380

ggggttattt aaaaatagct ggaaaatttc aatcagcatg agtttgaagc aacaatttat 52440

catcaccttt tatggtgggt ggggttaaga acatttcagc gggcaaagtg gtggtgatgg 52500

ggaagagaca ccagggggagg tgattcccat tgcattgctt tgtaaacaga ggcacaggtt 52560

cttcattttt gtcacacaaa atcacagcta tgcagaattt attaatttat tcttctgaga 52620

caagaaaaaa gccaccaaag gaaaccaaca gcttgctcct ctcacactgg gggaaccata 52680

tgagagactt atctatccct gactttaatt ttgacctgag gagagctcct cttaaggaaa 52740

acaaattaat tcaatgacta tactacttaa tcattgacct ttatttaata agagattttt 52800

ccataggata tgctgagctg tctcacttac atcagttgtg tctcctgagg tgggtgacag 52860

gagaccacaa atattgcata gcacacaaat cgttaatagc agctgtatac caaaccatta 52920

cctaaatatg tagagtacaa ttcattctca ctaatgtcag agagcatgct ataaaatggt 52980

gaatccggac agctgaagat actgaataat aacctctatt ttgaacaagt ttacagtgtt 53040

ccaatcagta attaaattga tacctgatga atatatgtgt gtgtatgtat tcatagcaga 53100

gatggttttc ctgagataag gattttgtta ttcggatagg ctgctgctgg aattgtcctt 53160

ctacccttgt ttctttgtcc ttagtcatca ctcatacctc ttttccactct tctgccatca 53220

cttttgtcac caaagtcatg gtcctttccc cgccgattgc tgctgcaggt ctagggcacc 53280

aagacttagg cagcactcac catgtgccaa gaactggacc acaggtacca tccagcattg 53340

ctcatggaga ctctgtccct ttctgtagga caccctcctt ttagctagca acccctccac 53400

cacctagagc ctctggacct ctcattttaa tattaagaac taggaaaact taccgctgag 53460

aataactagt acaactagaa ctggtagaga aatctgggtc tcttgggaat ggatttttag 53520

53580

53640

aacttgtgtg gtggaaataa gttctttttt caggcaaaag atgtgcaaac ccatctgggg 53700

aagaaacatt aaaaactaag gagacagtgt cctagataac tatgttcttt tcctgtttta 53760

gtctaaaata atgattagtt ttcttatata tcttcatttg tcttggttcc ttttagccca 53820

atttaataat attattgcag atattgatga aaacctttac cttcctctta attcatcaaa 53880

gtacttgata aaatttatac atagtacatt aattgggagg tttttatgag attaattaat 53940

ataatgaact gatgttgaaa ttatttaaaa cctgaattat tattgtatta agtaggacac 54000

ttaatacagt taatcagttc tgtctttatt catttgtgag aatttttggc aagctattgt 54060

gaatattcag ggaagggaat gtatttttag caggaatctt atacctccta catagaaatg 54120

aagcatttac tgaaacatcc atgaaacaaa atgtttctga atgtgtacta tacacttgtt 54180

ataagcccct tttcttctgt agctatattt tggagaaaaa tctttgcttt gacaaaaaaa 54240

attatgttga cttacacata tattttataa ctaagcagtg tttggtttgt gataaaggat 54300

acaaaaatat aaaaatgttc agcacacgta agtaaggcct tgttgacagt gtgagttatg 54360

ctactggata ctcaaaagga acattcagtg ttctcaggtg gtctctagac tgtctcaagc 54420

54480

gaagaattca gttttgtgtg ccttatcctg ttatttttgag aggcagccaa aagatgctgg 54540

tcagcaagga gaattgtaag ttgggcagcc aactctgatt tctcaacctc ttagctgttt 54600

tcttaaactc agaattttta atgaatttaa atgtccatat caggtagact ttggggatgc 54660

ttttaccagt gattttcaga atgttacttt ctggcatttc ttttcacgta gcattatatt 54720

aaaaatgaat tcattcatcc accttccctt gtccttacta attttccctc ctactccctt 54780

cccccttgtt cttgccatgg ggacatgcaa acactggtgg ttgatgtctg agcaaggctg 54840

ctgacagggg gaggaaggag atgtcaagca gaggtcaatg gcagtgtgcc cagcagccta 54900

54960

attatggtgg ttatgatact tgtcatgctg aacacccaat tgagcaccca ataagcacat 55020

aataatttaa tcatcctctg gcttggatgg cagtgttcta tcagtgttga cttcctggtt 55080

gtgacagttt tacagtgtta gtgtagaaga gaatccttgc tttagagagg tacttactga 55140

agtacttagg gttaatgcac cattgtgctg gaaaaagata cgcacacaca cgcacacaca 55200

cacacacaca cactctcaca cacacgcaca aatacatcca tgtgttaggc agagggagca 55260

aatgaggtaa aatgttaaca attaggaatt ctgggtgaag tggatagagg gactctttga 55320

ctgttcttga aacttctcta tacatttgat ctgtttcaaa ttcttcagaa aatcaaacta 55380

caaaaactta attcatttag tgaacatcta ctgaacatct gtatattaaa tagtgttaaa 55440

tgaatgtcaa ttaaaatgct caaacacagt agaggttgat tctcattcac ataagtccat 55500

ggtaggtgtt tttggcaggt gggtgagttt ctcccttagg gagattgagg aacccagact 55560

cctcccaagt tgcagcccca ccgtcttctg aggggatgca tccataccca cttcgaagta 55620

55680

agaaaattgt agtatatagc catatgccct gacaaagaag ggagaacaga ttttggtgga 55740

caactagcaa actctgatac aatctgttat taagcactgt gtgtggatag atgctaacta 55800

gaaggagatt atcttccctt cagcaaatat aaactgaatg ccgtttattt ggttgaaact 55860

aagctagatc atgggagtat agaaatttta taagaagaca tagtcacttc tgtcagtgag 55920

ctcaagaaga attagtatgc ggaatgtaat catacctaca gggggcttgt gccacttaag 55980

taaaatgaaa cattattttg agtacaattt agcaataaat gtactacgag atcattaaaa 56040

atcatgtttg aatgttattg tgtcaaggat gggaaaaaga cttttggggtt gtagacttga 56100

56160

tttatacttg ctaacattta tacttgctaa gtaaagactg tttttacaac catgacaaga 56220

acaaaacata ttagtaatgc aaatgccaca tttcctacaa tcaactaatc acactaacat 56280

atttgcatgg aagaatcact gggattgatc tggccacgtg tgtagtcatg cccaaaatgt 56340

56400

ttttattagt ggatatattt tggaggtcag acaccctctt ggctagatca tcacctttat 56460

aacaaatata tatactattc tcatggaaat atatttagac attgccctac tgggaatttt 56520

tttcaagtaa ttaatgtaca gcttgtgcaa cagcttgatc ttggcttcat ggaaataatt 56580

cactcttagc agcatctaat gccacaaagc atttatggat gtcagctcag aacttacttt 56640

tatttatctc tgagttactt tttttttttt ttttttgaga cagagtctca ctctgtcttt 56700

ggcttgtccc taacctctta acagacttaa tattaagctc catttcactc agtcgttctg 56760

ttgtcatata aatgagacat tctacaagca tagtttttag tttctgccag agcatcatac 56820

aacattgtga gctatgatga agataaagac ctagagaaga tatttaatat gaagttcatt 56880

atctaatatt tggtatgtgt ggcaaaatag caatctactg cttggttctg ctgtaatcta 56940

tttacccacc catcccatct ttctttcaat ttaaaaggat aatgatttta gtcacgatta 57000

tacataaacc cattaccata ggcaataaac aatggggcaa accattggtc ccatagttgg 57060

agtgtggtct gaagtgtgtt ttggtggaga gagatctatg tctggagata gctaacatgg 57120

atttggatcc cagatctgct cctacctgtt gctgtgcctg tgaccaaatc atgtgatctc 57180

tctggtttca gtttacttgt gaataaagta aataccttca tcaacacctg tttttgaata 57240

caatgttttt ctgtaatttt tgcttcttat aatgttataa tgatcatcct tacatctaaa 57300

tcttggttta cattttcatc aattcttttg gaaagattgg agaagtaaat tttggagatg 57360

tatgtcggct attaaaaatg tttaattttt taattaaaaa ttaaaacgtt gaaaaatcct 57420

gatgcaaaat aaatgcatta tgcttagtga actcttctca tttcgaagtt tattcacctt 57480

cttgtttttg caagtttcct gaaaaatgca tataaagtca ctaagttagc agaactttat 57540

aaaattatat aactatatat aatcttttga tatcagtgaa gccagctgat cctatagaaa 57600

taatgtagga attataatca ctagcacata atttaagagt cctgtggtct tattcatgtt 57660

atttaccctc tctgaatctt acatatagta agaggggttat tatacataat atgtgtacat 57720

gtatacaggt aagtaagtat atatgcttat gtgtaaaagc agagttattg tgagagtcaa 57780

atggaaatgt gaaagtactt tgtagttttt tattactatt attaattttt aataaaatgg 57840

taacattcat ttaataatca ttagttttaa cttcagattg tactggattt cctctagtat 57900

ttcttaagat tagtgaataa agtatttctc ctaataaata tattgactac tgtctttcga 57960

tcaaacatat taggtatatt tttacagtag catcaggcag tgaaaatttg aagctcttta 58020

tagaggactg atttatgatg aaaaggaata acatgaacaa atggaattat atgaagcttc 58080

cccagaaata tctaagaggg gccaatttta agaaatatct gacttctttt tcatggacat 58140

ttcaaaataa acctaactca tatggtacag tttttaagag ggaaaagaaa aaaccatctg 58200

agaatctctg gaattctgcc gaaagtatca cttggcattt tattctacct tctggatgca 58260

gttgattgac agtagtgtta tgatgccagg ggtatagtga ctagaaaaag aaaaccaggg 58320

aattcagtgt tcttgctcat gaagaacagc ttggttcttt aaaaacaatg agattttgcc 58380

accccatctc acaaacctat gatttgtgag aacaatccct tttgtgttgc aagactttta 58440

catttctctt cccacactat attagaagaa taaacattgc ttcataagta ccgattgata 58500

gtctcatttc atatttttaa aatagagtta ctttaaggtt aaatttttca tgtagattaa 58560

aatgactaag taaccattca catatttcaa ataaaatata tttttactac aaaaggaaaa 58620

taactagatt cttaagtgtt atagtcaagt gtaattgagt aatatgaatt ctaaatgaat 58680

ttctaagatc tgctcagctt tcactacttt aggaaggaac aacttaagaa aaattttaat 58740

aaagatatct cttcacacac atggcagtgt tgtacttaga gaacatgacc caaaattttt 58800

tatgactgca tattgaattc ctgatactct tgggaagctc caaaagcacc agtggagttt 58860

ccagatgtaa ctgtggctgc agacccgcca gtcccggtgt tggaagggat cattataggc 58920

tcttgtgtgc agactcatct tcagacccag aggaattaaa taacttgccc aaagtcgcac 58980

aactttctca tggtaggttg ggcactagaa taaatattgc ttttttcttaa gagttttagc 59040

ctccgtatta tgaaatcttc tatgttctgc tgatgatatc tcctttcttc atctgttttc 59100

tatttttaag caatggaaat acaaacttgc aactccccat ttccaacaca acttagaaaa 59160

aacaatattt aaagaaaaaa ttacaggcat ctcatctcct ttacctgaca gatgcttgat 59220

agtaatggcc tctagatagg gatgacatct aatataaatg tgtcctttca agtcaagctt 59280

tctctgttca ttagtagaaa tattgtatat caagtgtgca aaaattttct tcaacaggga 59340

gctttgtttc cctcctttta ttataacaat ctgagctttg tggtcccagg gtctcctagt 59400

gcctgtcttt aggtctgttt attcacatga agaaagcatg tcatatagta ttatctaaga 59460

ctcaggctgc ttatgcatga tgacagaagg gttcccaggc acaaacattc atccatgcat 59520

tcatccatcc acctattcat ccattgattt ggctgataat tattgactac tgttgagttg 59580

ccctcagatt tagtttctgt ccttctgcca tggggaaata tggggttaag ccacaacata 59640

ctcttctctt ctttttctgc accttcttag tatatttagt tccattttgt ctagccctgc 59700

ctctgacttc tttgttgtac ttcaggtttt ttatcattga aagttatttc tggatcatag 59760

atcattctct tggtcacttt gcttgttcac ttataaaatt aattcagaaa aaatgaccca 59820

cagtaattac cgtaaatcac agaccataaa ctataatact gtatattgta ttatagtaca 59880

gaaatattta tactttaaaa tgttttaaat atagatatta taaaaagata tgtctcatat 59940

aagtaatata aatacttttt tattacctct tctctcccta ttctccaggc cagtgtttta 60000

aaaatccatc tttatatgtc catcctggaa aaaactcatg atcataaatg agtttctcaa 60060

60120

60180

taatcctact tttcatccca 60240

aaaaaatgat aaaacatttt tcccaaaatg tagctttaac tatacttaaa 60300

tttggactaa aatgggagat atcttttcta ctattgaaaa gccgtgtctg tagattaatg 60360

ctaaaatcgg gtgtaaaagc aaaatttgtt tggcttgatt gccaatggcc cattcatttg 60420

gctacagaaa caatagcaca tagcaacaga taatgatgtg agatcaccta gctcaagtaa 60480

60540

agtcatctct gtaaaaatac attaaataga ggaatagaag tttgactttg aaaatacatt 60600

gcagacccaa tccgtctttc ctattttctg gtgaaaagta tcaaatatgt ggaacctgga 60660

actgctattc tccttcttaa aaatctttct taatattcta ttgataactg gtgcaagcct 60720

aactttttgt cttacccgat tcttctcaca ccaaagtgat aggaccttca ggtagccttt 60780

ggatagaaga taaataataa tttaactatt gatggaagtt agtattagaa ttagacttgg 60840

aagtctatgg aataaaatga ttctacaaca atttgtactt cagacattag tataacaaaa 60900

catgtttgcc cgtgcatgcg gaaacaacca atttcatgtg gatgcttata ttcacaaagg 60960

agtaaccacc tggggtttcc cactgttgct ccagagaaaa ctagcagcag gagaacttct 61020

ctgaaggtat caagacatct ttaaaaaaca cttgttaagt gttggttcag ctaaagcagg 61080

gagttttcag ttagtaatgg cttttaaaaa ttaaaacaag tttagcatgt aggtcattaa 61140

ccttgaatca ctgtcatgat tattattaac catctgttct caaatcgaaa gatatttttc 61200

61260

61320

cgctctggga tagagaaagg aactaactga cattttgctt cttaacttgt ttttatgcaa 61380

gttctaagtg gtttctggcc atgtacataa aagacaaata tctggaaaaa aaactagcag 61440

61500

taaaaagttt taaaaatatc taaggacagt 61560

atacagtcct aaagtaaagc tgttaggtaa atgctacaca atcctcttat tacagagtca 61620

cttacctgag aatataagaa gagggcctct tgtttaagag taaatgtgag ctgcaatcag 61680

gattctgcac tcatttggac acttagtttt gtttttccat gactggtgtt gcctgttact 61740

gagacaccta cctgtcatgt gaccacagct tatgttacaa tgtgtctagt cagacttaga 61800

gatgtgtgaa agagcagtac ctagacggga aactatgggt ctataaaggt tttgccttct 61860

tgggcggagt tcaaactagg aagccacaaa acttccagtt gcattttcac agattaatga 61920

61980

agccagttga ttaatcgatg aagtgatttg tagtggattc ttatattttg tgtaagggta 62040

tatgtgaggc cctatatatg aggctttcta tataatgaag tataattcag ttcagcattt 62100

caattcagca atcacttatt gggcctctac tcagttgcct tcaggggcttt ataatttaat 62160

tgataaaggg aggttaatta attaattata acaacagatc gcttaatagt gtaactacta 62220

62280

ggtgttatag acaataattt tctgattaac tttattatta ttatttcaat agcttttggg 62340

62400

acactcataa cctgagcagc atacactgca cccaatgtgt agtctttcat tcctcacctt 62460

cctcccaccc ttcccctcaa gtctccagag tccattatat cattcttatg ccttgcatc 62520

ctttagttta ggtggcagtt ataaatgaga acatgtaatg tttggttttc cactcctgag 62580

ttacttcact tagaataatg gtctccaact ctatctacgt agctacaaat gccattattt 62640

tgttcctttt tatggctgag tagtattcca tagcatccac acacaccccc ctatgcttta 62700

62760

ctggttccat atttttgcaa ttgtgaattg tgcagctata aacatgcatg tgcaagtgtc 62820

tttttcatat aatgacttct tttcctctgg gtagatacct aggagtggga tcgctggaac 62880

aaatgattgt tctactttta gttctttaag gaatctccat aacttttcca tggtggttgt 62940

actagtttac attcctacca gcagtgtaaa aaaatgttcc ctttttacca cttccatgcc 63000

63060

ttgtggtttt gatttgcatt tccctggtca ttaaagatgt tgagcatttt ttcatatgtt 63120

63180

63240

63300

actctgatga ttatttcttt tgctgtgcag aagctttata gttttaggtc ccatctattt 63360

atcttttttg ttgttgttgc atttgctttt ggtttcttgg tcatgaactc tttgcttaag 63420

63480

agatttaagt ctttgatcca tcttgagtgg atttttgtat aagttgagag atgaggatcc 63540

agcttcattc ttctacatgt ggcttgccaa ttatcccaac accatttgtt gaataggatg 63600

tccttttcccc accttatgtt tttgtttgct ttgttgaaga tcagttggct gtaagtattt 63660

agctttattt ctggattttc tattctgctc cattgatcta catgtctatt tttatagtag 63720

tacatgctg ttttcctaac tatagtcttg tagtatagtt tgaagttgggg taatctagtg 63780

cctccagatt tgttattttt tgcttagtct tgctttggct gtatggggctg ttgttttgtt 63840

63900

ggagtcgcat tgaatttata gattgttttt ggcagtgtgc tcattttcac aatattgatt 63960

ctgccaatcc atgaataagg gatgtgtttt cattagtttc tgttgtctgt gatttctttc 64020

agcaatattt tgtagttttc ctgtagagat cttccacctc tttggttagg tatattccta 64080

agcatttttt ttttttgcag ctgttgtaaa aaggctcaag ttcttaattt gattctcagt 64140

tttgttgctg ttggtgtata gcactggtac tgatttgtgt acattgattt tgtatctgga 64200

aactttactg aattaactta tcagatctag gagctttttg gatgagtctt taggttttct 64260

aggtatacaa acatatcatc ggcaaagagc aacagtttga cttcctcttt agcagtttgg 64320

atgctcttta tttctttctc ttgtctgatt gctctggcta ggatttccag tactatgttg 64380

aatagaagtg gtgaaagcag gcattcttgt cttattccag ttctcggggg aaatgctttc 64440

aaattttccc ccgttcaata taatgttggc tgtgggtttg tcataagtgg cttttattac 64500

cttaaggtgt gtatcttata tgccagtttt gctgagggtt ttaatcataa agcaatactg 64560

64620

cctgcttata tggtgtatca catttattga cttgcatatg ttaaagcaac cctgcatccc 64680

cggtatgaaa cccacctgat catggtggat tatctttttg atatgctgct ggattcattt 64740

agctagtatt ttattgagga tttttacatc tctgttcatc agggatattg gtctgtagtt 64800

ttcttttttt gttatgtcct ttttctggttt tgatattagg gtaatactgg cttcatagaa 64860

tgatttaggg aggattccct ctgtctctat cttttggaac agtttcaata gaatttgtac 64920

caatttttct ttgaatttct gatagcattc acctgtgaat ccatctggtc ctagactttt 64980

tttgtttcct gacatttttt ctattattgt ttcactctca ctatgcatta ttggtctgtt 65040

aataatttct atttcttcct gttttaatct aggaggtttg tatatatgca ggaatttgtc 65100

catctcttct tggttttcta gtttgtgtac gtaaatgtgt tcacagtagt cttgaataat 65160

cttttttatt tctgtggtat cagttgtagt atctcccatt tcatttctaa ttgagcttgt 65220

65280

cttttcaaag aagcaggttt ttgtttcatt tatcttttgt attgtatttt gtgtttcaat 65340

tttatttatt tatttattta tttttatttt tattttttga gatggagtct cactcttgtt 65400

acccaggctg gaatgcaaca gtatgatctt ggctcactgc aacatctgcc ttccaggttc 65460

aagtgattct cttgcctcag ctgcccgagt agctgggact acaggtgcct gccaccacac 65520

ctggctaatt tttgtatttt tagtagagac ggggtttcac catgttggcc aggcaggtct 65580

caaactcctg acttatggtg atccgcctgc cttggcctcc caaagtgctg cgattacagg 65640

65700

tttcttctgc tgggtttggg tttgctttgt cttgtttttc cagttcctag aggtgtaagc 65760

tcagattgtc tatttgtgct ctttcagact ttttgatgta gatatttaat gctatgaact 65820

65880

tgttgaattc aaatattttt aaaattttca tctttcttga tttcattgtt gacccaaaga 65940

66000

66060

ttcttaaatt tattgagact tgttcatatg gtctgtcttg gagaatattc catgtgttga 66120

tgaaaaggat gtagttgttg ggtaggattt tttgtaaata tctgttaagt ccatttgttc 66180

66240

gctgtcagtg gagtactgaa gtcccccact attattgtgt tgctgtctat ctcatgtctt 66300

aggtctagta gtgattgctt tataaatttg ggagcccaag tgttagatgc atatacactt 66360

aagattgtaa atttttcctg ttgaactaat tattttatca ttatataatg tctctctttg 66420

66480

tctcactttg agtttccatt tgcatggaat atctttttcc acccctttac cttaagttta 66540

tgtgagtcct tacgtgttag gtgagtctct tgaagacagc agatacttgg ttgatggatt 66600

tttatccatt ctgccattct gtatctttta agtggagcat ttaggccatt tacattcaac 66660

attagtattg aggtatgagg tactgttcta ttcatcatga tagttgttgc ctcaatacct 66720

tcttgttgtt gctgttgtta attgtgttat tattttatgg gtcctgttaa atttatgctt 66780

66840

catttctcag tgctggcttg gtagtggcaa attcagcatt tgtttgtctg aaaaagactt 66900

tatctctctt tcatttatga agcttagttt cactggatac aaaattcttg gctgataatt 66960

attttgttta agaggctaaa tatagggccc aatctcttct ggctagcagg gtttatgctg 67020

agaaatctgc tattaatctg ctatgttttc tttttatagga tacctgatgc ttttgcctca 67080

cagctcttaa gattctttcc ttcatcttga ctttagacaa cctgatggct gtgtgcccag 67140

gtggtaatct ttttgcattg aatttcccag gtgttctttg tgcttcttat atttggatat 67200

ctagatctct agcaagacta ggaagttttt cttgattatt ccctcaaata agtccttaat 67260

gaccccacta tataacatga aatatctgtt attggtactg aggtgctggc cacaaacaat 67320

tctgtgtgtc ctgaaaactc ttcagaatat tcgtcatctt tagcacttgt tatcttagtg 67380

tttgggcttg gcttagagtg atacatctca taacagggca acagaaagaa cggaacca 67440

agatttatat aacataagtc agtaaaacta gaggcaccag aggtttacat ttacattagg 67500

ttacattttc taacaggtag caaagcacat gaatgaagtt cagtggaagg ccttcctcag 67560

gaatccagta aaaaccaaac atacacacac acacacggac atccgtgagg caggaaggga 67620

tgtccactat agtacagaca agcatcctgg aaggccatca aggagtaggt gggtttcagt 67680

tgcctcagga atgtggcatg gacccaaact aagtgagtac agatacttgt cattgaggag 67740

aagattcaaa atagcatcct aggtgtaaaa actgaggcac ctggggcagg ggaactaggt 67800

ctctggaatg ttggcttaaa agcacccctc tcaggaaagg cctcatatgc catgcagggg 67860

gttatatatg tgttgtggga cacagatggc aaggagataa ttctatgcac caggctccac 67920

tactaacagg taaacagacc aacattaaca gagacttagg taaaaaggta ggtgcccagt 67980

ggtcagttct caggcacttc caagatgcac ctaacagaaa tgtaacttgg tgtctattgt 68040

gtcctaggtc taacaactga agagaagtga attagtacct cttgtggaca gagaaacagg 68100

ggcagagacc cattacaaag ctgtctcaga taggcatttg aagctgttta agtatgtaga 68160

ggcttaagtc aggctggttc tgaaatgtga gagagggtta agcttcatgg gaaatcagca 68220

68280

68340

caatatacaa caaaaagttg taaaatttcc atctccactt aatcgatctt atgtaaccca 68400

tacaatacat caaatgtcct ttccccactt tatgttttta tttgctttgt caaagatcac 68460

68520

cctattttta taccagtgcc atgctgtttt ggtgactatg gccttatagt atagtttgaa 68580

agcaggtaat gtgatgcctc cagatttttc ttttgctta atcttgcttt ggctatgtgg 68640

gctctttttt ggttccatat gaattttagg attgtttttt ctagttctgt gaagaatgat 68700

ggtggtattt tgatgggaat tgcatttaat tgtagatttc tcttggcagt attacccagg 68760

68820

ccaactgtta cctacacttc aatactttct gagggcaatt catcctccag taagtctccc 68880

tgaatcttct cttccttccc tggcttatta tatatccttc ctcttggttc ccatagcacc 68940

tatgcacact tctgtcattg cacttgccaa tttgttttat aatgatctgc tcatctgtct 69000

cctcacttag actatgagct cactgagagc aatggctgtt gcattcacct tatatcctca 69060

acaccattct gaaggcaaga gaaagaatac ccagaggtgg agctgggaag ctggttgtcc 69120

aagtagtgaa tgactctagt ttgaattgaa ctctatagcc agtgggcaat gtggatgtgt 69180

tgacagtttt ttaacagggg actagtgaaa acacattttg ggtttagaaa aaattgcaag 69240

tctgatgaca tacataggag aagagattag agataggaat ttcacttcag aaatttaacc 69300

69360

69420

tggatctgtt tttaaggatt gaatggaaat ttgagcattt tagctaatca ggcctaatat 69480

tgagcaaagc aaaactcttg caaattgtta tttcaagtgt gggctgagaa aatgaaaaaa 69540

tataaattct cacgttataa cctcttccgt gtgtctgatt tgatagaatc cagccccatt 69600

gcctccaaat tccattgcat cttagaccag caaacacaag tgaattctac ttaaccccag 69660

aattctgtat gaaaatctta ctgccttttt ttttctaatc atgtgtcaaa gtgtgggaag 69720

aacttttatt tatgttttaa taaattgtca gtataaccat ttttacttga aaatattata 69780

69840

69900

tagtagttta gtcacttaaa aagtgatatg attatgaaaa tacttaaact ttgtctttta 69960

actatttcta ataatgctat tggtataatt tcatattttt atactgatct tttctccaaa 70020

ctttagtaaa acatacttct gtaaacccct gcccacaaaa ctgaagtcca catttacttc 70080

tgaatgactg ataagtttgt aaaagtatgc atgaatttcg ttattaaatt aaagttttta 70140

ttatattttta tgcacaatgg tataaattat taaattaatt ttcaagctta tagaacattg 70200

ataaagattg tcattagaaa accctgagtt gattgttata cattacataa cctttcattg 70260

gtggattagt gaatatgtta tagggtgacc atgaatccaa agaatcaaag ctggctacag 70320

caaacagagg gtcaaaagga tatggaacta tgcatgatcc agcaaaacac tcaatatctg 70380

ttttcctgga atgttaaaag acaaagaaga aaacttgggg aacactagat gcatatagtt 70440

ctggttcttt aagaataaaa atatgggccg ggcccggtgg ctcatgcctg taatcccagc 70500

actttgtggg aggccaaggc gggtggatca caaggttagg agttcaagac cagccaggcc 70560

aacatagtga aaccctgtct ctactaaaaa tacaaaaaaa aattacaaaa aaaatacaaa 70620

aaaaaaaata gccaggtgtg gtgacaggca cctgtattcc cagctacttg ggaggctgag 70680

gcaggagaat cacttgaacc cgggaggcag aggttgcagt gagccaagat agtgccactg 70740

tgctccagcc tgggtgacat agtgagactc tgtctcaaaa aaaaaaaaaa gaataaaaac 70800

aagaatggtc agagtcctag taccttgtcc agtgtagtgc tgccttgaga ttgcattgca 70860

atctgtctga gagatagtaa aagaaagtga taccttcctt agccctgttt ctctttagac 70920

tatgctttcc cctctccaag ttaatatctc tcagtctaaa gcctgggaaa aggtgccaat 70980

tttgtttttc tttcttcctc acacctccta gaagttacac tgggacacta ttactttttt 71040

ccaggctttg gccatgtgta ttgttttgga gagtcaactt ccttttttct ttcattctgc 71100

aaatagtttt gagctgtcac tctgtactag gtgctataaa acttacaggt gcattttaca 71160

tgcctatttc ctataggcca cgatttaaca aaatgttcat aaatgagaat taggagtgca 71220

tgtattgaat caccacacat taactgaaca gctttcattg gccagagact atattgacag 71280

tggagattca aagataaact agagaaatct catgcttaaa taactttcta taataaatta 71340

tataagagaa gtaggttcag ggatcttggg agctcagaag caggatgagt taaacaaaag 71400

ttggattttg cctttagctt ggtttcatta tcctgaagga agagcctgaa atatagtgta 71460

gggtgcaagt agtatatgtg ggtggcaatc tcgggaaaca ggagcatgtg atgaataagg 71520

agaaaaagcc aatataaagg tactgcattg agggcaatga gggctctaat tctctgcacc 71580

ttctcaagca ttgtgcagat tggttttctg gattatcagc ctgaaggaca aaacgaagaa 71640

acagccatta gctcctgtct cccattgtct gagagctgcc actaggatat taacttcctg 71700

aaattctgca gaaatctcct cttactttgg cactggagat gcccatacgc agaaagcaaa 71760

aaggcacagc atatttaagg aagctcataa gaaacagtgc atccagaagt ggcgagaatt 71820

ggaggaatgg acatgagact ctaagaacca gcgcctttga tgttcctttt gatctgttat 71880

gtagctcttc ttgtacacag gtgagcaaag gcatgctgga caaatggatt cacatgtgct 71940

aaagcatggg gcaaaaacca catattaatt caggaaaaga caagatgcgt ggccctctct 72000

gtctctgtct aagggtgaat taaagagggg atatatgtac agagtggcag ggcaggactt 72060

gagataagaa ggctaggtgg gtgctctcat gctagtagca ttatagtaca ggtgatgaga 72120

agctcctgaa gaatcatctt aacatttgta ttttagagca acagtattga gttctgactt 72180

agagacagca aaactaaaga cagaaagact attttgatta ttaatgatgt agatataaga 72240

atatcgtcaa tgtgaactaa agcatgaagc tacttatgat atatcattaa aaggatttaa 72300

ctgattggag acaaacgaga gggatggggga aaagaattca tttgttttta gttgctcttt 72360

ttttcctact tattcctttg ttccgagtgt gaataaactt tgtaaacttt tatactaaaa 72420

cattctgctc attcatactt atttctttga tgaaacaagg aaacccttgt atagttataa 72480

acgtgtgaat caatttaaat attaggaaat ttttttaaat aaagctagtt ttctgaaggg 72540

gaaaaacttg gttcaatttt ttgctggcaa tctgctttgt gatttttgaa catgatatct 72600

acatctagac tcatgttttg ctagctggaa ttttttttca aattaacgct accattatta 72660

tatgctttac tatttagctt ttgcagcctt ggaaatctat gattaataca aataattctc 72720

tatggcaatt ttaaaaatac atgtaaaagc cttcaatcta cattgctact gtgtcgtagc 72780

72840

cagtcctagc tcaggagaaa ggaagctatt tgtatttttc agaatcaaat ttccctaaat 72900

gaatatagag aaagaattat aactgaaata ttgttgaaac agtggtcatc tcaaatctga 72960

aggtcattcc aaaaaagttt ctgagttttc attgcctcaa tctaaaagtt ggcctttttg 73020

gtaatagatg aaagtaaaat aattgaaagg gtctgttgca gttttggaat atcttgaaaa 73080

tatagtagag tgaagccttc ttcccttaaa taaaagacaa gttgctgatt gttttctttc 73140

tagccagata agaataatgc cttctttctc ttgttagtct taacacctca cttgttacta 73200

tgtgtcagaa aggcgagaca ccataaatgg agatactact gatggaggtc atctgacatg 73260

gggctggtag gcagtgggaa gactggtatg gacacaggtg gcttagggggt tggggaatga 73320

tatggaacta aggaaatgat aattagcaga acccagtgtg catgtgtgtg cattcgtgtg 73380

tccgtgtatg tgtgtactgt agcacaatgc aagaaagaaa aaacaaggca gacttttcat 73440

aatttcaggg ataaataaat cctttatcac ttcatgtaga atattggcta cttggaggta 73500

tatctaaacg taaatatata actatataac tacatgctaa ttaaaaacat acaaagaaga 73560

agtgcctaaa gaattacaac agaaagtggc atagtgatta ttagagttaa tataatataa 73620

ataaggccag gcatggtggc tcatgcctat aatcccagca cttttgggagg tcaagttgca 73680

gggatcactt gaggacaggg gatagagaca agcctagcca acatggtgaa acccatctct 73740

actaaaaata cagaaattag ctgggtgtgg tgatgggcgc tggtaatccc agctactcaa 73800

gaaactgaag caggagaatt gcttgaaccc ggaagctggg gctgcagtga gccaagatcg 73860

cgcactgcac tccagactgg gtgacagaga aagacccggt ctcaaaaaat taaaaaaatag 73920

tataaataat atttcaaaac acaagtctgt taagataaaa ggtacagagg aatggtgaga 73980

tgacttttt atttgtgtga taagggactg ttttctgtga ttgtgagaaa gaccaggagt 74040

taagaaaaag tggccatcaa taaatcagcc acttatgggg aagaaccata aaccactctc 74100

agatgaaata caaatgcagt cattatttaa tattattgga atatttgtat tagttttgg 74160

tatgtgctgc tagtgctggt acattttagt agtcaattaa tattttgtta atcttaattt 74220

ctaactaaat tccagagtga aatggaaata ataatgaaaa aattttattt acaaaacaga 74280

ttttgttttt ttctgttaag aatgatacac agttgtcctt cagtagccat aggggattgg 74340

tttcaggacc tcccttggggt actaaaatct gcagatgcct aagcccctgt tataaaatgg 74400

cttagtattt gtatataacc tatgcacatc ctctcatata ctttcaatca ggggtcccca 74460

accccagggc catgaccagt actggtccat agcctgttag gctgttcgat accagggctgc 74520

acagcaagag ctgagctcct cctcctgtca gctcagtggt ggcattagat tgccatagga 74580

gcacgaaccc tattgtgaac tgcacatgtg agggatctag gttgtgcgct ccttatgaga 74640

atctaatgat aaatgtaatg tgcttgaatc atcccaaaac cattcccctt cccctcacca 74700

tccctgtccg tggaaacatt tcttccagaa aaccagtccc tggtgccaga aaggttgggg 74760

actgctgctt taaataatct ctagattact gataatgccc aatacaatgt aaattctatg 74820

taaaatagttt ttatactata ttgtttagag aataatgaaa agaaaaagtc tacatgttca 74880

74940

tagattggtg cagtcattat ggacaatagt acggaggttc ctaaagaaat taaaattaga 75000

attacctaag acccagcaat ccctcctctg gatgtaccca aaggaaataa aatcatcacc 75060

tcataaagatatctgcactg ctatattcat tgcagcatta

gaaaccacct aggtatgtgt tggtgcatga atggataaaa gaaactgtgg tatatgtata 75180

tacaatggaa tattattcag ccttaaaaaa ggagaagacc ctgtcatttg ccacaacatg 75240

catggacctg gaggatatta agctgtggga aataagtcca acacacatcc acacacaaaa 75300

ttgcataatc tcacttatat gtggaatcta aaaagaaaaa gttcaaatat aaagttagaa 75360

taaaacagtg gttaccggcc ggatgtggta gctcacgcct gtaatcctag ccctttggga 75420

agccgaggtg ggtgaatcac ctgaggtcag gagttcaaga ccagcctgac caacatggtg 75480

aaatcctgtt tctactaaaa gtacaaaaat tagccgggca tagtggcagg tgcctgtaat 75540

cccagctact caggcagttg agaaaggaga atcacttgaa ctcaggaggc ataggttgca 75600

gtgagccgag atggcgccac ttcactccag cctgggcaaa agagcaaaac tctgtctcaa 75660

aataaaaaaa caaaaaacac agtccacaca ctggttacca tgagtgaggt ggcagggagg 75720

agattgggag atgtagatct aaggatacaa agtagcagat atgtaggagg aactaaaaag 75780

ctgacatgca ggatgacaac tatagttagt aatagtgtat tgtattcagg atttttgcta 75840

attgagtaga ttatagctgc tcttgccaca ggggaaaaag tgggtaacta cgtgagatag 75900

acaatggatg tgttaatttt tgtcactata ataacctttt caccatatac attcatctta 75960

taacagcatg ttgtttactg taaatatata caataaaatt tatttttaaa tatctgagta 76020

tgatttgatg atttgtgaaa atagagtgaa

attagaaaag aaacagaaag aacataccac acagaaagtc tgtctgaagg atctttgttt 76140

tctccaccaa tacaagtgtt cattgattca gaggtggatt atgagatatg accataaaac 76200

aaaaatttca agggaaatat attttattca atgaaaaatt ctcaacacaa ctgttatatg 76260

ccagtaaaca ctatatcttt taaataacag gtcatatcta ttatatttaa aattcaagga 76320

gagactacat tagagatgct attagatcaa cttctaattt caaagatttc taagatatgg 76380

aacagttact ccttatacaa attaaaaaag caaatgctga agaaattcag ctacatggat 76440

acaccatgag gtggaaagat gctccataac tcttagttaa actgcactaa ttacacataa 76500

aaggaaaatg tttcatttca ctgtaatttg gaaaccaaag aaagaaaaga ctgaattttt 76560

acatactgtt aaagagattg cgtatctgtt ctaagtttaa gacagaggca aaatgtattt 76620

tattcatttg tcctgcaccg tttagaaata aaattcaact tcctttttaat tttttttaag 76680

aataaaaaac tcagtctaag gaaagtctta aagttttcat tttaagtgat ccactgttct 76740

agaagtttaa tattttgttt aaaatgttta tgttctgtat tccaccaagt ctagttttaa 76800

aacaaaacaa acaacaacaa aatacttctc taacttggag tttaaggtga aagaaaccaa 76860

ttacgtggtt tggaaatgtc acacttttca tctctttttt aaaaaaattt ttaattcagg 76920

acagaaattg tatggattta gtgtaagtct tgggatctca caagtgtcag tatttcactc 76980

tcctccatat cttgatagca ataacttgaa ataggatctc agtagctcaa gcaatactgg 77040

gctctgagag ttggttaaaa attatttggc tgagcgcctg ttgctgaggg aagaactaat 77100

ctcgagcata tttttggagc caaataccaa attgtttgtg cttagcaaca cagcaccagg 77160

cttgcccttc agaatgattc tagaccaaat gccagaaatg ctctggttct gactacagag 77220

ttctattcac aaatgacagg aggcaagagg tcctcctcac tttcagaaga aaggtccttt 77280

gctttcttag tcaatggtag gaaaaccatt gtggttttca ttgcattaca taatttttaa 77340

ggtgattact tcaataagaa gtgctctgtg tatatgtgtg tttatagacg cattttttaa 77400

acactggaga atttctgaaa gtagtacaaa ccttgtaatg tcaagtagat gtgggaaaaa 77460

gggagtttac aacattctct cctgacattg ctctcctttg gcatctgcat ttttaaaatg 77520

ttaaaaatgt ttaaaaacgt gtgcttaaca cttaatttgg tgatagttgc tgttaccaag 77580

gcaactctgt aactccaccc agataaaaat aaatcttgaa gatgagtttc tgtgtctctg 77640

agcaaatatt tttgtgaata gtagaagcag agaaagttaa agatacctga gcttttgatc 77700

tttactagtt ttatagatat gtttatagtt atacattttt attcatacat tttagataaa 77760

taactttgta aagcaattga ttcttcttgt aaaaatcaag tatattctta atagactgat 77820

aaactttctt tttttgagac agagtcttgc tctattgccc aggctggaat acagtgccat 77880

gatcttggct cactgcaacc tacctctgcc tcctgggttc aagcaattct cctgcctcag 77940

cctcttgagt agctgagatt acaggtgcat ggtaccacac cccactaatt tttgtattct 78000

tagtagagat ggggttttgc cattttggcc aggctctgag aaacttttta aggtctcttt 78060

tgcagccagc tatttgtcta ccttatttca ttcttaatct cactagccaa tattttttct 78120

78180

ctggtaatga caaaaacaca tatttcaacc taatatacaa tagaaacaga atgccagtta 78240

ttcatggagg agaagaatag acttctgtat ttaaaataac attttgctct gtgttttaaa 78300

atcattcttc cttcatcaat tgtaagcatc ttgactataa tttatacacc taaagataaa 78360

taattcagta gcaatgataa ctgaaaacag gacacataca atgaactagc taaattacca 78420

tacattctca tccatttcaa aaatagctct gtactttttt cagattttgt tagaagaata 78480

ttcaatacaa atttttattc aatgaacact tcagatgtca agattgttac ccacatggac 78540

aacagtaacc taggtaaaga ttctgcagcc aggcgtggtg gctcacacct gtaatcccag 78600

cactttggga ggctgaggcg ggcagatcat gaggtcagga gatcgagact atcctggcta 78660

acatggtgaa accccatctc tactaaaaat acaaaaaatt agccaggtgt ggtgtcatgt 78720

gcttgtagtc ccagctgctc gggaggctaa ggcaggagaa tcgcttgaac ccgggaggtg 78780

gaggttgcgg tgagccgaga ttgcaccact gcactccagc ctgggtgaca gagcgagact 78840

ctgtctcaaa aaaaaaaaaa aaaaatttta tacctgggct ctgtgctcac cagcagaagg 78900

ggtaacatgg cttcttagga caaccttact tgaccattta cttctttgac actaggggta 78960

ttcttagatc agcaggtcct tccctccact tatgcacatg aggctcacag agagtctgggg 79020

aggcagggaa tttatgattg gaaacagtat actttttatc taagaaatta ttaatgtcac 79080

tgcattcaag tgattaacac catcaatatc ttcaagacta aggggattac atgatgtgta 79140

aaattagaaa actgtcatct actagtggct aggcacttta attatattaa gcatgcaaca 79200

agagaactct tcaaatgaat ccatctctcc tctgtattat ttccaaccct tggatcccca 79260

tctgtttctg cagacaacag ctatgctgct gaatgtctta atggtttgct gccccaacta 79320

gcttcaagat actgcaggtc aagcatagca tcttactctt ccctgcatct cgcacctc 79380

tcagaatgtt ggtcacatag aagatgtttg ctgaggagtt gaataagaat atgtacaagg 79440

gacacaatta gcattgttta aaaaagatgt aacaagatag ggtaaaggaa agctttggag 79500

gataaatctt tagaacaatc aataatatct tctcctctgt tggttagttg cccttcaatc 79560

tcagccactg aatcaaatac aacataatta ctattctgat atgttcttga atcgaatatc 79620

caataataag atattcggat gcatagccat gtctaatatc aaagcccatg cttttcgcta 79680

ttattgtact ccatacatta gcttccaaat ttatttgcaa tccaaatatt aaaagcaagt 79740

cataagctta gtatcgccaa tgtgatacta agtatccact tactaaactt tattttcaaa 79800

atgtggtttt atctcagttt aatgaacacg gcatgtttta atttacactt tcatattata 79860

tagtaagggc gtggttacag atatgttaat ttcctgtgct gcttcacaat gatggaacat 79920

aatagcaaat gaaactgtta atttgcagat acccataggc ctttggtgtc tgaatagaaa 79980

taaacacacc tacaactgag agaggaagca tgtgaagcat tccagtgaac agaggccatt 80040

tattcagtca cagacacagg agaaaaacaa caattaaaaa aaaatctctg atgaaaagtt 80100

cataaaaagt tcactcagtt taagcatatg tcctataact acttaaaata gagttcttct 80160

taaatatcat tctttgctgt ttttagattt cttctgcctg tatcaaatta atagaacaca 80220

gcatactttt aatttgctct ggtttcttag tggggcattt attaaacaca ttaaaacaat 80280

agtctcaggg ttttactgct gatgttaaag ttctgctttc ctacttacca actgtgtcat 80340

cttaaggcac atactttgcc tctctctcaa atctcccaaa tggagaatga taagaatacg 80400

tacctcaatt aaagaagcta taacaagtag aatgtttgga aaagtgccgg gtacaccata 80460

agccactat gagtattgga ttgtattacc tctgaaagct gcagaatgga attctcaaag 80520

ttatatgtcc ctaaaatcct cttaagtgac agaaatggag aaattagcag tctgtctaag 80580

agagcttttc tagagtctgg gcatatgttt ttaggacaag acagttcagc ttcagcttaa 80640

aatgagagag cacgtctgtg tccttactcc tgggtgccag gtttcttgtc cccatcttaa 80700

gacaaataat tttggtggag aagaggcagt ctctttgatt tcgctctaaa aaccttttct 80760

ggaggaggta gacactctcc acccccgttt tgagactcat gcagctgagg atgactggct 80820

gagtacaagc aattgttcct tctaagcagt ttcaattctt ataacttgtg gagatattct 80880

taagtccagg ggattttgtg tatggtggat ttttattaca aagtcctgta cttcatagga 80940

acaaaataat tcaaagtcag gaaccagatc aaagccacaa ctcagatatg gcaccttgag 81000

aagttcattt gtatttcact tgcataaaaa ccctcaccac tgctatctga ttttcacaaa 81060

tcattcaaca gctatccatg aagcacccac tgtgtgtctg gtctctgtgt cagtccctgg 81120

cttcatgtgt ctttccttct gtaccctgac tccccaactc atgaacacat gaagtaaaaa 81180

aatgaaaatc ttttttctgac ctctcttcaa aatcactttt ttcaaaacaa acacctctca 81240

cctgctcatc ctccagccag taaatcacag gggcctagaa atgtcactta caaatatttt 81300

ctgattctgt ccctcccttc aagcttgcca acattatcac agtttagggc ctgctcatct 81360

ttcccccaat ctccaattag atctctccac aatgcaattc tgcacattcc ctgttacaac 81420

ccttcaatta tttcccagcc catccaaaat aaaatctaag

gaactctgtg gcctacggtt ttctacagac taattttcca gcagttgact tccagtgcaa 81540

gtgaaaacct agtgtcatgc ctgcatgata gtaaatttg aagctgaaga gcccaaatgt 81600

atagaccatg ccatgaaagg tttatagtca tgacacagtg gccctatagt acagtgcttg 81660

aagctggctc tctactgtca gacagaccac ttgccagcca tgagacctgg ggcaaaatgc 81720

cttaattttt atgtgcctca agttctcatg tgagatgaga ataaaaatta cccctatttc 81780

ataagatttg ataaagtgtt tagcataata cctcataaca attgcaattc agtggtggtt 81840

attaattataa agaaaagatg attaacttta tcttaatgtt taacttgttc tgatagttat 81900

tgatctatag ctttgatatg gaggtttgag aatgacctgg aaagaattgg ccacaatgat 81960

taaaagatga ctgcaaaatg taaacctgca ataacagaaa 82020

gaatgaagtc actggtctca tgggaactga tatgggagaa aaaaacagat caaaaggcta 82080

ttcatgtttt gggcctcttt gtcaaaatgg aaatgagaaa ctggggaata aaaattaaag 82140

caattctagc atctggtttt aacataattc ttatccctaa aaagaatcta taagaaactc 82200

ccaaaatgac aggcagccgt gggtagcatt gcatttcaag taatctttta attgttaaaa 82260

tttaagtttc caacatgaac ataaaatttt caacctaaaa gaaatgagtt ccaaatctga 82320

gacaagtgaa aaaggataaa gcctactagg gggtaaattc catctcttta gagatctagt 82380

acccaattta gcaatgtcca atcaagcctt taactactac atttgaacac ctcatcattt 82440

caaaatgtta cttaatgatg ccaattaact gtacaatgtc tctgcatagc acatagccct 82500

aaaatgatt gtgcaatgtt actgtcagta aaactgaact acagggaatg ctcatattct 82560

atgtcattat atacagaaat gcaatatcaa taaagtgata tctgttggta ttagaaaaaa 82620

gtgaaaattt tcatatcttt ctattttctt ttttcctcaa tgggatgctc ttgttaaaga 82680

tagctctgca tagtaaggtt tgtataaaaca ttatttagct aaagttaaaa ggggtaacat 82740

actggttcta gcacagatat taaaacaaat tagtttgtag gtagggcagc aatcaattat 82800

attactaacc atagctttgg tccttttatc ctttcccatt tgattttaca cagtgggatg 82860

ttaaaggttg aatgtctttg gtatctataa acttaattga aagctgttat ttgtttgttt 82920

aagtctgttg atttttataa tcataatttt actcctatag atttcttgta ggagtactat 82980

83040

gaaagctact attgatctgt catttcttaa aaaattacta aaaagtgtta aaactttaaa 83100

tgttggagag tttatatttt aaaagttaca tgctagaaaa acatgatgtc tgagtatatt 83160

agaagttata gataattcat ctgtcaacta taaaactctc caacactgcc tttctttaat 83220

gaataatatg aaatttagca gtgaaaatgt gacaatgtac aatcctaaat aaatcaacaa 83280

atttagagat gtacctctaa aaccattgta aattcaacag tgtaattttc cattggactt 83340

tcacttattc attcattaaa caaatgtttg tgagtgcctg caatgtatga gacattgtac 83400

tgaagctagg cagtgtgagt tatcatatgg gattatcctt taaatacttc tgagggcaaa 83460

83520

ataacacttg aggactgttt tctttgcaag gcataaagtt atcacccttt caaacagtag 83580

atatttcaca tttaggatgc gagactccag ttccaacaaa gctcattgca cagctgctac 83640

cctgattaaa ctgctacatg aactctgagc aatgtagcat ggtagccgca tgcttctgct 83700

tgcatgatgg ttaattcctt ccattctcat tagtgatttt ctgagctttg aaattctgat 83760

ggtacctagg atataaagca tatttatcta actgaaaaac agataattag atgtaacata 83820

aaatatgaat ggctttgtca ctttattgta gcagagaatg aatgtgggat aaattaaagc 83880

tgatgctaga acatatgcct attttttagc tggaaaattt caagatttat gtactttggg 83940

cttgagaaag aaatggagtt tattttttat gcactgacat ctcttttttt ttttttttgg 84000

aagagctctc ttaggaatga atggtatgta aatacagtag gaatgtaatt atagattttc 84060

ctgacccagt tcctaaataa tagatatcat ttcagaagtg ccccaatacc tgaccttttg 84120

ctccaagcca tatcaaagca cacatctagt ctacttttca ctctcattcc tagccactat 84180

gacaatacta ttcagataaa acttctagtc ctctacttat gtgactcata ccaacttgac 84240

cttacgatag tgactggggg tgcatatcta ggttcatgct gtttgtccat tattatggtt 84300

ttgtgagaaa aggcaaaatt tctaggtaaa gtgttatgag gacgaataat ccaccaggca 84360

accaactgac cctttcattt gccatcttgt cacttcaaac agctctccag aacctgcagc 84420

cagcacagac caaagtcagg tttgtctcct cttctgttga tgaacaaagg ttgattccat 84480

atcgtggcta ttgtgaatag tggcagtaaa catggcagta ttgtatgaaa atatcacaga 84540

tagcccttaa atatgtgcaa ctatgatgat ctatcaaaat taaaaattaa aatttatttt 84600

taaaagttca gttagaaagc ttgtagttcc tggcaaacta ctacctttct cggcaaaaga 84660

atttgatatc tcttaaatat tttctgccta atgctgatag attgtattta catattccat 84720

taatgcaata aataaaatta caccaaaaca tcagcattat ttatttccag gggcatctct 84780

caaaataaat tcctccaaaa ttcacaaaac caaaaccaat gtgaaattgt actcagggat 84840

gcaaatgtag cccagtgaag catttgccca cttgtttggt attattgaag cacaattaga 84900

aaaatgtgca atgtatgccc aaaaattcta taataagggc caggcgcggt ggctcacacc 84960

tgtaatctca gcattttggg aggccaaggt gggcaaatca tgaggtcagg agatcgagac 85020

catcctagct aacaccatga aacccagtct ttactaaaaa tacaaaaaat tggcccagac 85080

gtggtggcgg gatcctgtag tcccagctac tcgggaggct gaggcaggag aatggcatga 85140

acccaggagg cagagtttgc actgagccta ctctccagcc tgaacgacag agcgagaccc 85200

catctcaaaa aaaaaaacca taataagaac tttttaatat actatattat aatgtaaaaa 85260

gactagatgt caaacaaatt aggtgatggg aaggaattga gggagaattt tagactaagc 85320

aattgagcag cacctgtttt tcaccacaaa tctgttacat gtattgctca attgtgctga 85380

atccatattg ggtcctggtg gctatgtaat agtctctttc ttggataaat gtttgtcctc 85440

tcttatggtt tactaatggt gtacagaaca gcattgaata gtggttattt cctatgactt 85500

cctagatatc tctctcataa tcctgaatgt tttaaagatc attcttagat agagtacagc 85560

tagacacgaa ccatagtgga aatcaggtag acaaaattta aaaggagtct taattgaagg 85620

tcattttatt gtcctcagta ttaatcttac ttaaaacaaa cctgtcactg agcagaactc 85680

aaaacaccag agccctttgc caaatgtgat tttttacaac aggagcgctg gcagttgaga 85740

ggagtattct gtcacacttg agagaattcg agtccctgaa gatttatatg aatgcttagc 85800

tattatcgaa ccatctcttc acagatgact tagtaaatgt ctgcctttgc atcagataat 85860

ggcttacaag ttaatctcct cttgctccct gttacacaca tatacacctt cttcctaaac 85920

agctcataag gtgaaagaaa gactcagatt tctgactatg taattgataa tatcacacgg 85980

actgcctgct catcatctgc tagtcacatt ggcagagttg acagttttgg agacactgaa 86040

gacagtgcat atattaggaa ataagcagtt tcctgatata aattttcttg tagtttataa 86100

attacatagc atttattatt ccctcatatt ttataacatt taataataga actgacacat 86160

atattcattt taaactcaat tgtgtataat aactatcata gcaacccttc agtgcctaaa 86220

tatcaaatct tccattcctc ccatgaacat cttgaatata taggtactgt ggttagctcc 86280

aacaagcttt tggttagaat tcattgcact gatacataga cattgtttta aaggcaattt 86340

caaatcaaag ctgtcagctg tgaatcaagc acaccttaaa aagtgacaca tttgtcacta 86400

gattccagcc tctcaaatta ctgacacgca tcctttttat gtaaagatga cattgttctt 86460

tcctgatata ttgcattcct catgaatttc ttatagtcat agaattttta taaaccattt 86520

cagaatcgct gaaataaaca tcaatatttt taactttttc attctgtcaa aaatattgta 86580

tgcagagata ttgctgtaag tgtgtatacc tgtgcttaag agactagggc tgaagagaag 86640

taatcaaccg aaccactggt gtaaatgtgc gtcacatttt tagtgactag aaattgaaat 86700

aattccaaca aatttatgtg ctttgggctt gagaattcag actgccttag gctaagataa 86760

aaatcttttc ctggtactat ataccttctt ttattgaatg actacctggc tctttctatt 86820

atatatgcag attttgtacc tctggtcatc tttgtaaatg gtgcctaaaa gatatttgaa 86880

gaataagtga ccagcaataa gaacaaatgt ctatacaaaa gcacccttta gttggatgta 86940

attcactact ttgagttgtt aataacctct aaggatgaca gtagctatta gttgaataaa 87000

ccattatgtc tattattaga acactagata gtttataagt ccaaacaatg cataaaatac 87060

ctatctcatg ttaccattgt ttaggttacc agataattgt tctgtccaat tattccactt 87120

aattttttgc ttgcccatta gctaaatggc aagataaaat ttgtcaaacg ggggggaatg 87180

tattgaaaat gctagacaac tacacttaaa atgaaaacag gccaggcgcg gtggctcagg 87240

cctgtaatcc cagcactttg ggaggccaag gcgggtggat cacctgaggt cgggagttca 87300

agaccagctt gaccaacatg gagaaactcc atctctacta aaaatacaaa attagccggg 87360

catggtggca catacctgta atcccaacta ctggggaggc tgaggcagaa gaatcgtttg 87420

aacccaggag gcggtggttg cagtgagccg agattgtgcc actgtattct agcctaggca 87480

acatgagcga aactccatct caaaaaaaaa aaaaaaaaga aagaaaagaa aacaaatgca 87540

taatttgcaa atattatttt tatattgtat gttatctagg gcttctaaat gcattcttct 87600

tataagccta ggtttgcaat aacattcatt tagaattgag taattttaaa tataatattt 87660

tataaaataa aatataataa ttctctcttaa ttctttgaaa atattaaatt aaaagggggt 87720

tgcaaactct gcattccaca tttccatccc aacatttaat tttagcaatt ttgtagtctg 87780

cctaaaatgc aatccatcat ttactgttta gaaaataggg aatgtacaca aaggcctttc 87840

agctttccct gaactccata aaaatctttt tgcttcttta ctgcccccct ttgtcaggag 87900

ttctgaggaa ctgtttttta tcttaagtct cacaaagcat ttaggagaat atttaaactt 87960

88020

atttaaattt tgaaattttt aatactggca aaatgaggtt tcaattttaa tataaattat 88080

aaacagtcac 88140

aattttccca tactaataat cataaaaaat cttacccaat ggtcatatag atatacttaa 88200

tggagttttg ggggggtatt tttgtatatt aaaaaattca tatatttgcc ttacttagaa 88260

88320

tgataattatatttgaaacg ttcaagattt tccaatgaat ttcttttgca tttgcgtatt 88380

tgtgcctttt tattataaaa ataggtggct ttttagttcc actgcataag tttcaacata 88440

ggtctacaaa tagtgcatct ttttgaagtt aatcattata atcacaaatt gaagttgcct 88500

gagctccaat tggagtctaa atggatgact gaatcttatt attcgaaacc cactgttgct 88560

acacaatatg gccacacaag agagtacaca agacccgtct gattcagcct cagtgccata 88620

aatattttaa tggtttcgtt ggaatctgga aatggagctc accacaggag atgcttcttc 88680

ctttgactct cattattatt tcctttacaa attaattaat aaaaacttag atgctaaatt 88740

agcacttgat gaaaacttat atagccttga cattttgatt ctgtgagtga ataaaaatac 88800

ttggagaaat aaaaatccta atcatgttca ggaataccca caaggtaaca agtacatttt 88860

taaactttaa aaacatttat tattcatgat aaaacatgtt gtgtgattta aatataaatt 88920

tttattattt gctttaactt atttccggat taaaaagtaa atgtttacct agctgttcta 88980

aatggtaatc ctcatgatta aaacagcaat ttgtcatatt tcagttacaa atgatctttt 89040

attattagtt atagaacata agtttcttca ttgactgagg cgatgtttca agtagataaa 89100

tctgttaaaa aaattgtggt catattctgt taaattctca taccaggcaa tttgtttgat 89160

attcaggaaa aacctagcca ctgaccaaaa actctacctg ccttctcagt tgtatcctct 89220

tggacttaaa ggggactgggg aaagttataa gatggttcat gatagtccat caacatccca 89280

agaacaaaaa cagatgttgt actgacagca tcatatgatc atatgcatgt aagagcacat 89340

tcatattgcc aaatcagttg gaatttttca cggttgaaag ttaaatgaaa tgcttagatg 89400

tatgagtcat cggagttaaa gacaattaca gccagattta tggctgtgct aaaataaagc 89460

tagttagaaa acagaccaaa ttccatgacg ataccaagtc tgactaatga ttcaccttaa 89520

atttcggagc aacatttatc ctcacttgtt tgtttatttg acaatgtgcc cttatccatt 89580

aagtaactag gaggaaggga aaagcactac gtgggtgagt gacaagacac tgacactgat 89640

ttgtgacttt ggataattcc tggatgctgt tatctgtttt ggcatagaga tggatctgta 89700

actgctaata attgccgact gtgaccatcc cagaggccat ttacttaacc caggtattc 89760

agacctgaca gcccgaggat aaacacgatt tccctccatc actaacttca tctgcaggggc 89820

ctaagcctcc ttcacagtct ctccagtgat ttattggcat ctccaagggt atctcacatg 89880

tgctgaagaa caaatctgct cactttcatc tgcttggttt tcccttttga aatctgctgc 89940

tttaaaatta ctaagggagg aatcatgcct gctgctaccc ttgccagtga ccttgcagtt 90000

tgtgccctga ttgttccaat taccacaatc aaaacagaag cgtttgcagt tactgcagtg 90060

ctctctctgt ggatgtcagg tctgactcag agagccaggc tggggaacag ccatttccac 90120

tcttgtacct ctgcaaaagg acttccatgt tccgtaaaca gactcccacc tctcattttc 90180

cccccaagca aagcatcata aattagagag catgtaacgg gaaagaaaat ccattagcca 90240

tttgggttca gtcagacaag ccagctcatg gaaagtttat acaggaaggt cacatttcaa 90300

ttgagatcag gagggtgaaa gggtccagct gtgtgatgag agagagaatg ttcgggaatg 90360

tggaacagag gtatccaagg cagaacaaac tcgtatatga aggctttaag ggtgtgcaaa 90420

tctagcatat tttatgacat aaaagagtcc tgattagcta gaatatgatg aatgtgagaa 90480

gaggtgaagg ctggagatag gaaaaattat tccagatctt ataagctata gtaagaaatt 90540

tgcatattat atatagactt gtgggaagcc attggatttt gtaagaagga gattaacatt 90600

atcttattta tgttatttgt gatttataac cccaaatgtg ccagatacaa acaaaccaaa 90660

aataataata ataataataa gaagaagaac aacaacagca atggaactgt ggtgatggtt 90720

ttggtcacaa aatgcatata tatctatttt tcacaatgca aaaatatttc attatttcaa 90780

attttaacat aaatgtgggt atgcatgagc ttacaaatct tgaagtttat tggggaatat 90840

tggtgagcat ggtttttatt gcatggtcac aacttactaa tgggaaacat ctgaatacct 90900

attgagttaa tgcatgcaca tttttatttt cctggaatac tgagaaaaag gttgctacat 90960

aatgtcttga tagcttctaa gtcatggctc aaaagtgaat gtggaatctg ctaatcggaa 91020

tggactcaga ttcagccaag ttctcaaaaa catttgcttt catagatgtc ttcaagaaac 91080

aaggagtctt gaatttaaat tgtgaagtgt ctatcttaga atagagagat ttaaaatctg 91140

actgtatttt gtttaaaaaa gcctatataa ctgtattata taaaattatt tatactacag 91200

ttaaaaaaag aatcccatcc tatttgtgcc taaataagtg cctgcttgta gcatgaaaac 91260

tatttgttga gggtccttag atcctcagag catgctgtga aagtaggtac aattgttctt 91320

tctatataag cctcttaaga taacagataa ttgccagaaa tacagcacac agtacaaaat 91380

taccttgttt tacttttgcc acaaaaaaca atttcttttg gctttgagca ataaagtcca 91440

atgatttttt tcctttcaaa atatcttcct ccctctccat aagttttata tttattcacg 91500

aaggaatatt ccaatatcgg atgtttttgt ctgtgtctct tcctggaaca aatgttaatt 91560

aatctctttg ggtttgtatg tcaagtggag gggtggggat tggggacagg tgatagttgt 91620

ctagggagtt aacttcatct ctataggaga gtggatagac gctgtatacg aaaagctctt 91680

gaaaagggaa atacagcagc cacttcctca gggcttccat ggtggtcaga ctccttgatt 91740

gctttagatt aactctggct tttgtccttc ggaggccacc agattggggtg gatagagacatt 91800

gtccttgctg ttcttttgac ctacctactt gtactttagg ggaaaaaaat gcctgtaata 91860

ggttaaatgc tttctcaaag atcaccaaag tatataacac atggcaaata gacagagaaa 91920

tgagacagta taatcagtat aatttataaa agtaccttac agcaggatcc catgggatat 91980

gggttttttt taaaaaaaat ctacctaatc ttttcattga actcctattc aggattcatt 92040

atattgaata tggctcagag acctggaaaa ttgtttccac ctttttaatt tattcaccat 92100

catttatgga agttttcaag gacgtttact tacctacctc agttaacaga ttgtactact 92160

tgggaagtct ataaatatga gcttaaagca ttttctgagt tttaaaataa tttagattgt 92220

gtagaatgtt aaaactaaaa gaggaaaaaa ttattcagtt cctcagttga acctagcaat 92280

ttatcttttc acagtgtgct caagtatagt ttttgaaaag taaagaagat ggtttttata 92340

caaacataaa cacatttcaa agattttatt caactaatta attagtagtg gagccaataa 92400

gctggtaaga ctggtttaaa ggaatatctg aggaataaag atttatagaa acagtcaaag 92460

aaattctaaa gagaattgac taatagatat aaatctagta aatatttgat taataatagc 92520

agtaacctat ggaattatgt tttctactga gcataaatga gcatgaatct ctttgggttt 92580

gtatgtcaag tggaagggtg gggattgggg acaagtgata gttgtcaagg gagttaactt 92640

catctctata ggagagtgga tagatgctgt ataagaaaag ctcttgaaaa gggaaataaa 92700

gcagccactg cacatctgca catataacct gtagatctgg gggctctaat aaaaaagtta 92760

atggcaatgt caaaatctgg tgttttatct tagataactt catagtcatt gattgagccc 92820

cttaaaaata acatttaaag gacatgtagt cattctgttt ctttattgcc aagttttcag 92880

caatttttct catgagaatg agtgctaaga aacttttggt ggagcgtggt ggctcaagcc 92940

tgcagtcttg cactttggga cgccaaggct ggccaattac ttgagatcag tagtttgaga 93000

ccaccctggc caacatggtg aaaccttgtc tctactaaaa atacaaaaaa aaaaaaaagt 93060

gggatgtggt ggcatgcgcc tgtaatcctg gctactctgg aggctgaggc acgagagtca 93120

cttgaacccg ggaggcagag gttgcagtga gccgagatcc tgccactgca ctccagcctg 93180

ggctacagag ggagactcca tctcaaacaa acaaacaaac aaaaaagaaa cttttaaaat 93240

ataacaatag agacattaca taggcccaca aaaccacctc caaaaaagca ttctatcacc 93300

tgcaagaaag catatatata tatctgcttt tgtgtatata tatatatata tatatatctg 93360

93420

ttacacatat attttgtgca tgtatatttt taactaaaaa tgtgctagga gttagatatg 93480

aactgatttt ggaggaggtg atatgctgta gagagagaga atgggagaat agcagtatta 93540

taatctctct ccattgtatt cagttttttt ctttgtctga atttttaata gaagtcagcc 93600

agaagatgtt agtttctggg aaatgtgttg agatttacag tcaaatccag agagaactag 93660

aggcttatga gtaaataagt aaaggttatg cagagaaagt attctttttc ctgtgtaaac 93720

ttgaatattg gccaggcgcg gtggacacct gtaatccagc actttgggag gccaaggcgg 93780

gtggatcgac tgaggtcagg agttcatgac cagcctgtcc aacatggtga aacccattct 93840

ctaccaaaaa tacaaaaatt agtgggtgtg gtggcaggat cctgtaatcc cagctactac 93900

ggaggctgag gcaggagaat tgctttaacc taggaggcgg aggttgcagt gagctgagac 93960

agcgccattg cactatagct acggcgataa gagtgagact tcatctaaaa aaaaaaaaga 94020

aaagaaaacc ttgaatattt cttgtacttg tgttcaaatc atacagttat gaaagtttac 94080

ccctagctgt tacacttaaa atgtacttct gaaatataca gagagatgat acagactatt 94140

aatgagttcc actaaacttt taatggttta gaaaatacaa atattttctt atttttctgg 94200

aattccagcc attaatgtaa aacattggtt tcaacataaa taacacactg gcatgcacat 94260

atgcctaagc atgggccccc acacatacag acattctgaa agaccacttt ttaaaaatat 94320

tcagtaccgt atattgtgca ttccttcttt atccacatac ttaagctgct gcaagcatcc 94380

cattgataac accagtaata aaagatggga ccatcagtaa tgagatttga aagccccttt 94440

tgcaagaaag taaggactag aaggtggaaa tcactctgtc ttagagtcat atggattggg 94500

gctttgctag aagtgtgtgc tctcagggaa agctgccttt ttatttttctc cagagaaaag 94560

cctttttgtc agtaaaagaa gatgtatcat ccaatgcata tgtaaaattc taaacagcag 94620

ataaaacaac attcactatt aatctctgca aaagaagata tattgaaaaa atcctcaagt 94680

gtccctcttt gggtttcttt gttatatatt aaagcagtta tctttagatg catgagaatc 94740

acctgaagac cttattttta aaattcagat tcctgtcagt tcactcccaa agattccgat 94800

tcagtagtta agagacaaag cctaggaatg tgaatttaca atcaacacct caggtgatag 94860

ccatgcatgt tcttaatgct ctactactat ctatgcataa aaggaagata aagttttaaa 94920

aacttgaaat gtggtataac agtttagtat tgaataatat acatttttac ttattgtaac 94980

aaattatgat atctacttgg ggcaacagta tcttttttt tggatctgaa tcctaatttt 95040

ggctaggtat cactgaggga ttcttagtct aaaacaatta aatggagtta gtggtttttt 95100

ttagtaactc ttgattttct gtttttttcc attggcatct tacaaaattt attcattcat 95160

ttttcccttt ttcacttggc attatttgtt agacagtgga caaaagaact atagaaagta 95220

gagaagcatg tgatgttgtc ctgctcttag attctcgcaa ctcaggagag gacattcgct 95280

tacaccaatc atctcaaaac atggcagttt atgctgaact cagtccaatgggagagcatt 95340

tgactgagca catagggaga gaagttagct ctgttgaagg ataatcaacg aagaattctt 95400

aggaaaggta cagtcattca ttgaatattt gctcggcact tactaggtgc atatgtgcac 95460

taagatctaa ggatgggctg atgaagaacc caggtccctt ttcttctagt ggacatgcag 95520

actggcctaa aaaaaaaaag gtaactggaa aatggataag gaaactgagt cactcggttt 95580

atttattatc actcggttta tttgcttttg tttgtatttt cattttgaca cagcacagtg 95640

tcatcttaac gcatcctcca aagtgaagga tggggtggat aacactttag ttggcatttc 95700

tgtagccagg agccaggatc tttctcccat aattgcatta acctgggaag gcaccctcta 95760

ggtagatttg tatagcaccc tggttaatca attatcagtt tacttcttgt ctcactaagc 95820

tttaacacct tacatttatg aagcagtgta aatataactt tagcatcttg atcacagcaa 95880

gcacctgatt tgtatttttt tattagctca agtgaaatca gatcagagaa gtacattaca 95940

ggtcataaaa tatgtgcaaa tttcataatg acctcctttt aaaatgtgca aaaataagat 96000

tgttaaggca cattccagag ccttgggggg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 96060

cgtgtgtgtg tgtgcttgtc ttttgagaat atctgtatat cagaaaattt ggctgagaag 96120

caatcttctt cttagtggtt ctttttctct tttgaaaata aagtactaaa aatacttaaa 96180

gatgcagaac agcaacctgt tcccagtgag actctcgttt aattaatgtg gtgatctata 96240

tagagaaaag ggacaattgc aaaagtccct caataattat ctaaccacag tctttaggta 96300

attacagcag aaagattttc aagacacaaa acaccctgga aaatttgacc tcttattttg 96360

attcaggcct ttcatttctt aaatattttc tttaatgttg atgtttatgc ttgacaaggt 96420

cagcctaatg ccagatgaat ccctggaact caaaacattg ctgaattcac agttgaagga 96480

ttttaatata atataccagc ttttaaaaat cctacagtga gaataacagg actgaataaa 96540

aaaattaaga aatgctcagg tagaaataaa tagagaaatt tagaaaaaaa ataaaacgta 96600

ttcaaaataa gtattaagca ttggcaaaga aaaaatagta gcagacaatt acatgttcca 96660

tttgtaaaga tgattattaa ttagtggtct tgcaaaacat tggagaaaat ttgctgaacc 96720

atcacattca taaatattaa aaccacccat tagtgaaaat ctttttacta aacttcacaa 96780

ctgatagtca aataatgttc agtttttctc cattgcaata aaaaataaag gcttttgcct 96840

tcagatcagt ctctgggcct tattaattca gtcagccaga agccacatgg aaatattttg 96900

ttttgttaaa agccagcttg ccctcatgat cttttaaaat cttttaaaaa tcttccatca 96960

gccctctccc tgacttgaat tatggcagtg ctttctaaac tggtaaactc aatctccttg 97020

gtgtgcctca agatagagta cataaaccct ccttagaaat tgagctctca attctaaatt 97080

gcactctcca tgagagcaag caagaatgct ttgctttgta ttaagtggtc acaatattaa 97140

atataaccat agacagcact gtattttcta aacaccttat tttcttttaa tgactgacat 97200

aaattagatc ataagtatac aaatgcatat ctgttgtatt tttcagcacc atgtgttttt 97260

ttttcttttt tctgagttat tttcctgctt tcggcagcct ttttctctcag gtgccttgtg 97320

atccacagtg gtgtgtgttc acactaacca aagcaatagt cttacctgcc agaaatagct 97380

gtgacattta aagagaggtc caggggaagg cacagtgctt aacatccaag tctgaagagc 97440

taatagtgaa attggggcat cagctacaga gagatttagg ggaagtaaca ggcaggttaa 97500

atattttatg gaaatgattt ctgttctgta tatgattgca attaacacat gtcaatctgt 97560

ttcattaatt tgttaactca tctattatgc tatgccatga agaaaataaa attggagttc 97620

tttatttttt tgagatggag tctcactctc ttgcccaggc tggagtgcag tggcaggatc 97680

tcagctcact gcaatctcca ccacccaggt tcaagcgatt cttctgcctc agccacctga 97740

gtaactggga ctacaggtgc gtgcaaccat gcctggctaa tttttgtatt tttagtagag 97800

atggggtttc accatgtggg ccaggctggt cccaaactcc tgacctcaag tgatccgcct 97860

gtcttggcct cccaaggtgc tgggattaca ggcgtgagcc accgcgcccc gccacaaaac 97920

tgaagttcta agcttcagtt tagatgctca ctaaatgctt gttttgcaat acctgactgt 97980

aactggcagg aatatgtttt gaaagtcctc attttccagg tatgcagatg aaatataggg 98040

gcattatcta ctatgtcaaa ttataatgat ttatcagtgg cacatgaaag tcgcctcaca 98100

tttcttaatc agtgatatac cattatgtca tgccaccttt taatgtaata tgtttacatc 98160

tttctttaga tgtaagcatt catttagttc atcacggtgg ctttcacact tactccaaga 98220

acgctatgag ttcctttgat gtgctcaagt ctcctgcccc agggagaaag ggagtggtga 98280

98340

tttttttaac ttaatgagta tgcagtgacg gtggtgatga tgatgatact aaggtttaaa 98400

tgattagata gtcaaatctg ggctggaatt gtaatactgt tttgactttt aatcttagag 98460

aagctccagt ctgcttattt tctgggcata aacacatgag aacaataaca cagttctgtt 98520

atctgaatgt tgttatattt tgtttgaaac attcagtgac tttcaaatat tgtatttgcc 98580

taagaaaatt caacagagtc agacattctc ttccaggtta aatttggtga gtctgctagg 98640

aaaataaatt ttgtgcactg gtcattctga tctagtggac gttctaataa aagcaccttt 98700

gtgctgccta cgtcttcact ttaaagataa gatacctggg tactcgacac caaattatag 98760

tttgagatct caaaaatggg atagggaaac cacagctcaa aaacaaaaat actagcactg 98820

gaaaagatag aactagtgaa gatgaatcat tctctagact ttaaattcag agatatcaaa 98880

attaagaaaa agtaggagga ataaaaaaag agggtaagca aaacaatata agtttgtata 98940

gcaagagggt ataaagcaaa tacaatattt ttcagaaaaa ttaaataaaa atagattac 99000

ataacattgt ttttaatctc aaagatcaaa tttcaatttt catctcattt taaaacccat 99060

atgcacagtc tcctttatat acatcagttg ggtgtcaaag tgacttttt cttgtttcca 99120

99180

cacacacata tgttattata tgtgtgcttt agacttggtt tttagttaat gtaacatgac 99240

agggccacct gagttatttg tttacaaact agctggaaag ccaccctgga ggagaaacct 99300

ggcaacaaaa tggtctgcag ctttgttatt gttatctata ggattggatg ccattattgc 99360

tgtaaaatag ttcacaagaa ctcagtctat gggaaagact caaaaattct ttgcctgtta 99420

aagaaaaatc aggatattgg actggttagt ttaactaaaa agtgatgata ctcagattct 99480

gcttggattc actgcttctc agcagttgtt ttgtttcttt ctaattgata ttttattttt 99540

cagagaaccc attataaaac tcttcttctt cccttaaaat cacaaccaca caacagcaat 99600

taaaacatgc tttgacgtaa gactgatatg gttttaaacc cagcttgact atcgaatttt 99660

ttactttagg caaaacacct ctgacattta tgtcttatcg tcagtaaaaa ggggtgatta 99720

acagttttac aagattattc aataaataaa tataaattcc tccttttcct tcctttcctt 99780

tcttcatctt cagcatctgc atgccataag ctcattttag ttctctggac tcatgttaac 99840

atgtcccacc tttcccaaat taaacatcat ctctgttatt ggctccattc ttttcctctc 99900

atttgagaca attctttatc aaccaacacc ctctctgctc tgtattgtga aactctgctc 99960

100020

agcaaaaaat ctactcaaat ccccaattgt taccctcaaa attaattgtc ccacccctag 100080

ctttctcatt gcacaactct ttgtcaaaat gttttctacc atcacagcct tcaatgatct 100140

ttctggttcc tttatctcct gaagtctgac ttctacctcc atctttttct ggactattca 100200

acacactttg agaaaaaaaca tacttttgtt aaacaggtat gcatccctga agcataaaat 100260

acatagtact gaaagtgcac atgtgtggtt cttcccattt tttttacagc acttgaaact 100320

gacaagtagt agtaccaatt acttagtaaa agacctttttt catttcattt ctgaaatatt 100380

gttattttcc tttttcatct tccatctctg actacacctc caattttacc tctttgctgc 100440

cttccttcct aagaaagttc ttcatgcaat gccatcttgt ttttcttcac ttgcctcttt 100500

ttctcacttt aattttatga actctgatga cttacctctg tagtgtaact actcaaaata 100560

100620

cagactcaac ctacctaaaa aatggcttat ctgccctaaa atctactttg ttcttttttt 100680

ctctactgct aataattatc ttcctagttg gtcaagctca aaacctaatc atttttactc 100740

cttgtccctg tgtcagctgt ccacattcaa gcagcgtatc atttctgcac atttttcaag 100800

caagtcagta actgcctttt gtttgggact gtcttttcat atagtgaaca gccttggaag 100860

100920

tagtgcctct ttctaaagca aagggacatc tttactggcc attataaaat atccatgttt 100980

cctgagctct gcgttcctct tttctaatgc aacccactga gcatgtaggt gtcacctgag 101040

cttttctgtg ggaattgcgg cttgaggaat cagtgcaaga aaatcatgat actcttgcta 101100

atgctattaa tgtgagtagt aaagttaatt gtctctgacc cagcactatt gtgtctttgc 101160

ccagcactca aaagactggc aggcttgcaa gtaggacaaa atgttagatt tttcacagtt 101220

acttgtagtt tgcacctata 101280

attttgtagc atttgcttct tatctatgtc actaggatgt gcttagtgac agacccatct 101340

atcatctatt actcaagttt ttggctgtat tcctaggcaa cagagagaag gggaacaaac 101400

aagaggacct gtgcacagtt tgagaaaggc aaaacaccga gcttaattgc agacttgaat 101460

gtagctagca aacgaagtaa ggcaaaaggt tcctttttttt tttttttaga tggagtctca 101520

ctctgtcgcc agtctggagt gcagtggtgc tgtctcggct cactgcaacc tccgcctcct 101580

gggttccagc gattcttctg cctcagcctc ccgagtagct gggactacag gcatgtgcca 101640

101700

tggtctcaat ctcttgacct tgtgatccgc ccattcggcc tcccaaagtg ctgagattat 101760

aggtgtgagc ctccgttccc ggccaaaagt ttccattttt taaatagttg ggtttttagt 101820

ttcgattctt tccaaaaaaa ggttttctta aaaaaataaa attagcaata agatgaaata 101880

101940

tttcaaaagt gcttaaaata atctagcaca tagtagatgc tcagtaaata tttgatatta 102000

tgactgtgca tgggtcatta taggctactt tatgtatatc atttcattta gtacaacatc 102060

actctgaaaa atgttttatt gttaccgttt ttcagttgaa acatttacgt tgctcaagat 102120

ctcactggta ccatctacta ttaggtcagt ctgccaccaa atctcatgct cttaaatgcc 102180

ctttttctcc tgagcttcca acaaatagtg tactgtatat aattgttgaa gggaggggac 102240

tgtgagacaa aatatttaga gtgaatgtgt agccacaatt tcagttcctc aacaaagtga 102300

taaaattagg aatcatcctc aatatatatt cttccaacac acacacacac atacacacac 102360

acacacacac aaataccaca agcccacttg aatgcacccc acctacacat tgcaaccata 102420

gagacaattg cagcattaaa tacagaatat tctgtgtgtt gtttgtttgt tctccctttg 102480

ctacaaaaat cagaatttct actcaataaa cagcaaaggg agatacaaat gaaccaaatt 102540

102600

tcagtaatgt aatccagaaa taatggatgc cttaaaagta attaaaagaa tgcaaataaa 102660

catttagtgc caattaaaga aaaagaaata caacattaga caaaataaaa gatattcatt 102720

tgatgcaatg aggaaataat cttttattcc tctttaaatt ctctgtggaa taaggcatgg 102780

ttataaataa ataaacatct gccccatgga cttaatggat cgttaattt tattgcgata 102840

atcataatga aattgttgggg agggattagt atctctagtg taatgctaag aaagataaag 102900

cctgtgccca ggcaaaagct ttcttggttg gtcaaaaggt ttgaagacat ttcaaactat 102960

103020

ggaaacaaaa tgaacaattt atttctgaca acctcatagt ctttgttctg tcagaacaat 103080

aatggaaagg tctaaaccag aaaatgctat gcattgaatt tataataaac tattttttcc 103140

tgtaacaaaa aattgataaa cttgatattt gcagatttaa tgattatgtg tttaaaaaaa 103200

atctggtttt tgcccttgca aaaaatcata tatatacaca tagatatgta tgtgtgtgtg 103260

103320

cctttaacct cctattttat tccaataaaa atattggtat tagagatagt tctgatattt 103380

catcatgaat agttaacatt gcatttggaa aggattaatt tttttgaaac gtaattttac 103440

cttaataagt agcccagcgt aatattttag taattacaca gatttttttt tcaagacatt 103500

103560

103620

tcaaataatg catataaaac tcttgaaatg gtaccaaata cagagtaagc accaaataaa 103680

103740

tcatttgaat gaccttttaa ggatacacct agcccattat ctttcttgat aatcttgtaa 103800

gatgattcct tttttatctc cgatctgttg aggcatggat agaggttttc agagaaaaca 103860

ttttctaggt aactgaaaga aagtagcaac aacaaactgt gacaaaactt aacaatgaga 103920

gaatttacaa gatagaataa ttgcaactcc ttttgaaatc aaccactatg gtcctctggc 103980

tgggatagct aagcaaagat attccagcct gaaggttgag atctacttga agagttttct 104040

atccagattg tgagggcccc tcaaacttca cttagtatct gtttctatta gtatggaaac 104100

ttctggaacc ttgtggtatc acattcactt gactacttta ttcctgctct agctatctta 104160

aagcctttct taatctttta tcttttagag aagatacttc taggttttaa atccaccgat 104220

cttgaagcta ttgccttcac tctctgcttc agagcccatc cttttgtata tgagtagttt 104280

gttttgccta aagtactttc tcccagtcag attttaagtc cagtttctca tctgtttttg 104340

agagcaaact cctgggcctt ggctcactaa catcttgaca gcatatttct tctttcctat 104400

gggcttttca gcattccctg ggtttttcta aaatatgaaa gcagactctt tatctcttac 104460

tttgtcaaag cctaccctcc ccactgattt ctcacccagt tgctagtttt aagacctgcc 104520

tctggccggg cgcagtggct cacgcctgta atcccagcac tttgggaggc caaggtaggt 104580

ggatcacgag gtcaggagat cgagaccatc ctggctaaca cagtgaaacc ctgtctctac 104640

taaaattaca aaaaaattag ccaggcgtgg tggtgagcgc ctgtagtccc agctactcgg 104700

gaggctgaag caggagaatg gcgtgatccc gtgaggcaga gcttgcagtg agctgagatc 104760

gcgccactgc actccagcct gggcgacaga gcgagactct gtctcaaaaa aaaaaaaaaa 104820

104880

tattgattct gagctcagca caagagcaaa cctttctcag cttgacccat cttcacatcg 104940

ttaatgtctt attcagtcac tacccaaggg gctgaccttc aagattctaa tccatgaaag 105000

105060

agaggaggat cagcccttag acatgaaaag taaaaatagt ttattcccag atttcccttt 105120

gtgcattagt atattcaacc gagtctatcc aagtaacagg acaaaaaaag ctggcagttg 105180

ttgctgcgct gtgaagtctt attaggtgag tcagctaatt atatggcact accataaata 105240

cagcaggcac tgccctgctt gttaggcttg ccaaggaaaa taaggattta aagcagcata 105300

ctacctcttt gctatataat gacattttct tcttaaaaat gattttgcac caattcctga 105360

tttatccacc aattattttt taatttatgg ttgaatgtat ttaaacctga attcagagat 105420

105480

tctcctccac tgccaaacct ttaaaaactg aaataaattg tttttatttc atcttttctc 105540

tttttctctc tctctaaggt gattgccaag actaaagaaa cagctagaag ggcaaaagac 105600

aagaaaatca gtaagatagt aacagattat ccaaagtaga gcacggctca ggtgcagtgg 105660

ctcatgcctg taatcccagc actttcggag gctgacgcag gaggatcact tgagtccagg 105720

agtttgagac cagcctgggc aacataatga aacttcatct ctataaaaaa aaaaaattta 105780

aatagccgag catggtggtg taagcctata gtcccagcta tttgggaggc tgaggctgga 105840

ggatcacttg ggcccaggag ttggagacta cagtgagcta tgattgtatc actgcattac 105900

agcctgggca atagggcaag accctgcctc taaacaaaag ataaacaaag tagagcataa 105960

atggcttcta aatatatgtt atttatgtgt aagactgggt tctctaaagg tatcatttaa 106020

ttaaaataga tttgcattct caatctgtag gtatggatta tgtataatgt atttaagata 106080

tgacttacag cgttcaccaa tgtgactatt cccaagtgat ccagatggct gatgacatag 106140

taatttgtac atttgctgag acctgatctg agtaggtatg taacataact gagggagagc 106200

aagtccattt gccgaaagaa agcctagcat atgacccagg agccacatct tcactcagcc 106260

ttgttgctag gtttggctta gcatatataa tagcatagca tgtataattt atgacaaaaa 106320

attatacttt gcacttttta attagaacat tcaaaatgat ctcaggaagt ggcaccagag 106380

atcatcagtg gtctactgta cttcgtgtgt atgtgtctgt gagtatgtat gtgtttgtgt 106440

gtgttcccac attctaaggc atgtctttta caggttagta gaaaatgttg atagaaaatt 106500

atagatttca acatctaaaa cacagtaggt cactacattg ttaaaacttg gaatttttta 106560

tcttgttgta aagtcaggcc aaccaaacct aaaatactgc tacattgaaa tagtgcaaaa 106620

tattcaaaat actatagtta tagatttggt agtaggactg taccagacct gtcactctat 106680

acaagactta tgccttgccc tttcacttac ctgttccctt ttacatctat cttactagat 106740

gtaatgctat aaattatatt tctaatatat tataatttat catgtattat aatgtatcaa 106800

atattacaaa ttatgttgca actcccctta cctttcgtct gcatattgcc tcagaaagaa 106860

cagatggatc caacagactt caaccacagg cccttagtga caaaatagctc ttaatgctgg 106920

gcttgccact ttgatgcatt tctaaagtta tagaatgtta aatgcaccaa gtcctttggt 106980

cattttattt ctaccttaga tctaagccat aactatactt tcccaaaaat taaagtttga 107040

attttaactt aaccatatat aattggaaaa ggaggttggg ttcgttaagt gtaattttat 107100

catgctttat tatcctttgg gcattggata cagcagaaca tgccaatttc tatggcttct 107160

catgtgacag aatatactta ctaggatgca attaaatact cctcagagta tgtaaacaat 107220

aaatgtaatc attacattat ttttatattg ttctttctta tgcataatag taagactgaa 107280

aatatagtgt tatttctgaa atatgcatat tgttttgctt ttgatgatta aataacattg 107340

tccaaagttt taggtttttt gaaatcttat attttttaac aaaatatcta gcctttccaa 107400

aacaagacct caataattcg tttaagaccc agagttgttc ctctccacat agatctctta 107460

aaaaggcaga ggatttatga cctcaagaga aatcagagta tccaaagttt gctttaattc 107520

aatgttttaa aaataaaatt ccttagattt tatcaaaaat tgagattagt ttgattttga 107580

atcagatgcc ctttgctccc caccccaaaa tggcattatg agcagactag gaattgataa 107640

tagaaaattg aacatatgaa atatatcttt accttgcttt ttaacaaggt attcatgtct 107700

atcgccttca tttttaagtg catcaataaa atacatggta attctcttag tgaaatatac 107760

tccctgtct gaggtagaga agtagagaat attcacattt 107820

ttgaaacgtc

cacgggtgtg tgcttaagtt gaaccttttt ttcctcttaa gtcaaagttc ttttttagtt 107940

tcttctttta tctttttggc tactatctct ctccttcatc ctcctggtgt gagttgttga 108000

gtgaaggtat taattccatt atttgaggct aagtgacatt gttcaataat gcagcaaaac 108060

aatggttcta cccaaaatat cttcaagtgt aaaagcagtg ggcaaaagag aaagtgcgct 108120

tctgctgctt tgaatgttta aggctgtgaa agttgatcac acaaattggg tcattcttgt 108180

tatacccaac taaaacaatc aagaagcctg ggaggaaaag cattcaagaa acatcacatt 108240

gctccaaaag tgtaattttc tacaagtccg catgctgagg ctgcctgttg taacctggga 108300

ccaatttttt ctgtaactgc tgaaaaaact tgctgcagct ctaggactaa ttttgcccac 108360

cactgtcact caccaattga agcttactag ctccccagaa cctttctagt gccaatgaac 108420

tttctcaaag agcagcgtgt atcatttctc tttttcagaa cacctccaac ctcctctttg 108480

ttctttggggt ataccaaaga ccaaccagcc ttgaatttca atttttcttc ccacataaaa 108540

gttttaattt agaaatgtat ctctacattt ctaactttga caaagcatag ataccagata 108600

108660

accctcaaca tttgccaaca tttgatggac ttcaaaatga gcatatcttt tttaaaaaaa 108720

attattcaca ctgacagcaa gtacattggt atactctata ttaaattata ccacaggggtt 108780

tacaaacaat tggtgatgtc gggcagtggt ttccaaggaa catacttaac aagacactca 108840

caaggcccta caaacctgca tttttaacaa gggccctaga tgattctaga agagtgtggt 108900

ttggaaagca atttttgcct ttattatgtg tcattttaaa tatatttaaa attaaagtta 108960

taagtcatag aattgaataa agataatttc cttacagaaa gtattactag gtatctaaat 109020

109080

109140

ttcacttccc tggaattgta cttcccaata agctattagc agtgaaggaa gcttcgtctc 109200

atgatctgtt ttatagagca cttcagctgg gacgagtacg aaatgataat cagttatatc 109260

agctattcaa ccctacaggt ttatttaaaa agaacttgaa taagcttttt agggagaaag 109320

109380

tgagggtcat tccattgtaa ttttttgata accatttttc tttctgtgtg tcaaatgcag 109440

atataagata ctgaactgag tctatttcac tgttcgtaaa acaatcccat ttgaaaaaaa 109500

aaagtctaca gctattccag ggatagggcc tagtagagag agaataaaag gtattttctt 109560

actatgtctc tatatcctac cctgtaggtt ctcttattaa gcatacaggc atataccaaa 109620

109680

109740

tagtttttt tcttgtttgt ggtaaaaata aatagaaggt gcacttcaca ccttcaagta 109800

tgattatatt ttgaaaacaa gtcatgaata ctcataaaat gcaaatttta atgttctttt 109860

tttgttacag ccaaactata ttaggcacag ttgtaaattg gagttgaaat ttaatatttc 109920

tttatagata acaatgtttt tagaaatagg tttatgaaac agtaaatata caggtatagg 109980

110040

tgccaaatat tttagtatgc ttaaaatcta cgaatgtgat agagtcaaca aatttagatc 110100

110160

ctttatctac agggatacat tctgaaaccc ccactaggac acctgaaatt gcggatagta 110220

gcaaacccta catatactgt tttttccaat gcttatgtac ctatgaaaaa gtttaattta 110280

110340

taatatactg taataaaagt tatgtgggta tggtctcgct ttctctttcc ctctctctct 110400

gtctctaaat atcttagtat tttggggttg caattggtgg tgggcaactg aaaccatgga 110460

110520

aaactcatgt ttcttctata tcccacccat ttcccccacc caaacctaga tagatatctt 110580

110640

110700

aatttcccca actacctcat atgtgttttc catttgctta tgtagggttc ccaatgagaa 110760

tgaaataaag ttcttaggtt gcaattggct aatgctctct cacttctact ttaagcggca 110820

ggttcccact aacttctttt tagttgcaat ttacttattg aaattagacg tattctttgt 110880

cttgtgtagt ttctcacagt gcaaaatttg ctgattgtag ccactgttgt aagcaatgaa 110940

catgtttttc accaccttat atttgctgta agttgtcagt gatagttaaa tgttaatcaa 111000

attcaaattc ggatcacgta gggcttttct ttttttgttt tctttttcta tttatatatt 111060

tatttattta ttttgagacg gagtctcact ccgtcaccag gctggagtgc aatggtgtga 111120

tctgggctca ctgcaatctc cacctcccgg gttcaagtga ttcccctggc tcagtctccc 111180

gagtagctgg gactatagga gaaccaccac gcccggctaa ctttttgtat tttagtagag 111240

atggggtttc accatgttgg ccaggatgct atagatctcc tgacctcacc gatcatgtag 111300

gacttcaatt gtcgaacaaa cgaaccttta atagcagtta caccattagg atgacctgat 111360

ccaacatcga ggtcgtaaac cctattgtcg atttggactc tagaatagga ttgtgctgtc 111420

atccctagtg tagcttgttc ccacttgatg aagttattgg atcagtgaac aatagcccac 111480

ttaaactagt acagtcttag tttaagatgg tgatgtgtat gtacttccat cagagggcac 111540

ataatacagt aaatcctcac ttaacttcat caatagtttc tggaaactgt gacttgaagc 111600

111660

tcctatggca aatttctgga cacaaaaaca ccatcaaact cctaaataaa gataaatcac 111720

ttctgacatt aaacattgaa attaatgtga gctatatata cgtttaagaa agattaatac 111780

111840

cctggcagct cagggagcaa tatgggaacc caccccggac aggacgctgt tccattactg 111900

cagggtgctc ttgtacacac ccactcaccc aggctggaac catgcagaca cacacactca 111960

cctaacctac acatctgtgt acatccttca aagttcagcc aaataacata taaacaaatc 112020

cagtaatatc catcagtctt agttccgtca taacaactcc tttttgatca tcaaacaaca 112080

aacagggtag gtctgccata tttacttgtc tggtccatat caaaattttc taacaaatta 112140

tattagaaaa tcaaatctct gtcagtttca aaatcatgga aaaaaatttg ccttatttcc 112200

cttatacttg gatatcctaa cagtaatcta aatattaatg agaaagttaa tgatgtcgtt 112260

tccttctccc tgttgtaaag aaggttttgc tgtcccgttt gatcactaag actaattgac 112320

actcagaaaa agcataggaa acttctcagc atcacaaaag ctctgtcatc tagagaagct 112380

aggacttgag ctcaagtcct gtgacatgga aggccttgtg cctagccatc ctgcagcaga 112440

ggcgtatcta ccaagaagtg aaacactacg aaaacagtat gtttactcca cattttaaag 112500

tgaggtagtt tggggtggtt catattttat ttaatttata tattatttgg atttttttta 112560

gtttataaaa agggcattgg caagggcaga atgatctgta agcttctctg cccacctacc 112620

ataagcatga tctttagtgt gaccttttct tactgttagc cattttctta tacttctgcg 112680

tccctgtcag tcacttccat gtgaagacat ggggaagctt ttttacatca gacatgttgt 112740

112800

tcacattgcc tctctgttct ttgaattttc acttaccttt atcttcttat aattactttg 112860

ctgaaataaa tgcaaagcaa caaaaggtat ttagtgaaga ataccaacaa agccatgacc 112920

atttcaggct gagttttgta gtattctttg tctaggaaga gatacctaga aaaattttct 112980

gaccatgtat ttgattattt tccttcaata tgtatagtct cagtcttcaa atttcagaaa 113040

agaatttgtt tcttcattgt catttaaaat taatgtgtta aatatgtatg cttttacatt 113100

ataagtggtt ataaaagtta aacacttaga aaaaaagtca aaataacata catactatcc 113160

aacaaaataa ctttcatatt ttattgtgtt ttcttccaaa ctttttacct ttgcgtctga 113220

attctgtgta ggttgtatctatatataga caacacttta tagcctgcta aatattatac 113280

cataaatagg tagttgttac ataattctca ggtaatagta atacaggtct ttatcataat 113340

ctactgagta gttgaatgat aattttttttt aagacaaggt ctccctctgt cacccaggct 113400

agaatgcagt ggcatgcaca tggctcactg tagcctctac ctcccaggct caagtgatcc 113460

tcctgcctca gcctcccaag tggctgggac tgtaggcatg tgccaccatg cccagctatt 113520

tatttgtatt tttagtagag atggggtttc attgtaacag cccaggctgg tcttgaactc 113580

ctggactcaa atgatccacc tgcctcagcc tcccaaagtg ctgaaatcac aggagtgaac 113640

113700

tctaaaaatt ttgtttcctg ctgtcattga tcttgtgaaa aatatctttg gactatagct 113760

gtggattatt tcctaaatag taaattactt gagcaaaaag tttacatact ttgagggttg 113820

ataacccatg ttgccgcaat gtttccccgg aggcattgtg gagtttagaa tgccagtagt 113880

aatattaagg tgtgccattt tcaagatccg tggccaacat ccctatatgt aagatttttc 113940

caaaacatgg ttctgatttt taaaagtgaa aaatgctact tcatcatgtt ctttttgtgc 114000

ttcttacttt aaatattaga atgaagaagg agccccacag gaaggaattc tggaagatat 114060

gcctgtggat cctgacaatg aggcttatga aatgccttct gaggtaggag tccaagctga 114120

atctttctaa caagacagta ccaaaaacct gtcattgtca catttctctt tcattagtgc 114180

ttagtgagaa tcatttgctc tctacatgct cattacgtgg acaacttgca agttaagaat 114240

agtttttaca tttttaaagg gtccttaaaa aaaaagagga ggaggaagat gaagaagagg 114300

aagaaaggat gtaaaagaaa tcatatgtag tccacatagc ttaatatact tactacttga 114360

ccctttacag gaaaagttta ctaacccctg cattagagaa tatattttta gaaactttac 114420

attctaaaat aaatttctaa atggaaagtt agggaaatca atggaatgcc aaaggaaggt 114480

tattattttt tgccatacat gtccaatggg atgacgcata gtaaaataaa agttacccac 114540

114600

114660

taatagaaaa tgtatcaaaa gggaaattag aaaatactgt tagatgaata aaactggccc 114720

114780

aaaaaaaaaa cctacctgca aagaaaatcc caggccgaga tggcatcact ggtaaattct 114840

accaaacatt taaaagaggaa ttaatactaa ttagttaaca ccaattaata tctcttacaa 114900

aacagaagag gagacatttc ccaactaatt ttgtgagacc aatattaccc tgataatcaa 114960

aaccaaatga agatatcaca agaaaagaaa ctatataatg gctccattaa aaattgagtt 115020

caagtatgtt gtagtttggt tatgtattat tcctcacggc attattaaaa ggcatgtcga 115080

ggatgggcac agcagttcac acctgtaatc ccgcactttg tgagccaaag tggccaggtt 115140

acttgaggcc aggagttgga gaccagtctg gccaacatgg tgaaacccca tctctactaa 115200

aaatacaaaa attagccggg catggtggta cacgcctatg gttccagcta cttgggaggc 115260

tgaggcatga gagtcacttg aacccaggag gcagaggttg cagtgagctg agatggcacc 115320

cctgcactcc aatcttggta acagagcaag actgtctcac acagacacac gaaaggcata 115380

ttgataataa ttcaacttat agaaattgag attaaattgt ttgtttgcct aataagaatt 115440

115500

115560

agaaattcat tcattcattt cttcattatg attcctttaa caaacataat tgattgtctt 115620

115680

taaagatctg tttcaatcaa tcaggagaag tttttattgag gaggtaatgt tgatctgggt 115740

gggaaaaggt aagagatata gtaggtcaaa acaaacagag gacattctgg cacaagggaa 115800

tatcagaagc aaaggcatgt atgtctgagc atgcaaatgg atatgtctga gaacagtgaa 115860

taattatgac tcaagcttag gaacaaggaa aatggtgata gattgaattt gcagctatgg 115920

gtcaaagaca agttatagag tattaggata atcttgtcat ttcagcttgt attctattca 115980

gaaaacaact tgagttattg aagttatgct tatttgtttg tttttaagca gaatcctgat 116040

attattagag ttgctcttta ggaggaataa tctgatccct ttaattaaat ccattaatat 116100

ttgtgttgtg gatgctatcc agatactgta tggagagctt gaggtttgaa atacaagtaa 116160

taattgaagc catagatgaa gacgaaattt tcaactggga gagtgaaagt agggaaaatg 116220

tatcttgcct tcaaacatct taatttcctt ctgagaatta gagcatctta gtctggaaaa 116280

ggctttatag acagcttgat tttgttctca cattttacag gtgaagaaac tgagaaccag 116340

acagtccaac ttatttgtcc taccaaacta ggtatatgat cattaaatgg tgcatccgga 116400

tcagaaccta gatattttaa ctctgactac tactgtaatt cacttttata tcagacaaga 116460

aagacacaac tattaaaaat aagataatat ttgctgcaga atatttgcaa aaacattgat 116520

tgtaaatttt agtgtaagtg gggagccatt tcctatctca ttggctgtca gtgctgatgc 116580

gtaattgaaa cttatactaa cagtgtgtgc tgtctttttg atttttctaa tattaggaag 116640

ggtatcaaga ctacgaacct gaagcctaag aaatatcttt gctcccagtt tcttgagatc 116700

116760

116820

cctgccccca ctcagcattt cggtgcttcc ctttcactga agtgaataca tggtagcagg 116880

gtctttgtgt gctgtggatt ttgtggcttc aatctacgat gttaaaacaa attaaaaaca 116940

117000

gttgttagtg atttgctatc atatattata agatttttag gtgtctttta atgatactgt 117060

117120

catgaaacta tgcacctata aatactaaat atgaaattttt accattttgc gatgtgtttt 117180

117240

aatattttat ttttatccca tctcacttta ataataaaaa tcatgcttat aagcaacatg 117300

117360

ggaattttag aagaggtaga gaaaatggaa cattaaccct acactcggaa ttccctgaag 117420

caacactgcc agaagtgtgt tttggtatgc actggttcct taagtggctg tgattaatta 117480

ttgaaagtgg ggtgttgaag accccaacta ctattgtaga gtggtctatt tctcccttca 117540

117600

117660

117720

acaataaata atattcgacc atgaataaaa aaaaaaaaaa agtgggttcc cgggaactaa 117780

gcagtgtaga agatgatttt gactacaccc tccttagaga gccataagac acattagcac 117840

atattagcac attcaaggct ctgagagaat gtggttaact ttgtttaact cagcattcct 117900

cacttttttt tttttaatcat cagaaattct ctctctctct ctctcttttt ctctcgctct 117960

cttttttttt ttttttttac aggaaatgcc tttaaacatc gttggaacta ccagagtcac 118020

cttaaaggag atcaattctc tagactgata aaaatttcat ggcctccttt aaatgttgcc 118080

aaatatatga attctaggat ttttccttag gaaaggtttt tctctttcag ggaagatcta 118140

ttaactcccc atgggtgctg aaaataaact tgatggtgaa aaactctgta taaattaatt 118200

taaaaattat ttggtttctc tttttaatta ttctggggca tagtcatttc taaaagtcac 118260

tagtagaaag tataatttca agacagaata ttctagacat gctagcagtt tatatgtatt 118320

catgagtaat gtgatatata ttgggcgctg gtgaggaagg aaggaggaat gagtgactat 118380

aaggatggtt accatagaaa cttcctttttt tacctaattg aagagagact actacagagt 118440

gctaagctgc atgtgtcatc ttacactaga gagaaatggt aagtttcttg ttttatttaa 118500

118560

118620

118680

tttgagatta ggaaagttgt gaccatgaat ttaaggattt atgtggatac aaattctcct 118740

ttaaagtgtt tcttccctta atatttatct gacggtaatt tttgagcagt gaattacttt 118800

atatatctta atagtttatt tgggaccaaa cacttaaaca aaaagttctt taagtcatat 118860

aagccttttc aggaagcttg tctcatattc actcccgaga cattcacctg ccaagtggcc 118920

tgaggatcaa tccagtccta ggtttatttt gcagacttac attctcccaa gttattcagc 118980

ctcatatgac tccacggtcg gctttaccaa aacagttcag agtgcacttt ggcacacaat 119040

tgggaacaga acaatctaat gtgtggtttg gtattccaag tggggtcttt ttcagaatct 119100

ctgcactagt gtgagatgca aacatgtttc ctcatctttc tggcttatcc agtatgtagc 119160

tatttgtgac ataataaata tatacatata tgaaaatatg

ttcttacaaa gagctcctaa aacccttgta atttcctgag tagtaggggt gctagggtca 119280

tcttttgttc taatatttgg tctttgactc tgctttctga cagagctcct tagtccctgg 119340

gtgagagtag catcttctct tctaatgaag tgactcttgc tgggttcctg gatgggggct 119400

ggtcaccaga aaggtcaagc catgataaga agcttgaagc ttttggcccc attcacatct 119460

tctggggacg ggagagaaga ggagctggag attgagttaa taagcaacaa tgcttccatg 119520

atgaagactc cataaaaatc cctaaaagac aggattcaga gtgctttgaa ataggtgaac 119580

atgcagaggt gctgggaatt gtggtgtgtc cagagaaggc atgcaagctc cccacgcctc 119640

ccccatacct ttccctgtgc atctcttcca tctggctgtt cctgagttgt atccttttat 119700

acactagcaa 119760

attatcaaac ctgaggagag ggccgtggag accttggatt tgtagacaag tcaaacagaa 119820

gctatgagta acatgaggac tcattgcttg tgattgtcat cttcagtggg aaggggaaaa 119880

atcttgtaaa actgagtcct taacctgtgg gtcaatgcta actccaggta gatagtgtcc 119940

gatttgaatt acgggacacc cagttggtag ccacaaagaa tgggagaatt gcttggtgta 120000

gaaaacacac cccacacaca catgtggtgt cagaaatgaa cgggaaatat tgtgttccgg 120060

aaatattgag tgttgtgagt gagtgtatag aaagaaaaac agcgtttcct tttcactact 120120

agattaaaac aaacacactc atgcattcac acatctcaaa gacaactatt aattctcaaa 120180

gacagtgctg tctaaatcca tactgaggaa gaaaacacat ttttcttttca aatctgtaaa 120240

cctgacagac tgcctctgtc cacacactaa tggaactctg tgtttcatct gaaatgtgtt 120300

catcccactt tgttctttct gtcttgggca gggcaagagt gcaacagggc tgacattttc 120360

atatgagctc tgtccctgtt attggctata ctttagacaa attattatgt gtcaaatata 120420

gatgtaagtg atttatcaat attaagtcat ttaattctca aaacaacctt aataggttcc 120480

attatgattc taattttaca cataagccaa aggaggcacc cacaggctag ataactttcc 120540

cacggccaca cagctagtaa gcggcagagc caagaggccc aacattacag caccacagtc 120600

tgtgctctca gccccttggc cacatagtgt cagagtgagg acacacagct atttaagaaa 120660

acttccagaa gtctaggaaa tggggtgata gccccacttt tctaggtata ataattagat 120720

atttgttttt cttcaggtac ctaaagaaaa tttactagag tttgagcctt tagtaagttt 120780

tgctagtaca tctgtttttc ttcaggtgcc tgaagacaaa catatacaca cacacacaca 120840

120900

120960

121020

caatggcaca atctcagttc actgcaacct ccgcctccca ggttcaagcg attctcctgc 121080

ctcagcctct cgagtaggtg ggattacagg aacacaccac cttagcccga ctaatttttg 121140

tatttttagt agagacaggg ttcaccacgt tggccaggct ggtctcaaac tcctgacc 121198

<210> 2

<211> 3215

<212> DNA

<213> Homo Sapies

<400> 2

aggagaagga gaaggaggag gactaggagg aggaggacgg cgacgaccag aaggggccca 60

agagagggggg cgagcgaccg agcgccgcga cgcggaagtg aggtgcgtgc gggctgcagc 120

180

agccttctgc ctttccaccc tcgtgagcgg agaactggga gtggccattc gacgacagtg 240

tggtgtaaag gaattcatta gccatggatg tattcatgaa aggactttca aaggccaagg 300

agggagttgt ggctgctgct gagaaaacca aacagggtgt ggcagaagca gcaggaaaga 360

caaaagaggg tgttctctat gtaggctcca aaaccaagga gggagtggtg catggtgtgg 420

480

gtgtgacagc agtagcccag aagcagtgg agggagcagg gagcattgca gcagccactg 540

gctttgtcaa aaaggaccag ttgggcaaga atgaagaagg agccccacag gaaggaattc 600

tggaagatat gcctgtggat cctgacaatg aggcttatga aatgccttct gaggaagggt 660

atcaagacta cgaacctgaa gcctaagaaa tatctttgct cccagtttct tgagatctgc 720

tgacagatgt tccatcctgt acaagtgctc agttccaatg tgcccagtca tgacatttct 780

caaagtttt acagtgtatc tcgaagtctt ccatcagcag tgattgaagt atctgtacct 840

gcccccactc agcatttcgg tgcttccctt tcactgaagt gaatacatgg tagcagggtc 900

tttgtgtgct gtggattttg tggcttcaat ctacgatgtt aaaacaaatt aaaaacacct 960

aagtgactac cacttatttc taaatcctca ctattttttt gttgctgttg ttcagaagtt 1020

gttagtgatt tgctatcata tattataaga tttttaggtg tcttttaatg atactgtcta 1080

agaataatga cgtattgtga aatttgttaa tatatataat acttaaaaat atgtgagcat 1140

gaaactatgc acctataaat actaaatatg aaattttacc attttgcgat gtgttttatt 1200

1260

tgcttataag caacatgaat 1320

taagaactga cacaaaggac aaaaatataa agttattaat agccatttga agaaggagga 1380

1440

cactgccaga agtgtgtttt ggtatgcact ggttccttaa gtggctgtga ttaattattg 1500

aaagtggggt gttgaagacc ccaactacta ttgtagagtg gtctatttct cccttcaatc 1560

aactgttgtt tgatgtgtat gtgtttataa 1620

ttgttataca tttttaattg agccttttat taacatatat tgttattttt gtctcgaaat 1680

aattttttag ttaaaatcta ttttgtctga tattggtgtg aatgctgtac ctttctgaca 1740

ataaataata ttcgaccatg aataaaaaaa aaaaaaaagt gggttcccgg gaactaagca 1800

gtgtagaaga tgattttgac tacaccctcc ttagagagcc ataagacaca ttagcacata 1860

ttagcacatt caaggctctg agagaatgtg gttaactttg tttaactcag cattcctcac 1920

tttttttttt taatcatcag aaattctctc tctctctctc tctttttctc tcgctctctt 1980

tttttttttt tttttacagg aaatgccttt aaacatcgtt ggaactacca gagtcacctt 2040

aaaggagatc aattctctag actgataaaa atttcatggc ctcctttaaa tgttgccaaa 2100

2160

actccccatg ggtgctgaaa ataaacttga tggtgaaaaa ctctgtataa attaatttaa 2220

aaattatttg gtttctcttt ttaattattc tggggcatag tcatttctaa aagtcactag 2280

2340

gagtaatgtg atatatattg ggcgctggtg aggaaggaag gaggaatgag tgactataag 2400

gatggttacc atagaaactt ccttttttac ctaattgaag agagactact acagagtgct 2460

aagctgcatg tgtcatctta cactagag aaatggtaag tttcttgttt tatttaagtt 2520

2580

2640

ggtattaaat taagaaatag aggacagaac tagactgata gcagtgacct agaacaattt 2700

gagattagga aagttgtgac catgaattta aggatttatg tggatacaaa ttctccttta 2760

aagtgtttct gagcagtgaa ttacttttata 2820

tatcttaata gtttatttgg gaccaaacac ttaaacaaaa agttctttaa gtcatataag 2880

ccttttcagg aagcttgtct catattcact cccgagacat tcacctgcca agtggcctga 2940

ggatcaatcc agtcctaggt ttatttttgca gacttacatt ctcccaagtt attcagcctc 3000

atatgactcc acggtcggct ttaccaaaac agttcagagt gcactttggc acacaattgg 3060

gaacagaaca atctaatgtg tggtttggta ttccaagtgg ggtctttttc agaatctctg 3120

3180

aaata 3215

<210> 3

<211> 3211

<212> DNA

<213> Homo sapiens

<400> 3

gccattcgac gacaggttag cgggtttgcc tcccactccc ccagcctcgc gtcgccggct 60

cacagcggcc tcctctgggg acagtccccc ccgggtgccg cctccgccct tcctgtgcgc 120

180

aaaaaagaga gaggcgggga ggagtcggag ttgtggagaa gcagagggac tcagtgtggt 240

gtaaaggaat tcattagcca tggatgtatt catgaaagga ctttcaaagg ccaaggagggg 300

agttgtggct gctgctgaga aaaccaaaca gggtgtggca gaagcagcag gaaagacaaa 360

aggggtgtt ctctatgtag gctccaaaac caagggaggga gtggtgcatg gtgtggcaac 420

agtggctgag aagaccaaag agcaagtgac aaatgttgga ggagcagtgg tgacgggtgt 480

gacagcagta gcccagaaga cagtggaggg agcagggagc attgcagcag ccactggctt 540

tgtcaaaaag gaccagttgg gcaagaatga agaaggagcc ccacaggaag gaattctgga 600

agatatgcct gtggatcctg acaatgaggc ttatgaaatg ccttctgagg aagggtatca 660

agactacgaa cctgaagcct aagaaatatc tttgctccca gtttcttgag atctgctgac 720

agatgttcca tcctgtacaa gtgctcagtt ccaatgtgcc cagtcatgac atttctcaaa 780

gtttttacag tgtatctcga agtcttccat cagcagtgat tgaagtatct gtacctgccc 840

ccactcagca tttcggtgct tccctttcac tgaagtgaat acatggtagc agggtctttg 900

tgtgctgtgg attttgtggc ttcaatctac gatgttaaaa caaattaaaa acacctaagt 960

gactaccact tatttctaaa tcctcactat ttttttgttg ctgttgttca gaagttgtta 1020

taggtgtctt ttaatgatac tgtctaagaa 1080

taatgacgta ttgtgaaatt tgttaatata tataatactt aaaaatatgt gagcatgaaa 1140

ctatgcacct ataaatacta aatatgaaat tttaccattt tgcgatgtgt tttattcact 1200

tgtgtttgta tataaatggt gagaattaaa ataaaacgtt atctcattgc aaaaatattt 1260

tatttttatc ccatctcact ttaataataa aaatcatgct tataagcaac atgaattaag 1320

aactgacaca aaggacaaaa atataaagtt attaatagcc atttgaagaa ggaggaattt 1380

tagagaggt agagaaaatg gaacattaac cctacactcg gaattccctg aagcaacact 1440

gccagaagtg tgttttggta tgcactggtt ccttaagtgg ctgtgattaa ttattgaaag 1500

tggggtgttg aagaccccaa ctactattgt agagtggtct atttctccct tcaatcctgt 1560

1620

tatacatttt taattgagcc ttttattaac atatattgtt atttttgtct cgaaataatt 1680

ttttagttaa aatctatttt gtctgatatt ggtgtgaatg ctgtaccttt ctgacaataa 1740

ataatattcg accatgaata aaaaaaaaaa aaaagtgggt tcccgggaac taagcagtgt 1800

agaagatgat tttgactaca ccctccttag agagccataa gacacattag cacatattag 1860

cacattcaag gctctgagag aatgtggtta actttgttta actcagcatt cctcactttt 1920

tttttttaat catcagaaat tctctctctc tctctctctt tttctctcgc tctctttttt 1980

tttttttttt tacaggaaat gcctttaaac atcgttggaa ctaccagagt caccttaaag 2040

gagatcaatt ctctagactg ataaaaattt catggcctcc tttaaatgtt gccaaatata 2100

tgaattctag gatttttcct taggaaaggt ttttctcttt cagggaagat ctattaactc 2160

cccatgggtg ctgaaaataa acttgatggt gaaaaactct gtataaatta atttaaaaat 2220

tattggttt ctctttttaa ttattctggg gcatagtcat ttctaaaagt cactagtaga 2280

2340

aatgtgatat atattgggcg ctggtgagga aggaaggagg aatgagtgac tataaggatg 2400

gttaccatag aaacttcctt ttttacctaa ttgaagagag actactacag agtgctaagc 2460

2520

ttaagcaagg aaaggatttg ttattgaaca gtatatttca ggaaggttag aaagtggcgg 2580

ttaggatata ttttaaatct acctaaagca gcatatttta aaaatttaaa agtattggta 2640

ttaaattaag aaatagaggga cagaactaga ctgatagcag tgacctagaa caatttgaga 2700

2760

gtttcttccc ttaatattta tctgacggta atttttgagc agtgaattac tttatatatc 2820

ttaatagttt atttgggacc aaacacttaa acaaaaagtt ctttaagtca tataagcctt 2880

ttcaggaagc ttgtctcata ttcactcccg agacattcac ctgccaagtg gcctgaggat 2940

caatccagtc taggtttat tttgcagact tacattctcc caagttattc agcctcatat 3000

3060

agaacaatct aatgtgtggt ttggtattcc aagtggggtc tttttcagaa tctctgcact 3120

agtgtgagat gcaaacatgt ttcctcatct ttctggctta tccagtatgt agctatttgt 3180

gacataataa atatatacat atatgaaaat a 3211

<210> 4

<211> 3022

<212> DNA

<213> Homo sapiens

<400> 4

attctggtgt gatccaggaa cagctgtctt ccagctctga aagagtgtgg tgtaaaggaa 60

ttcattagcc atggatgtat tcatgaaagg actttcaaag gccaaggagg gagttgtggc 120

tgctgctgag aaaaccaaac agggtgtggc agaagcagca ggaaagacaa aaggggtgt 180

tctctatgta ggctccaaaa ccaaggaggg agtggtgcat ggtgtggcaa cagtggctga 240

gaagaccaaa gagcaagtga caaatgttgg aggagcagtg gtgacggggtg tgacagcagt 300

agcccagaag acagtggagg gagcagggag cattgcagca gccactggct ttgtcaaaaa 360

ggaccagttg ggcaagaatg aagaaggagc cccacaggaa ggaattctgg aagatatgcc 420

tgtggatcct gacaatgagg cttatgaaat gccttctgag gaagggtatc aagactacga 480

acctgaagcc taagaaatat ctttgctccc agtttcttga gatctgctga cagatgttcc 540

atcctgtaca agtgctcagt tccaatgtgc ccagtcatga catttctcaa agtttttaca 600

gtgtatctcg aagtcttcca tcagcagtga ttgaagtatc tgtacctgcc cccactcagc 660

atttcggtgc ttccctttca ctgaagtgaa tacatggtag cagggtcttt gtgtgctgtg 720

gattttgtgg cttcaatcta cgatgttaaa acaaattaaa aacacctaag tgactaccac 780

ttatttctaa atcctcacta ttttttttgtt gctgttgttc agaagttgtt agtgatttgc 840

tatcatatat tataagattt ttaggtgtct tttaatgata ctgtctaaga ataatgacgt 900

attgtgaaat ttgttaatat atataatact taaaaatatg tgagcatgaa actatgcacc 960

1020

1080

cccatctcac tttaataata aaaatcatgc ttataagcaa catgaattaa gaactgacac 1140

aaaggacaaa aatataaagt tattaatagc catttgaaga aggaggaatt ttagaagagg 1200

tagagaaaat ggaacattaa ccctacactc ggaattccct gaagcaacac tgccagaagt 1260

gtgttttggt atgcactggt tccttaagtg gctgtgatta attattgaaa gtggggtgtt 1320

gaagacccca actactattg tagagtggtc tatttctccc ttcaatcctg tcaatgtttg 1380

1440

1500

aaatctattt tgtctgatat tggtgtgaat gctgtacctt tctgacaata aataatattc 1560

gaccatgaat aaaaaaaaaa aaaaagtggg ttcccgggaa ctaagcagtg tagaagatga 1620

ttttgactac accctcctta gagagccata agacacatta gcacatatta gcacattcaa 1680

ggctctgaga gaatgtggtt aactttgttt aactcagcat tcctcacttt ttttttttaa 1740

tcatcagaaa ttctctctct ctctctctct ttttctctcg ctctcttttt tttttttttt 1800

ttacaggaaa tgcctttaaa catcgttgga actaccagag tcaccttaaa ggagatcaat 1860

tctctagact gataaaaatt tcatggcctc ctttaaatgt tgccaaatat atgaattcta 1920

ggatttttcc ttaggaaagg tttttctctt tcagggaaga tctattaact ccccatgggt 1980

gctgaaaata aacttgatgg tgaaaaactc tgtataaatt aatttaaaaa ttatttggtt 2040

tctcttttta attattctgg ggcatagtca tttctaaaag tcactagtag aaagtataat 2100

ttcaagacag aatattctag acatgctagc agtttatatg tattcatgag taatgtgata 2160

2220

gaaacttcct tttttaccta attgaagaga gactactaca gagtgctaag ctgcatgtgt 2280

catcttacac tagagagaaa tggtaagttt cttgttttat ttaagttatg tttaagcaag 2340

gaaaggattt gttattgaac agtatatttc aggaaggtta gaaagtggcg gttaggatat 2400

attttaaatc tacctaaagc agcatatttt aaaaatttaa aagtattggt attaaattaa 2460

gaaattagagg acagaactag actgatagca gtgacctaga acaatttgag attaggaaag 2520

2580

2640

tatttgggac caaacactta aacaaaaagt tctttaagtc atataagcct tttcaggaag 2700

cttgtctcat attcactccc gagacattca cctgccaagt ggcctgagga tcaatccagt 2760

cctaggttta ttttgcagac ttacattctc ccaagttatt cagcctcata tgactccacg 2820

gtcggcttta ccaaaacagt tcagagtgca ctttggcaca caattgggaa cagaacaatc 2880

taatgtgtgg tttggtattc caagtggggt ctttttcaga atctctgcac tagtgtgaga 2940

tgcaaacatg tttcctcatc tttctggctt atccagtatg tagctatttg tgacataata 3000

aatatataca tatatgaaaa ta 3022

<210> 5

<211> 3127

<212> DNA

<213> Homo sapiens

<400> 5

gccattcgac gacaggttag cgggtttgcc tcccactccc ccagcctcgc gtcgccggct 60

cacagcggcc tcctctgggg acagtccccc ccgggtgccg cctccgccct tcctgtgcgc 120

180

aaaaaagaga gaggcgggga ggagtcggag ttgtggagaa gcagagggac tcagtgtggt 240

gtaaaggaat tcattagcca tggatgtatt catgaaagga ctttcaaagg ccaaggagggg 300

agttgtggct gctgctgaga aaaccaaaca gggtgtggca gaagcagcag gaaagacaaa 360

aggggtgtt ctctatgtag gctccaaaac caagggaggga gtggtgcatg gtgtggcaac 420

agtggctgag aagaccaaag agcaagtgac aaatgttgga ggagcagtgg tgacgggtgt 480

gacagcagta gcccagaaga cagtggaggg agcagggagc attgcagcag ccactggctt 540

tgtcaaaaag gaccagttgg gcaaggaagg gtatcaagac tacgaacctg aagcctaaga 600

aatatctttg ctcccagttt cttgagatct gctgacagat gttccatcct gtacaagtgc 660

tcagttccaa tgtgcccagt catgacattt ctcaaagttt ttacagtgta tctcgaagtc 720

ttccatcagc agtgattgaa gtatctgtac ctgcccccac tcagcatttc ggtgcttccc 780

tttcactgaa gtgaatacat ggtagcaggg tctttgtgtg ctgtggattt tgtggcttca 840

atctacgatg ttaaaacaaa ttaaaaacac ctaagtgact accacttatt tctaaatcct 900

cactattttt ttgttgctgt tgttcagaag ttgttagtga tttgctatca tatattataa 960

gatttttagg tgtcttttaa tgatactgtc taagaataat gacgtattgt gaaatttgtt 1020

aatatatata atacttaaaa atatgtgagc atgaaactat gcacctataa atactaaata 1080

1140

attaaaataa aacgttatct cattgcaaaa atattttatt tttatcccat ctcactttaa 1200

taataaaaat catgcttata agcaacatga attaagaact gacacaaagg acaaaaatat 1260

1320

attaacccta cactcggaat tccctgaagc aacactgcca gaagtgtgtt ttggtatgca 1380

ctggttcctt aagtggctgt gattaattat tgaaagtggg gtgttgaaga ccccaactac 1440

tattgtagag tggtctattt ctcccttcaa tcctgtcaat gtttgcttta cgtattttgg 1500

1560

attaacatat attgttattt ttgtctcgaa ataatttttt agttaaaatc tattttgtct 1620

gatattggtg tgaatgctgt acctttctga caataaataa tattcgacca tgaataaaaa 1680

aaaaaaaaaa gtgggttccc gggaactaag cagtgtagaa gatgattttg actacaccct 1740

ccttagagag ccataagaca cattagcaca tattagcaca ttcaaggctc tgagagaatg 1800

tggttaactt tgtttaactc agcattcctc actttttttt tttaatcatc agaaattctc 1860

tctctctctc tctctttttc tctcgctctc tttttttttt tttttttaca ggaaatgcct 1920

ttaaacatcg ttggaactac cagagtcacc ttaaaggaga tcaattctct agactgataa 1980

2040

aaaggtttt ctctttcagg gaagatctat taactcccca tgggtgctga aaataaactt 2100

gatggtgaaa aactctgtat aaattaattt aaaaattatt tggtttctct ttttaattat 2160

tctggggcat agtcatttct aaaagtcact agtagaaagt ataatttcaa gacagaatat 2220

tctagacatg ctagcagttt atatgtattc atgagtaatg tgatatatat tgggcgctgg 2280

tgaggaagga aggaggaatg agtgactata aggatggtta ccatagaaac ttcctttttt 2340

acctaattga agagagacta ctacagagtg ctaagctgca tgtgtcatct tacactagag 2400

agaaatggta agtttcttgt tttatttaag ttatgtttaa gcaaggaaag gatttgttat 2460

tgaacagtat atttcaggaa ggttagaaag tggcggttag gatatatttt aaatctacct 2520

aaagcagcat attttaaaaa tttaaaagta ttggtattaa attaagaaat agaggacaga 2580

actagactga tagcagtgac ctagaacaat ttgagattag gaaagttgtg accatgaatt 2640

taaggattta tgtggataca aattctcctt taaagtgttt cttcccttaa tatttatctg 2700

acggtaattt ttgagcagtg aattacttta tatatcttaa tagtttattt gggaccaaac 2760

acttaaacaa aaagttcttt aagtcatata agccttttca ggaagcttgt ctcatattca 2820

ctcccgagac attcacctgc caagtggcct gaggatcaat ccagtcctag gtttattttg 2880

cagacttaca ttctcccaag ttattcagcc tcatatgact ccacggtcgg ctttaccaaa 2940

acagttcaga gtgcactttg gcacacaatt gggaacagaa caatctaatg tgtggtttgg 3000

3060

3120

3127

<210> 6

<211> 140

<212> PRT

<213> Homo sapiens

<400> 6

Met Asp Val Phe Met Lys Gly Leu Ser Lys Ala Lys Glu Gly Val Val

1 5 10 15

Ala Ala Ala Glu Lys Thr Lys Gln Gly Val Ala Glu Ala Ala Gly Lys

20 25 30

Thr Lys Glu Gly Val Leu Tyr Val Gly Ser Lys Thr Lys Glu Gly Val

35 40 45

Val His Gly Val Ala Thr Val Ala Glu Lys Thr Lys Glu Gln Val Thr

50 55 60

Asn Val Gly Gly Ala Val Val Thr Gly Val Thr Ala Val Ala Gln Lys

65 70 75 80

Thr Val Glu Gly Ala Gly Ser Ile Ala Ala Ala Thr Gly Phe Val Lys

85 90 95

Lys Asp Gln Leu Gly Lys Asn Glu Glu Gly Ala Pro Gln Glu Gly Ile

100 105 110

Leu Glu Asp Met Pro Val Asp Pro Asp Asn Glu Ala Tyr Glu Met Pro

115 120 125

Ser Glu Glu Gly Tyr Gln Asp Tyr Glu Pro Glu Ala

130 135 140

<210> 7

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense oligonucleotide

<400> 7

taacacattt tcacctct 18

<210> 8

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 8

ttaacacatt ttcacctc 18

<210> 9

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 9

cttaacacat tttcacct 18

<210> 10

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 10

gcttaacaca ttttcacct 19

<210> 11

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 11

gcttaacaca ttttcacc 18

<210> 12

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 12

cgcttaacac attttcacc 19

<210> 13

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 13

cgcttaacac attttcac 18

<210> 14

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 14

cgcttaacac attttca 17

<210> 15

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 15

tcgcttaaca cattttca 18

<210> 16

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 16

tcgcttaaca cattttc 17

<210> 17

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 17

atcgcttaac acattttc 18

<210> 18

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 18

catcgcttaa cacattt 17

<210> 19

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 19

catcatatcc aatttctt 18

<210> 20

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 20

ccatcatatc caatttctt 19

<210> 21

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 21

accatcatat ccaatttctt 20

<210> 22

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 22

ccatcatatc caatttct 18

<210> 23

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 23

accatcatat ccaatttc 18

<210> 24

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 24

gaccatcata tccaattt 18

<210> 25

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 25

agcgcacagg aagggc 16

<210> 26

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 26

aaggagcgca caggaagggc 20

<210> 27

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 27

ggagcgcaca ggaagggc 18

<210> 28

<400> 28

000

<210> 29

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 29

aggagcgcac aggaaggg 18

<210> 30

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 30

aaaggagcgc acaggaaggg 20

<210> 31

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 31

ggagcgcaca ggaagg 16

<210> 32

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 32

aaggagcgcacaggaagg 18

<210> 33

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 33

aaaggagcgc acaggaag 18

<210> 34

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 34

aggagcgcac aggaag 16

<210> 35

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 35

aaggagcgca caggaa 16

<210> 36

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 36

aaaggagcgc acagga 16

<210> 37

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 37

acaattccca aataatatt 19

<210> 38

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 38

aacaattccc aaataatatt 20

<210> 39

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 39

aacaattccc aaataatat 19

<210> 40

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 40

aaacaattcc caaataatat 20

<210> 41

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 41

aaaattccc aaataata 18

<210> 42

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 42

taaacaattc ccaaataata 20

<210> 43

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 43

ttaaacaatt cccaaataat 20

<210> 44

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 44

taaacaattc ccaaataa 18

<210> 45

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 45

ttaaacaatt cccaaata 18

<210> 46

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 46

tttaaacaat tcccaaat 18

<210> 47

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 47

atttaaacaa ttcccaaa 18

<210> 48

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 48

aaaatttaaa caattccc 18

<210> 49

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 49

aaaaatttaa acaattcc 18

<210> 50

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 50

cacaactccg actcct 16

<210> 51

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 51

ccacaactcc gactcc 16

<210> 52

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 52

tccacaactc cgactc 16

<210> 53

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 53

ctccacaact ccgact 16

<210> 54

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 54

cttctccaca actccg 16

<210> 55

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 55

aagggaatat cagaagca 18

<210> 56

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 56

cctaatctct cagccctt 18

<210> 57

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 57

cctaatctct cagcc 16

<210> 58

<211> 14

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 58

atcctcgcgt ttcc 14

<210> 59

<211> 14

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 59

catcctcgcg tttc 14

<210> 60

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 60

gcacttccat ttcattatt 19

<210> 61

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 61

cacttccatt tcattatt 18

<210> 62

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 62

atttagcatc tccatc 17

<210> 63

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 63

tacactcatt taaccatt 18

<210> 64

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 64

gtacactcat ttaaccatt 19

<210> 65

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 65

gtacactcat ttaaccat 18

<210> 66

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 66

gtacactcat ttaacca 17

<210> 67

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 67

tgtacactca tttaacca 18

<210> 68

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 68

tgtacactca tttaacc 17

<210> 69

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 69

gaaagtcctt tcatga 16

<210> 70

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 70

tgaaagtcct ttcatg 16

<210> 71

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 71

cctttgaaag tccttt 16

<210> 72

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 72

gcctttgaaa gtcctt 16

<210> 73

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 73

ggcctttgaa agtcct 16

<210> 74

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 74

ttggcctttg aaagtc 16

<210> 75

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 75

agcagccaca actccc 16

<210> 76

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 76

tcaatttctt tattctttta 20

<210> 77

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 77

atcaatttct ttatttctttt 20

<210> 78

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 78

catcaatttc tttattctt 19

<210> 79

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 79

catcaatttc tttattct 18

<210> 80

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 80

gcatcaattt ctttatttc 18

<210> 81

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 81

aagcatcaat ttctttat 18

<210> 82

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 82

aatattattaaa attaactcat 20

<210> 83

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 83

aatatttaaa attaactca 19

<210> 84

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 84

acacttcata aaatattattaa 20

<210> 85

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 85

cacacttcat aaaatattt 19

<210> 86

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 86

tcacacttca taaaatattt 20

<210> 87

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 87

tcacacttca taaaatatt 19

<210> 88

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 88

ttcacacttc ataaaattt 20

<210> 89

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 89

ttcacacttc ataaaatat 19

<210> 90

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 90

attcacactt cataaaatat 20

<210> 91

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 91

attcacactt cataaaata 19

<210> 92

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 92

taattcacac ttcataaaat 20

<210> 93

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 93

ataattcaca cttcataaa 19

<210> 94

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 94

tataattcac acttcataaa 20

<210> 95

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 95

tataattcac acttcataa 19

<210> 96

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 96

cagtattcca aattccat 18

<210> 97

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 97

tcagtattcc aaattcca 18

<210> 98

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 98

agttcaactc tcaatta 17

<210> 99

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 99

aagttcaact ctcaatta 18

<210> 100

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 100

taagttcaac tctcaat 17

<210> 101

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 101

cattttttat cttaaattct 20

<210> 102

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 102

tcatttttta tcttaaattc 20

<210> 103

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 103

catattttttt actaatca 18

<210> 104

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 104

tcatattttt tactaatca 19

<210> 105

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 105

atcatattttttactaatca 20

<210> 106

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 106

tcatattttt tactaatc 18

<210> 107

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 107

atcatattttttactaatc 19

<210> 108

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 108

aatcatattt tttactaatc 20

<210> 109

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 109

aatcatattt tttactaat 19

<210> 110

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 110

taaatcatat tttttactaa 20

<210> 111

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 111

ctaaatcata ttttttacta 20

<210> 112

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 112

ctaaatcata ttttttact 19

<210> 113

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 113

tctaaatcat attttttact 20

<210> 114

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 114

ctaaatcata ttttttac 18

<210> 115

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 115

tctaaatcat attttttac 19

<210> 116

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 116

ttctaaatca tattttttac 20

<210> 117

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 117

tttctaaatc atatttttta 20

<210> 118

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 118

ttttctaaat catattttttt 20

<210> 119

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 119

cagttttcta aatcatat 18

<210> 120

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 120

atgtatcaaa ccaatca 17

<210> 121

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 121

catgtatcaa accaatca 18

<210> 122

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 122

catgtatcaa accaatc 17

<210> 123

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 123

ccatgtatca aaccaatc 18

<210> 124

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 124

ccatgtatca aaccaat 17

<210> 125

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 125

accatgtatc aaaccaa 17

<210> 126

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 126

agatcctacc attacaac 19

<210> 127

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 127

aagatcctac catttaca 18

<210> 128

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 128

tattacatat tcactaaa 18

<210> 129

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 129

aatctctatc tctcatcc 18

<210> 130

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 130

caatctctat ctctcatc 18

<210> 131

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 131

gattcaaatt ttacttcca 19

<210> 132

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 132

attcaaattt tacttcca 18

<210> 133

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 133

tttatcacaa ccctctttcc 19

<210> 134

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 134

ctctttatca caacctct 18

<210> 135

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 135

cactctttat cacaacct 18

<210> 136

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 136

cactctttat cacaacc 17

<210> 137

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 137

tcactcttta tcacaacc 18

<210> 138

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 138

ttcactcttt atcacaacc 19

<210> 139

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 139

cttcactctt tatcacaacc 20

<210> 140

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 140

tcactcttta tcacaac 17

<210> 141

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 141

ttcactcttt atcacaac 18

<210> 142

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 142

ccttcactct ttatcacaac 20

<210> 143

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 143

accttcactc tttatcacaa 20

<210> 144

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 144

ccttcactct ttatcaca 18

<210> 145

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 145

accttcactc tttatcaca 19

<210> 146

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 146

caccttcact ctttatcaca 20

<210> 147

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 147

accttcactc tttatcac 18

<210> 148

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 148

caccttcact ctttatcac 19

<210> 149

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 149

caccttcact ctttatca 18

<210> 150

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 150

tattcatatc ctctctaa 18

<210> 151

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 151

ataagcacat tcaaacta 18

<210> 152

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 152

ttacctattt aaaaatact 19

<210> 153

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 153

tttacctatt taaaaatact 20

<210> 154

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 154

ttactataaa ttaaacata 19

<210> 155

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 155

ctataccata acaatacaaa 20

<210> 156

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 156

tataccataa caatacaa 18

<210> 157

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 157

ctataccata acaatacaa 19

<210> 158

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 158

gctataccat aacaataca 19

<210> 159

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 159

ctataccata acaataca 18

<210> 160

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 160

agctatacca taacaatac 19

<210> 161

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 161

ctataccata acaatac 17

<210> 162

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 162

gctataccat aacaatac 18

<210> 163

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 163

agctatacca taacaata 18

<210> 164

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 164

tagctatacc ataacaat 18

<210> 165

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 165

tagctatacc ataacaa 17

<210> 166

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 166

atagctatac cataacaa 18

<210> 167

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 167

atagctatac cataaca 17

<210> 168

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 168

aatagctata ccataaca 18

<210> 169

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 169

aatagctata ccataac 17

<210> 170

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 170

taagattccc atatcatt 18

<210> 171

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 171

tcacaatatc atatttata 19

<210> 172

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 172

ttcacaatat catatttata 20

<210> 173

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 173

cacaatatca tattata 18

<210> 174

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 174

ttcacaatat catatttat 19

<210> 175

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 175

cttcacaata tcatatttat 20

<210> 176

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 176

tcacaatatc atatttat 18

<210> 177

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 177

cttcacaata tcatattta 19

<210> 178

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 178

ttcacaatat catatta 18

<210> 179

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 179

cttcacaata tcatattt 18

<210> 180

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 180

gcttcacaat atcatatt 18

<210> 181

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 181

tgcttcacaa tatcatat 18

<210> 182

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 182

atgcttcaca atatcata 18

<210> 183

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 183

cttcctcaac tactaaat 18

<210> 184

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 184

gttcttcctc aactactaa 19

<210> 185

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 185

actagtttca ttcaaccc 18

<210> 186

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 186

actagtttca ttcaacc 17

<210> 187

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 187

cactagtttc attcaac 17

<210> 188

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 188

ctttatatta aataaccct 19

<210> 189

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 189

actttattt aaataaccct 20

<210> 190

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 190

actttattt aaataaccc 19

<210> 191

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 191

agcactttat attaaata 18

<210> 192

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 192

ttatttcttc tcataatta 19

<210> 193

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 193

ttgatattat ctaacta 17

<210> 194

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 194

cattgatatt atctaac 17

<210> 195

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 195

taagaatcaa aaccttca 18

<210> 196

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 196

ataagaatca aaaccttc 18

<210> 197

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 197

tttctttata ttatttcata 20

<210> 198

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 198

ttttctttat attatttcat 20

<210> 199

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 199

cacatttaaa aacatttct 19

<210> 200

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 200

acacatttaa aaacatttct 20

<210> 201

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 201

gacacattta aaaacattt 19

<210> 202

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 202

cgacacattt aaaaacatt 19

<210> 203

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 203

cgacacattt aaaaacat 18

<210> 204

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 204

tcgacacatt taaaaaca 18

<210> 205

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 205

tattattata atcataaa 18

<210> 206

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 206

ttattattat aatcataa 18

<210> 207

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 207

cataaatttt ataatatct 19

<210> 208

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 208

ccataaattt tataatatc 19

<210> 209

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 209

ccataaattt tataatat 18

<210> 210

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 210

gccataaatt ttataata 18

<210> 211

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 211

agccataaat tttataat 18

<210> 212

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 212

cagccataaa ttttataa 18

<210> 213

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 213

agctatttac aattcaaa 18

<210> 214

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 214

catacttcta tttatttatt 20

<210> 215

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 215

acatacttctatttatttat 20

<210> 216

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 216

tacatacttc tattattta 20

<210> 217

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 217

atacatactt ctatttattt 20

<210> 218

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 218

aatacatact tctattttt 20

<210> 219

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 219

caatacatac ttctatttat 20

<210> 220

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 220

aatacatact tctatta 18

<210> 221

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 221

caatacatac ttctattt 18

<210> 222

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 222

atttctttat ttcaattca 19

<210> 223

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 223

tattctcttta tttcaattca 20

<210> 224

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 224

tattctcttta tttcaattc 19

<210> 225

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 225

atatttcttt atttcaattc 20

<210> 226

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 226

aatatttctt tatttcaatt 20

<210> 227

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 227

aatatttctt tatttcaa 18

<210> 228

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 228

taaaatcatt ccacttccac 20

<210> 229

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 229

aaaatcattc cacttcca 18

<210> 230

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 230

taaaatcatt ccacttcca 19

<210> 231

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 231

ttaaaatcat tccacttcca 20

<210> 232

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 232

ttaaaatcat tccacttcc 19

<210> 233

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 233

ctccaacatt tgtcac 16

<210> 234

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 234

ccctccaacat ttgtca 16

<210> 235

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 235

gctcctccaa catttg 16

<210> 236

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 236

tcttctgggc tactgc 16

<210> 237

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 237

ttgacaaagc cagtgg 16

<210> 238

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 238

aaatctacct caaaactat 19

<210> 239

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 239

gaattttaaa atctacctc 19

<210> 240

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 240

aataaatata tttcactctc 20

<210> 241

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 241

ctccttaatt taataaat 18

<210> 242

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 242

cctccttaat ttaataaa 18

<210> 243

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 243

aacttctttc tcacaatttt 20

<210> 244

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 244

taaaacttct ttctcacaat 20

<210> 245

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 245

taaaacttct ttctcacaa 19

<210> 246

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 246

ataaaacttc tttctcacaa 20

<210> 247

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 247

taaaacttct ttctcaca 18

<210> 248

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 248

ataaaacttc tttctcaca 19

<210> 249

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 249

aataaaactt ctttctcaca 20

<210> 250

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 250

ataaaacttc tttctcac 18

<210> 251

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 251

aataaaactt ctttctcac 19

<210> 252

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 252

aaataaaact tctttctca 19

<210> 253

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 253

taatataatt attatccta 20

<210> 254

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 254

taatataattattaccct 19

<210> 255

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 255

ttaatataat tattatccct 20

<210> 256

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 256

taatataattattaccc 18

<210> 257

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 257

ttaatataat tattatccc 19

<210> 258

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 258

attaatataa ttattatccc 20

<210> 259

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 259

attaatataa ttattatcc 19

<210> 260

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 260

gttttttcc acaactat 18

<210> 261

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 261

atgtttttt ccacaact 18

<210> 262

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 262

aatgtttatt tccacaac 18

<210> 263

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 263

acaaattaaa tactttcatt 20

<210> 264

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 264

acaaattaaa tactttcat 19

<210> 265

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 265

aacaaattaa atactttcat 20

<210> 266

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 266

aacaaattaa atactttca 19

<210> 267

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 267

attaatccac ttctacaa 18

<210> 268

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 268

cattaatcca cttctacaa 19

<210> 269

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 269

ccattaatcc acttctacaa 20

<210> 270

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 270

cattaatcca cttctaca 18

<210> 271

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 271

ccattaatcc acttctaca 19

<210> 272

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 272

cattaatcca cttctac 17

<210> 273

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 273

gccattaatc cacttcta 18

<210> 274

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 274

gccattaatc cacttct 17

<210> 275

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 275

catcact 17

<210> 276

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 276

ttctctatat aacatcact 19

<210> 277

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 277

tctctatata acatcac 17

<210> 278

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 278

tttctctata taacatcac 19

<210> 279

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 279

attttctcta tataacatc 19

<210> 280

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 280

aatttttctct atataacatc 20

<210> 281

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 281

aattttctct atataacat 19

<210> 282

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 282

aaatttttctc tatataacat 20

<210> 283

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 283

taaatttttct ctatataaca 20

<210> 284

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 284

taaatttttct ctatataac 19

<210> 285

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 285

ataaattttc tctatataac 20

<210> 286

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 286

ataaattttc tctatataa 19

<210> 287

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 287

tataaatttt ctctatataa 20

<210> 288

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 288

atataaattt tctctatata 20

<210> 289

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 289

aatataaatt ttctctatat 20

<210> 290

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 290

atataaattt tctctatat 19

<210> 291

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 291

ataaattaaa atatttctcc 20

<210> 292

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 292

tataaattaa aatatttctc 20

<210> 293

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 293

ctataaatta aaatatttct 20

<210> 294

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 294

aatttttctt taataatcac 20

<210> 295

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 295

aactttaca taccacatt 19

<210> 296

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 296

aactttaca taccacat 18

<210> 297

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 297

ctttgacaaa caaaacta 18

<210> 298

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 298

atcctataat acatttcttt 20

<210> 299

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 299

actcatccta taataca 17

<210> 300

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 300

ccactcatcc tataataca 19

<210> 301

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 301

cccactcatc ctataatac 19

<210> 302

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 302

cccactcatc ctataata 18

<210> 303

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 303

cccactcatc ctataat 17

<210> 304

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 304

tatcccactc atcctataa 19

<210> 305

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 305

taagtatctc aaaacatc 18

<210> 306

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 306

gtttattatc aaattaca 18

<210> 307

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 307

agtttattat caaattac 18

<210> 308

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 308

acatcttatc ctatttat 18

<210> 309

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 309

cacatcttat cctatttat 19

<210> 310

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 310

acacatctta tcctatttat 20

<210> 311

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 311

cacatcttat cctattta 18

<210> 312

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 312

acacatctta tcctatta 19

<210> 313

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 313

acacatctta tcctattt 18

<210> 314

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 314

taatatataa acacatctta 20

<210> 315

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 315

taatatataa acacatctt 19

<210> 316

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 316

ataatatata aacacatctt 20

<210> 317

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 317

aataatatat aaacacatct 20

<210> 318

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 318

aataatatat aaacacatc 19

<210> 319

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 319

taatctattt attcaacaa 19

<210> 320

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 320

ataatctatt tattcaacaa 20

<210> 321

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 321

ataatctatt tattcaaca 19

<210> 322

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 322

aataatctat ttattcaaca 20

<210> 323

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 323

ataatctatt tattcaac 18

<210> 324

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 324

aataatctat ttattcaac 19

<210> 325

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 325

attattcatc acaatcca 18

<210> 326

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 326

cattattcat cacaatcca 19

<210> 327

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 327

acattattca tcacaatcca 20

<210> 328

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 328

attattcatc acaatcc 17

<210> 329

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 329

cattattcat cacaatcc 18

<210> 330

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 330

acattattca tcacaatcc 19

<210> 331

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 331

tacattattc atcacaatcc 20

<210> 332

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 332

acattattca tcacaatc 18

<210> 333

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 333

tacattattc atcacaatc 19

<210> 334

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 334

gtacattatt catcacaat 19

<210> 335

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 335

gtacattatt catcacaa 18

<210> 336

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 336

tgtacattat tcatcaca 18

<210> 337

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 337

tgtttcaaac tcataaat 18

<210> 338

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 338

ttgtttcaaa ctcataaa 18

<210> 339

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 339

ttcaacattt ttatttcaca 20

<210> 340

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 340

ttcaacattt ttatttcac 19

<210> 341

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 341

attcaacatttttttttcac 20

<210> 342

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 342

attcaacattttttttca 19

<210> 343

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 343

aattcaacat ttttatttca 20

<210> 344

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 344

taattcaaca ttttttttc 20

<210> 345

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 345

ttaattcaac atttttattt 20

<210> 346

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 346

tttaattcaa catttttttt 20

<210> 347

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 347

atttaattca acatttttat 20

<210> 348

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 348

catttaattc aacattttta 20

<210> 349

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 349

catttaattc aacattttt 19

<210> 350

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 350

tcatttaatt caacattttt 20

<210> 351

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 351

tcatttaatt caacatttt 19

<210> 352

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 352

ctcatttaat tcaacatttt 20

<210> 353

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 353

ctcatttaat tcaacattt 19

<210> 354

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 354

actcatttaa ttcaacattt 20

<210> 355

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 355

actcatttaa ttcaacatt 19

<210> 356

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 356

actcatttaa ttcaacat 18

<210> 357

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 357

gaactcattt aattcaaca 19

<210> 358

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 358

ttgaactcat ttaattca 18

<210> 359

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 359

ttaatatcat caaactacaa 20

<210> 360

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 360

acttaatatc atcaaactac 20

<210> 361

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 361

ttaatatcat caaactac 18

<210> 362

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 362

tacttaatat catcaaacta 20

<210> 363

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 363

cttaatatca tcaaacta 18

<210> 364

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 364

cttacttaat atcatcaaac 20

<210> 365

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 365

ttacttactt aatatcatca 20

<210> 366

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 366

atttacttac ttaatatc 18

<210> 367

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 367

aatttactta cttaatatc 19

<210> 368

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 368

catattactt acttaatatc 20

<210> 369

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 369

catattactt acttaatat 19

<210> 370

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 370

acaatttact tacttaatat 20

<210> 371

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 371

catattactt acttaata 18

<210> 372

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 372

acaatttact tacttaata 19

<210> 373

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 373

tacaatttac ttacttaata 20

<210> 374

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 374

acaatttact tacttaat 18

<210> 375

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 375

tacaatttac ttacttaat 19

<210> 376

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 376

atacaattta cttacttaat 20

<210> 377

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 377

tatacaattt acttacttaa 20

<210> 378

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 378

tatacaattt acttactta 19

<210> 379

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 379

ttatacaatt tacttactta 20

<210> 380

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 380

ttatacaatt tacttactt 19

<210> 381

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 381

ttatacaatt tacttact 18

<210> 382

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 382

gttatacaat ttacttac 18

<210> 383

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 383

ccattctaat tataccat 18

<210> 384

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 384

ccattctaat tatacca 17

<210> 385

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 385

ctgataatct ctctaaat 18

<210> 386

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 386

aatagcatcc ttccacac 18

<210> 387

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 387

aatagcatcc ttccaca 17

<210> 388

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 388

caatagcatc cttccac 17

<210> 389

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 389

aataagaaag gaacgc 16

<210> 390

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 390

actatgatac ttcactc 17

<210> 391

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 391

ttactcctac aaattttttt 20

<210> 392

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 392

ttactcctac aaattttttt 19

<210> 393

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 393

attactccta caaattttttt 20

<210> 394

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 394

ttactcctac aaattttt 18

<210> 395

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 395

attactccta caaattttt 19

<210> 396

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 396

aattactcct acaaattttt 20

<210> 397

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 397

caattactcc tacaaatttt 20

<210> 398

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 398

caattactcc tacaaattt 19

<210> 399

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 399

ccaattactc ctacaaattt 20

<210> 400

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 400

ccaattactc ctacaaatt 19

<210> 401

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 401

caattactcc tacaaatt 18

<210> 402

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 402

ttgttacctt tcaataaa 18

<210> 403

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 403

ccaaaaacat acaactat 18

<210> 404

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 404

tccaaaaaca tacaactat 19

<210> 405

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 405

ttccaaaaac atacaactat 20

<210> 406

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 406

ttccaaaaac atacaacta 19

<210> 407

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 407

cttccaaaaa catacaacta 20

<210> 408

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 408

cttccaaaaa catacaact 19

<210> 409

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 409

cttccaaaaa catacaac 18

<210> 410

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 410

tacttccaaa aacatacaac 20

<210> 411

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 411

ctacttccaa aaacatacaa 20

<210> 412

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 412

tacttccaaa aacatacaa 19

<210> 413

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 413

tctacttcca aaaacataca 20

<210> 414

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 414

ctacttccaa aaacataca 19

<210> 415

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 415

ttctacttcc aaaaacata 19

<210> 416

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 416

attctacttc caaaaacata 20

<210> 417

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 417

attctacttc caaaaacat 19

<210> 418

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 418

attctacttc caaaaaca 18

<210> 419

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 419

aaccaatttc tattaca 18

<210> 420

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 420

caaccaattt ctatttaca 19

<210> 421

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 421

acaaccaatt tctatttaca 20

<210> 422

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 422

acaaccaatt tctatttac 19

<210> 423

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 423

aacaaccaat ttctatttac 20

<210> 424

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 424

acaaccaatt tctattta 18

<210> 425

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 425

aacaaccaat ttctattta 19

<210> 426

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 426

tctaaacaac caatttct 18

<210> 427

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 427

aacactacca tatattcat 20

<210> 428

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 428

aacactacca tatatttca 19

<210> 429

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 429

aacactacca tatatttc 18

<210> 430

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 430

ccctcatatt ctataata 18

<210> 431

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 431

ccctcatatt ctataa 16

<210> 432

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 432

aaaattaatt tatttccca 19

<210> 433

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 433

gaaaattaat ttatttccc 19

<210> 434

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 434

gaaaatactt aacattata 19

<210> 435

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 435

tgatattcct aatcttct 18

<210> 436

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 436

ttgatattcc taatcttc 18

<210> 437

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 437

ttgatattcc taatctt 17

<210> 438

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 438

ccagatcaaa cattaaa 17

<210> 439

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 439

ttattctatc aattataa 18

<210> 440

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 440

tttattctat caattataa 19

<210> 441

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 441

ttttattcta tcaattataa 20

<210> 442

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 442

attttattct atcaattata 20

<210> 443

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 443

tttattctat caattata 18

<210> 444

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 444

ttttattcta tcaattata 19

<210> 445

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 445

attttttttattcaattat 19

<210> 446

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 446

gattttttc tatcaatt 18

<210> 447

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 447

ctgattttat tctatcaa 18

<210> 448

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 448

gcaaaaataa ttccataca 19

<210> 449

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 449

tactaacttc tctcccaat 19

<210> 450

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 450

atactaactt ctctcccaat 20

<210> 451

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 451

actaacttct ctcccaa 17

<210> 452

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 452

atactaactt ctctcccaa 19

<210> 453

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 453

catactaact tctctcccaa 20

<210> 454

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 454

catactaact tctctccca 19

<210> 455

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 455

atcatactaa cttctctccc 20

<210> 456

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 456

catactaact tctctccc 18

<210> 457

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 457

tatcatacta acttctctcc 20

<210> 458

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 458

tcatactaac ttctctcc 18

<210> 459

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 459

atcatactaa cttctctcc 19

<210> 460

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 460

atatcatact aacttctctc 20

<210> 461

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 461

atcatactaa cttctctc 18

<210> 462

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 462

atatcatact aacttctct 19

<210> 463

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 463

tatcatacta acttctc 17

<210> 464

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 464

attatatatc cttaacta 18

<210> 465

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 465

cattatatat ccttaacta 19

<210> 466

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 466

acattatata tccttaacta 20

<210> 467

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 467

cattatatat ccttaact 18

<210> 468

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 468

acattatata tccttaact 19

<210> 469

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 469

cacattatat atccttaact 20

<210> 470

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 470

cattatatat ccttaac 17

<210> 471

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 471

acattatata tccttaac 18

<210> 472

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 472

cacattatat atccttaac 19

<210> 473

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 473

ccacattata tatccttaac 20

<210> 474

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 474

cacattatat atccttaa 18

<210> 475

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 475

ccacattata tatccttaa 19

<210> 476

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 476

ccacattata tatcctta 18

<210> 477

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 477

gccacattat atatcctta 19

<210> 478

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 478

gccacattat atatcctt 18

<210> 479

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 479

gccacattat atatcct 17

<210> 480

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 480

tcaattaaat aaacctct 18

<210> 481

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 481

catatactcc attaccc 17

<210> 482

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 482

ccatatactc cattaccc 18

<210> 483

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 483

cccatatact ccattacc 18

<210> 484

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 484

cccatatact ccattac 17

<210> 485

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 485

cattccata tactccat 18

<210> 486

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 486

atcttacatt cacatatt 18

<210> 487

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 487

taaatcttac attcacatat 20

<210> 488

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 488

taaatcttac attcacat 18

<210> 489

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 489

tacattaatc tataattaaaa 20

<210> 490

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 490

tacattaatc tataattaa 19

<210> 491

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 491

gtacattaat ctataatt 18

<210> 492

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 492

tgtacattaa tctataat 18

<210> 493

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 493

atgtacatta atctataa 18

<210> 494

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 494

taaaataaca ttatactca 19

<210> 495

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 495

gtaaaataac attatactc 19

<210> 496

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 496

gtaaaataac attack 18

<210> 497

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 497

tatattattt tcatacttt 19

<210> 498

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 498

ctatattatt ttcatacttt 20

<210> 499

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 499

ctatattatt ttcatactt 19

<210> 500

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 500

cctatattat tttcatactt 20

<210> 501

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 501

ctatattatt ttcatact 18

<210> 502

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 502

cctatattat tttcatact 19

<210> 503

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 503

acctatatta ttttcatact 20

<210> 504

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 504

cctatattat tttcatac 18

<210> 505

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 505

acctatatta ttttcatac 19

<210> 506

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 506

cacctatatt attttcatac 20

<210> 507

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 507

cacctatatt attttcata 19

<210> 508

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 508

acacctatat tattttcata 20

<210> 509

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 509

cacctatatt attttcat 18

<210> 510

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 510

acacctatat tattttcat 19

<210> 511

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 511

gacacctata tattttca 19

<210> 512

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 512

gacacctata ttatttc 18

<210> 513

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 513

tgacacctat attatttt 18

<210> 514

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 514

atcactgaca cctatat 17

<210> 515

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 515

gctaaatatt actcactc 18

<210> 516

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 516

ttgctaaata ttactcac 18

<210> 517

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 517

cttgctaaat attactca 18

<210> 518

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 518

cacattaact actcatat 18

<210> 519

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 519

acacattaac tactcatat 19

<210> 520

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 520

tacacattaa ctactcatat 20

<210> 521

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 521

cacattaact actcata 17

<210> 522

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 522

acacattaac tactcata 18

<210> 523

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 523

tacacattaa ctactcata 19

<210> 524

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 524

tacacattaa ctactcat 18

<210> 525

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 525

gtacacatta actactcat 19

<210> 526

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 526

agtacacatt aactactca 19

<210> 527

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 527

gtacacatta actactc 17

<210> 528

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 528

agtacacatt aactactc 18

<210> 529

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 529

tatatcttca ttatttttccc 20

<210> 530

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 530

tatatcttca ttatttttcc 19

<210> 531

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 531

catatatctt cattattt 18

<210> 532

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 532

atcatatatc ttcattattt 20

<210> 533

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 533

aatcatatat cttcattatt 20

<210> 534

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 534

caatacaact taattcca 18

<210> 535

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 535

caaccacta aataata 17

<210> 536

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 536

gcaacccact aaataata 18

<210> 537

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 537

gcaacccact aaataat 17

<210> 538

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 538

agcaacccac taaataa 17

<210> 539

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 539

tcttaatttt tttctattat 20

<210> 540

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 540

ctcttaattt ttttctatta 20

<210> 541

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 541

atctcttaat ttttttctat 20

<210> 542

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 542

aatctcttaa ttttttttcta 20

<210> 543

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 543

caatctctta atttttttc 19

<210> 544

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 544

tcaatctctt aatttttttc 20

<210> 545

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 545

atactcaatc tcttaatttt 20

<210> 546

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 546

atactcaatc tcttaattt 19

<210> 547

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 547

atactcaatc tcttaatt 18

<210> 548

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 548

gatactcaat ctcttaatt 19

<210> 549

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 549

gatactcaat ctcttaat 18

<210> 550

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 550

gatactcaat ctcttaa 17

<210> 551

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 551

aaatattctt acttctatt 19

<210> 552

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 552

aaaatattct tacttctatt 20

<210> 553

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 553

aaatattctt acttctat 18

<210> 554

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 554

aaaatattct tacttctat 19

<210> 555

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 555

caaaatttc ttacttctat 20

<210> 556

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 556

caaaatttc ttacttcta 19

<210> 557

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 557

tcaaaatatt cttacttcta 20

<210> 558

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 558

tcaaaatatt cttacttct 19

<210> 559

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 559

gtcaaaatat tcttacttc 19

<210> 560

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 560

taaatattcc ttaaccta 18

<210> 561

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 561

ttaaatttc cttaaccta 19

<210> 562

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 562

tttaaattt ccttaaccta 20

<210> 563

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 563

ttaaatttc cttaacct 18

<210> 564

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 564

atttaaatat tccttaacct 20

<210> 565

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 565

tttaaattt ccttaacc 18

<210> 566

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 566

atttaaatat tccttaacc 19

<210> 567

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 567

tattaaata ttccttaacc 20

<210> 568

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 568

ttatttaaat attccttaac 20

<210> 569

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 569

ttattaaat attccttaa 19

<210> 570

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 570

tttattattaaa tattccttaa 20

<210> 571

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 571

tttatttaaa tattcctta 19

<210> 572

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 572

ttttatttaa atattcctta 20

<210> 573

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 573

attattttat ttaaatttc 20

<210> 574

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 574

acattatttt atttaaatat 20

<210> 575

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 575

cacattattt tattaaata 20

<210> 576

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 576

ccacattatt ttattataaat 20

<210> 577

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 577

tttcccacat aaaattaaaa 19

<210> 578

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 578

atttcccaca taaaattaaaa 20

<210> 579

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 579

tatttcccac ataaaattaa 20

<210> 580

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 580

ttatttccca cataaaatt 19

<210> 581

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 581

tttttttccc acataaaatt 20

<210> 582

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 582

tttatttccc acataaaat 19

<210> 583

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 583

atttatttcc cacataaaat 20

<210> 584

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 584

atttatttcccacataaaaa 19

<210> 585

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 585

tattatttc ccacataaaa 20

<210> 586

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 586

tattatttc ccacataaa 19

<210> 587

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 587

ctatttattt cccacataaa 20

<210> 588

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 588

ctatttattt cccacataa 19

<210> 589

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 589

tctatttatt tcccacataa 20

<210> 590

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 590

ctatttattt cccacata 18

<210> 591

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 591

tctatttatt tcccacata 19

<210> 592

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 592

ctctatttat ttcccacat 19

<210> 593

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 593

ctctatttat ttcccaca 18

<210> 594

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 594

cttcaatatt attatcct 18

<210> 595

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 595

aacttcaata ttattatcct 20

<210> 596

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 596

aacttcaata ttattatcc 19

<210> 597

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 597

taacttcaat attattatcc 20

<210> 598

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 598

aacttcaata ttattatc 18

<210> 599

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 599

taacttcaat attattatc 19

<210> 600

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 600

ttaacttcaa tattattatc 20

<210> 601

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 601

ttaacttcaa tattattat 19

<210> 602

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 602

cttaacttca atattattat 20

<210> 603

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 603

cttaacttca atattatta 19

<210> 604

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 604

ccttaacttc aatattatta 20

<210> 605

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 605

ccttaacttc aatattatt 19

<210> 606

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 606

tccttaactt caatattatt 20

<210> 607

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 607

atccttaact tcaatattat 20

<210> 608

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 608

atccttaact tcaatatta 19

<210> 609

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 609

catccttaac ttcaatatta 20

<210> 610

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 610

atccttaact tcaatatt 18

<210> 611

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 611

catccttaac ttcaatatt 19

<210> 612

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 612

tcatccttaa cttcaatatt 20

<210> 613

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 613

catccttaac ttcaatat 18

<210> 614

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 614

tcatccttaa cttcaatat 19

<210> 615

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 615

atcatcctta acttcaatat 20

<210> 616

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 616

catccttaac ttcaata 17

<210> 617

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 617

tcatccttaa cttcaata 18

<210> 618

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 618

atcatcctta acttcaata 19

<210> 619

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 619

tcatccttaa cttcaat 17

<210> 620

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 620

atcatcctta acttcaat 18

<210> 621

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 621

atcatcctta acttcaa 17

<210> 622

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 622

cattgatt aatacat 17

<210> 623

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 623

tgttcataac tatatcca 18

<210> 624

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 624

gttatatactctattaat 18

<210> 625

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 625

taaaattaaa tttaatcca 19

<210> 626

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 626

ttaaaattaa atttaatcca 20

<210> 627

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 627

tttaaaatta aatttaatcc 20

<210> 628

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 628

tacctaccaa ctttcttta 19

<210> 629

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 629

cctaccaact ttcttta 17

<210> 630

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 630

acctaccaac tttcttta 18

<210> 631

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 631

tacctaccaa ctttcttt 18

<210> 632

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 632

tagaatttaa acattatc 18

<210> 633

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 633

ttgtactcta catattta 18

<210> 634

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 634

tacacacaca tatattcatc 20

<210> 635

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 635

cctaaaaatc cattcccaa 19

<210> 636

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 636

cctaaaaatc cattccca 18

<210> 637

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 637

gcattattaa tacacctc 18

<210> 638

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 638

tgcattatta atacacctc 19

<210> 639

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 639

gcattattaa tacacct 17

<210> 640

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 640

tgcattatta atacacct 18

<210> 641

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 641

tgcattatta atacacc 17

<210> 642

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 642

gttcattata ttaattaa 18

<210> 643

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 643

ccaacttaca attctcct 18

<210> 644

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 644

ccaacttaca attctcc 17

<210> 645

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 645

cccaacttac aattctc 17

<210> 646

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 646

taacactatt taatatac 18

<210> 647

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 647

ttaacactat ttaatatac 19

<210> 648

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 648

tttaacacta tttaatatac 20

<210> 649

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 649

tttaacacta tttaatata 19

<210> 650

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 650

attaacact attaatata 20

<210> 651

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 651

atttaacact atttaatat 19

<210> 652

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 652

catttaacac tattaatat 20

<210> 653

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 653

catttaacac tattaata 19

<210> 654

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 654

tcatttaaca ctatttaata 20

<210> 655

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 655

tcatttaaca ctatttaat 19

<210> 656

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 656

ttcatttaac actatttaat 20

<210> 657

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 657

attcatttaa cactatttaa 20

<210> 658

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 658

cattcattta acactattta 20

<210> 659

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 659

cattcattta acactattt 19

<210> 660

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 660

acattcattt aacactattt 20

<210> 661

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 661

acattcattt aacactatt 19

<210> 662

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 662

gacattcatt taacactat 19

<210> 663

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 663

gacattcatt taacacta 18

<210> 664

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 664

tgacattcat ttaacact 18

<210> 665

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 665

aaatttctat actcccat 18

<210> 666

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 666

aaaatttcta tactcccat 19

<210> 667

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 667

taaaatttct atactcccat 20

<210> 668

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 668

aaaatttcta tactccca 18

<210> 669

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 669

taaaatttct atactccca 19

<210> 670

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 670

ataaaatttc tatactccca 20

<210> 671

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 671

tataaaattt ctatactccc 20

<210> 672

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 672

taaaatttct atactccc 18

<210> 673

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 673

ataaaatttc tatactccc 19

<210> 674

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 674

ataaaatttc tatactcc 18

<210> 675

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 675

tataaaattt ctatactcc 19

<210> 676

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 676

ttataaaatt tctatactcc 20

<210> 677

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 677

tataaaattt ctatactc 18

<210> 678

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 678

ttataaaatt tctatactc 19

<210> 679

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 679

cttataaaat ttctatactc 20

<210> 680

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 680

cttataaaat ttctatact 19

<210> 681

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 681

tcttataaaa tttctatact 20

<210> 682

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 682

cttataaaat ttctatac 18

<210> 683

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 683

tcttataaaa tttctatac 19

<210> 684

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 684

ttcttataaa atttctatac 20

<210> 685

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 685

ttcttataaa atttctata 19

<210> 686

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 686

cttcttataa aatttctata 20

<210> 687

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 687

tgtcttctta taaaattt 18

<210> 688

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 688

acaataacat tcaaacat 18

<210> 689

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 689

cacaataaca ttcaaacat 19

<210> 690

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 690

acacaataac attcaaacat 20

<210> 691

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 691

cacaataaca ttcaaaca 18

<210> 692

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 692

acacaataac attcaaaca 19

<210> 693

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 693

catattaaat atcttctcta 20

<210> 694

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 694

aacttcatat taaatatc 18

<210> 695

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 695

gaacttcata ttaaatatc 19

<210> 696

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 696

ccaccaaaac acacttca 18

<210> 697

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 697

gtatttactttattcaca 18

<210> 698

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 698

ttacttctcc aatctttcca 20

<210> 699

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 699

tttacttctc caatctttcc 20

<210> 700

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 700

caaaatttac ttctccaatc 20

<210> 701

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 701

caaaatttac ttctccaat 19

<210> 702

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 702

ccaaaattta cttctccaat 20

<210> 703

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 703

caaaatttac ttctccaa 18

<210> 704

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 704

ccaaaattta cttctccaa 19

<210> 705

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 705

tccaaaattt acttctccaa 20

<210> 706

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 706

tccaaaattt acttctcca 19

<210> 707

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 707

ctccaaaatt tacttctcca 20

<210> 708

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 708

tctccaaaat ttacttctcc 20

<210> 709

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 709

ctccaaaatt tacttctc 18

<210> 710

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 710

tacatctcca aaatttac 18

<210> 711

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 711

catacatctc caaaatttac 20

<210> 712

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 712

catacatctc caaaattta 19

<210> 713

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 713

acatacatct ccaaaattta 20

<210> 714

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 714

acatacatct ccaaaattt 19

<210> 715

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 715

gacatacatc tccaaaatt 19

<210> 716

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 716

gacatacatc tccaaaat 18

<210> 717

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 717

cgacatatacat ctccaaaat 19

<210> 718

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 718

cgacatatacat ctccaaaa 18

<210> 719

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 719

cgacatatacat ctccaaa 17

<210> 720

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 720

ccgacataca tctccaaa 18

<210> 721

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 721

cgacatatacat ctccaa 16

<210> 722

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 722

ccgacataca tctccaa 17

<210> 723

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 723

ccgacataca tctcca 16

<210> 724

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 724

gccgacatac atctcc 16

<210> 725

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 725

tcctacatta tttctata 18

<210> 726

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 726

ttcctacatt atttctata 19

<210> 727

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 727

attcctacat tatttctata 20

<210> 728

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 728

aattcctaca ttatttctat 20

<210> 729

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 729

aattcctaca ttatttcta 19

<210> 730

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 730

taattcctac attatttcta 20

<210> 731

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 731

ataattccta cattatttc 19

<210> 732

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 732

tataattcct acattatttc 20

<210> 733

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 733

taattcctac attatttc 18

<210> 734

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 734

tataattcct acattattt 19

<210> 735

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 735

ttataattcc tacattattt 20

<210> 736

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 736

ttataattcc tacattatt 19

<210> 737

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 737

attataattc ctacattatt 20

<210> 738

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 738

attataattc ctacattat 19

<210> 739

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 739

gattataatt cctacatta 19

<210> 740

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 740

gattataatt cctacatt 18

<210> 741

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 741

aagtactttc acatttcc 18

<210> 742

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 742

tccttttcat cataaatca 19

<210> 743

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 743

ttccttttca tcataaatca 20

<210> 744

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 744

ttccttttca tcataaatc 19

<210> 745

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 745

attccttttc atcataaatc 20

<210> 746

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 746

ttattccttt tcatcataaa 20

<210> 747

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 747

ttattccttt tcatcataa 19

<210> 748

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 748

atgttattcc ttttcatc 18

<210> 749

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 749

tagtcactat acccct 16

<210> 750

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 750

ctagtcacta tacccc 16

<210> 751

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 751

ttctagtcac tataccc 17

<210> 752

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 752

acacttgact ataacac 17

<210> 753

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 753

atttatcttc tatccaaa 18

<210> 754

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 754

tatttatctt ctatccaaa 19

<210> 755

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 755

ttatttatct tctatccaaa 20

<210> 756

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 756

ttatttatct tctatccaa 19

<210> 757

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 757

attattttc ttctatccaa 20

<210> 758

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 758

attattttc ttctatcca 19

<210> 759

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 759

tattatttat cttctatcca 20

<210> 760

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 760

ttattattta tcttctatcc 20

<210> 761

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 761

attattatttatcttctatc 20

<210> 762

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 762

attattattt atcttctat 19

<210> 763

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 763

aattattatt tatcttctat 20

<210> 764

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 764

aattattatt tatcttcta 19

<210> 765

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 765

aaattattat ttatcttcta 20

<210> 766

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 766

taaattatta tttatcttct 20

<210> 767

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 767

ttaaattatt atttatcttc 20

<210> 768

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 768

taattaatta acctcctt 19

<210> 769

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 769

taattaatta acctccct 18

<210> 770

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 770

ttaattaatt aacctccct 19

<210> 771

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 771

ttaattaatt aacctccc 18

<210> 772

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 772

attaattaat taacctccc 19

<210> 773

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 773

aattaattaa ttaacctccc 20

<210> 774

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 774

attaattaat taacctcc 18

<210> 775

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 775

aattaattaa ttaacctcc 19

<210> 776

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 776

taattaatta attaacctcc 20

<210> 777

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 777

taattaatta attaacctc 19

<210> 778

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 778

ataattaatt aattaacctc 20

<210> 779

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 779

tataattaat taattaacct 20

<210> 780

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 780

tataattaat taattaacc 19

<210> 781

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 781

ttataattaa ttaattaacc 20

<210> 782

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 782

ataacaccaa tatattatt 19

<210> 783

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 783

tataacacca atatattatt 20

<210> 784

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 784

ctataacacc aatatattat 20

<210> 785

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 785

tataacacca atatatta 18

<210> 786

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 786

ctataacacc aatatatta 19

<210> 787

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 787

tctataacac caatatatta 20

<210> 788

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 788

ctataacacc aatatatt 18

<210> 789

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 789

tctataacac caatatatt 19

<210> 790

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 790

ctataacacc aatatat 17

<210> 791

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 791

tctataacac caatatat 18

<210> 792

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 792

gtctataaca ccaatatat 19

<210> 793

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 793

gtctataaca ccaatata 18

<210> 794

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 794

gtctataaca ccaatat 17

<210> 795

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 795

tgtctataac accaatat 18

<210> 796

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 796

ttgtctataa caccaat 17

<210> 797

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 797

tattgtcta taacacc 17

<210> 798

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 798

cacaacacat atataaccc 19

<210> 799

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 799

ccacaacaca tatataaccc 20

<210> 800

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 800

ccacaacaca tatataacc 19

<210> 801

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 801

cccacaacac atatataacc 20

<210> 802

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 802

tcccacaaca catatataac 20

<210> 803

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 803

ccacaacaca tatataac 18

<210> 804

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 804

cccacaacac atatataac 19

<210> 805

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 805

tcccacaaca catatataa 19

<210> 806

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 806

gtcccacaacacatatataa 20

<210> 807

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 807

tcccacaaca catatata 18

<210> 808

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 808

gtcccacaac acatatata 19

<210> 809

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 809

gatcgattaa gtggag 16

<210> 810

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 810

agatcgatta agtgga 16

<210> 811

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 811

aattttttct aaacccaaa 19

<210> 812

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 812

caatttttttc taaacccaaa 20

<210> 813

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 813

caatttttttc taaacccaa 19

<210> 814

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 814

gcaatttttt ctaaaccca 19

<210> 815

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 815

gcaatttttt ctaaaccc 18

<210> 816

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 816

tgcaattttt tctaaacc 18

<210> 817

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 817

tctattctca catttata 18

<210> 818

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 818

tctctattct cacatttata 20

<210> 819

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 819

ttctctattc tcacatttat 20

<210> 820

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 820

tctctattct cacatttat 19

<210> 821

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 821

ttctctattc tcacattt 18

<210> 822

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 822

ttttctctcta ttctcacatt 20

<210> 823

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 823

tttctctatt ctcacatt 18

<210> 824

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 824

ttttttctct attctcacat 20

<210> 825

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 825

aacttttttc tctattctca 20

<210> 826

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 826

taactttttt ctctattctc 20

<210> 827

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 827

ttaacttttt tctctattc 19

<210> 828

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 828

gttaactttt ttctctat 18

<210> 829

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 829

ttagtcattc ttcacacc 18

<210> 830

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 830

ccattcaatc cttaaaaaca 20

<210> 831

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 831

ccattcaatc cttaaaaac 19

<210> 832

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 832

tccattcaat ccttaaaaac 20

<210> 833

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 833

ttccattcaa tccttaaaa 19

<210> 834

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 834

tttccattca atccttaaaa 20

<210> 835

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 835

tttccattca atccttaaa 19

<210> 836

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 836

cataaaattt tcaactta 18

<210> 837

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 837

tcataaaatt ttcaactt 18

<210> 838

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 838

atcataaaat tttcaact 18

<210> 839

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 839

ttgtctttta acattcca 18

<210> 840

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 840

cactttcttt tactatctct 20

<210> 841

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 841

atcactttcttttactatct 20

<210> 842

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 842

tcactttctt ttactatc 18

<210> 843

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 843

atcactttcttttactatc 19

<210> 844

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 844

tatcactttc ttttactatc 20

<210> 845

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 845

atcactttcttttactat 18

<210> 846

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 846

tatcactttc ttttactat 19

<210> 847

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 847

tctcttatat aatttattat 20

<210> 848

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 848

ctcttatata atttatta 18

<210> 849

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 849

tacttctctt atataatt 18

<210> 850

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 850

ctacttctct tatataat 18

<210> 851

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 851

actacttgca ccctaca 17

<210> 852

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 852

cacccacata tactactt 18

<210> 853

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 853

ctccttttc atcacat 17

<210> 854

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 854

tctcctttt catcacat 18

<210> 855

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 855

ttctccttat tcatcacat 19

<210> 856

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 856

ttctctcctta ttcatcacat 20

<210> 857

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 857

ttctctcctta ttcatcaca 19

<210> 858

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 858

aattatttta ctttcatct 19

<210> 859

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 859

tgctaattat catttcct 18

<210> 860

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 860

ttatattaac tctaataatc 20

<210> 861

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 861

gccacttttt cttaactc 18

<210> 862

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 862

cataccaaaa actaatac 18

<210> 863

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 863

acataccaaa aactaatac 19

<210> 864

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 864

acttatcaac acttaaact 19

<210> 865

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 865

cacttatcaa cacttaaact 20

<210> 866

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 866

cacttatcaa cacttaaac 19

<210> 867

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 867

acacttatca acacttaaac 20

<210> 868

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 868

cacttatcaa cacttaaa 18

<210> 869

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 869

acacttatca acacttaaa 19

<210> 870

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 870

cacacttatc aacacttaaa 20

<210> 871

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 871

acacttatca acacttaa 18

<210> 872

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 872

cacacttatc aacacttaa 19

<210> 873

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 873

acacttatca acactta 17

<210> 874

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 874

cacacttatc aacactta 18

<210> 875

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 875

cacacttatc aacactt 17

<210> 876

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 876

ctatatttcc accaacaat 19

<210> 877

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 877

tctatatttc caccaacaat 20

<210> 878

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 878

tctatatttc caccaacaa 19

<210> 879

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 879

atctatattt ccaccaacaa 20

<210> 880

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 880

tttattctaa ctttatattt 20

<210> 881

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 881

attcactcta ttttcacaa 19

<210> 882

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 882

taattcactc tattttcaca 20

<210> 883

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 883

taattcactc tattttcac 19

<210> 884

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 884

ataattcact ctattttcac 20

<210> 885

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 885

taattcactc tattttca 18

<210> 886

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 886

ataattcact ctattttca 19

<210> 887

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 887

tataattcac tctattttca 20

<210> 888

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 888

tataattcac tctattttc 19

<210> 889

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 889

ttataattca ctctattttc 20

<210> 890

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 890

ttataattca ctctatttt 19

<210> 891

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 891

attataattc actctatttt 20

<210> 892

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 892

ttataattca ctctattt 18

<210> 893

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 893

attataattc actctattt 19

<210> 894

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 894

tattataatt cactctattt 20

<210> 895

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 895

attataattc actctatt 18

<210> 896

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 896

tattataatt cactctatt 19

<210> 897

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 897

ttattataat tcactctatt 20

<210> 898

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 898

tattataatt cactctat 18

<210> 899

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 899

ttattataat tcactctat 19

<210> 900

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 900

attattataa ttcactctat 20

<210> 901

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 901

ttattataat tcactcta 18

<210> 902

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 902

attattataa ttcactcta 19

<210> 903

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 903

aattattata attcactcta 20

<210> 904

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 904

aaattattat aattcactct 20

<210> 905

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 905

ataacattaa cttacattt 19

<210> 906

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 906

aataacatta acttacattt 20

<210> 907

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 907

aataacatta acttacatt 19

<210> 908

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 908

taataacatt aacttacatt 20

<210> 909

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 909

taataacatt aacttacat 19

<210> 910

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 910

ctaataacat taacttacat 20

<210> 911

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 911

ctaataacat taacttaca 19

<210> 912

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 912

tctaataaca ttaacttaca 20

<210> 913

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 913

ctaataacat taacttac 18

<210> 914

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 914

tctaataaca ttaacttac 19

<210> 915

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 915

ttctaataac attaacttac 20

<210> 916

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 916

ttctaataac attaactta 19

<210> 917

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 917

tttctaataa cattaactta 20

<210> 918

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 918

tctaataaca ttaactta 18

<210> 919

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 919

cttttctaat aacattaac 19

<210> 920

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 920

tcttttctaa taacattaac 20

<210> 921

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 921

tctttttctaa taacattaa 19

<210> 922

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 922

ttcttttcta ataacattaa 20

<210> 923

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 923

aataacatt 19

<210> 924

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 924

ctttcacctt aaactccaa 19

<210> 925

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 925

ctaaatccat acaatttct 19

<210> 926

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 926

actaaatcca tacaatttct 20

<210> 927

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 927

ctaaatccat acaatttc 18

<210> 928

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 928

actaaatcca tacaatttc 19

<210> 929

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 929

cactaaatcc atacaatttc 20

<210> 930

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 930

actaaatcca tacaattt 18

<210> 931

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 931

cactaaatcc atacaattt 19

<210> 932

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 932

acactaaatc catacaattt 20

<210> 933

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 933

tacactaaat ccatacaatt 20

<210> 934

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 934

cactaaatcc atacaatt 18

<210> 935

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 935

acactaaatc catacaatt 19

<210> 936

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 936

tacactaaat ccatacaat 19

<210> 937

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 937

ttacactaaa tccatacaat 20

<210> 938

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 938

acactaaatc catacaat 18

<210> 939

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 939

tacactaaat ccatacaa 18

<210> 940

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 940

ttacactaaa tccatacaa 19

<210> 941

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 941

cttacactaa atccatacaa 20

<210> 942

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 942

ttacactaaa tccataca 18

<210> 943

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 943

cttacactaa atccataca 19

<210> 944

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 944

acttacacta aatccataca 20

<210> 945

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 945

ttacactaaa tccatac 17

<210> 946

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 946

cttacactaa atccata 17

<210> 947

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 947

actacacta aatccata 18

<210> 948

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 948

acttacacta aatccat 17

<210> 949

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 949

gccaaataat ttttaacc 18

<210> 950

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 950

gtaatcacct taaaaatta 19

<210> 951

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 951

actattcaca aaaatattt 19

<210> 952

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 952

tactattcac aaaaatattt 20

<210> 953

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 953

tactattcac aaaaattt 19

<210> 954

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 954

ctactattca caaaaatatt 20

<210> 955

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 955

ctactattca caaaaatat 19

<210> 956

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 956

tctactattc acaaaaatat 20

<210> 957

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 957

ctactattca caaaaata 18

<210> 958

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 958

tctactattc acaaaaata 19

<210> 959

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 959

ttctactatt cacaaaaata 20

<210> 960

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 960

tctactattc acaaaaat 18

<210> 961

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 961

ttctactatt cacaaaaat 19

<210> 962

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 962

ctataaacat atctataaa 19

<210> 963

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 963

actataaaca tatctataaaa 20

<210> 964

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 964

actataaaca tatctataa 19

<210> 965

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 965

aactataaac atatctataa 20

<210> 966

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 966

taactataaa catatctata 20

<210> 967

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 967

taactataaa catatctat 19

<210> 968

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 968

taactataaa catatcta 18

<210> 969

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 969

ggatgagaat gtatgg 16

<210> 970

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 970

tattcttcta acaaaatc 18

<210> 971

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 971

atattcttct aacaaaatc 19

<210> 972

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 972

aatattcttc taacaaaatc 20

<210> 973

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 973

tgaatattct tctaacaa 18

<210> 974

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 974

ttgaatattc ttctaaca 18

<210> 975

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 975

tattgaatat tcttctaa 18

<210> 976

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 976

tgacattaat aatttctt 18

<210> 977

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 977

gtacatattc ttattcaa 18

<210> 978

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 978

ttacatcttt tttaaacaat 20

<210> 979

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 979

ttacatcttt tttaaacaa 19

<210> 980

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 980

attcttatca ttctccatt 19

<210> 981

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 981

tattcttatc attctccatt 20

<210> 982

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 982

attcttatca ttctccat 18

<210> 983

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 983

tattcttatc attctccat 19

<210> 984

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 984

gtaataaaaa tccaccat 18

<210> 985

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 985

tgtaataaaa atccacca 18

<210> 986

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 986

atcactatct tcaatcat 18

<210> 987

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 987

acttttttct aataccaaca 20

<210> 988

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 988

cttttttcta ataccaac 18

<210> 989

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 989

acttttttct aataccaac 19

<210> 990

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 990

cacttttttc taataccaac 20

<210> 991

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 991

acttttttct aataccaa 18

<210> 992

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 992

cacttttttc taataccaa 19

<210> 993

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 993

tcactttttt ctaataccaa 20

<210> 994

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 994

cacttttttc taatacca 18

<210> 995

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 995

tcactttttt ctaatacca 19

<210> 996

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 996

ttcactttt ttctaatacc 20

<210> 997

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 997

ttcactttt ttctaatac 19

<210> 998

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 998

ttttcactt ttttctaata 20

<210> 999

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 999

aaattttcac ttttttctaa 20

<210> 1000

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1000

aaattttcac ttttttcta 19

<210> 1001

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1001

aaaattttca cttttttcta 20

<210> 1002

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1002

ttatacaaac cttactat 18

<210> 1003

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1003

tttatacaaa ccttactat 19

<210> 1004

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1004

atgtttatac aaacctta 18

<210> 1005

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1005

cattcaacct ttaacatccc 20

<210> 1006

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1006

cattcaacct ttaacatcc 19

<210> 1007

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1007

acattcaacc tttaacatcc 20

<210> 1008

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1008

acattcaacc tttaacatc 19

<210> 1009

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1009

gacattcaac ctttaacat 19

<210> 1010

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1010

agacattcaa cctttaaca 19

<210> 1011

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1011

agacattcaa cctttaac 18

<210> 1012

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1012

aaagacattc aaccttta 18

<210> 1013

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1013

caaagacatt caaccttt 18

<210> 1014

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1014

ccaaagacat tcaacct 17

<210> 1015

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1015

accaaagaca ttcaacc 17

<210> 1016

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1016

taaactctcc aacatttaaa 20

<210> 1017

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1017

tataaactct ccaacatta 20

<210> 1018

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1018

atataaactc tccaacattt 20

<210> 1019

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1019

tataaactct ccaacatt 18

<210> 1020

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1020

atataaactc tccaacatt 19

<210> 1021

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1021

aatataaact ctccaacatt 20

<210> 1022

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1022

tataaactct ccaacat 17

<210> 1023

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1023

atataaactc tccaacat 18

<210> 1024

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1024

aatataaact ctccaacat 19

<210> 1025

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1025

aaatataaac tctccaacat 20

<210> 1026

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1026

aatataaact ctccaaca 18

<210> 1027

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1027

taaaatataa actctccaac 20

<210> 1028

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1028

taaaatataa actctccaa 19

<210> 1029

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1029

atttcatatt attcattaaaa 20

<210> 1030

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1030

aatttcatat tattcattaa 20

<210> 1031

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1031

atttcatatt attcattaa 19

<210> 1032

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1032

aatttcatat tattcatta 19

<210> 1033

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1033

aaatttcata ttattcatta 20

<210> 1034

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1034

taaatttcat attattcatt 20

<210> 1035

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1035

taaatttcat attattcat 19

<210> 1036

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1036

ctaaatttca tattattcat 20

<210> 1037

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1037

ctaaatttca tattattca 19

<210> 1038

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1038

ctaaatttca tattattc 18

<210> 1039

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1039

tttacatacc attcattc 18

<210> 1040

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1040

attacatac cattcattc 19

<210> 1041

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1041

tattacata ccattcattc 20

<210> 1042

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1042

attacatac cattcatt 18

<210> 1043

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1043

tattacata ccattcatt 19

<210> 1044

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1044

tattacata ccattcat 18

<210> 1045

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1045

gtatttacat accattcat 19

<210> 1046

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1046

gtatttacat accattaca 18

<210> 1047

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1047

gtatttacat accattc 17

<210> 1048

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1048

tgtatttaca taccattc 18

<210> 1049

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1049

ctgtatttac ataccatt 18

<210> 1050

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1050

tgtaaataca atctatca 18

<210> 1051

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1051

atgtaaatac aatctatc 18

<210> 1052

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1052

gcattcatat aaatcttca 19

<210> 1053

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1053

gcattcatat aaatcttc 18

<210> 1054

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1054

taagcattca tataaatc 18

<210> 1055

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1055

caatgaattc taaccaaa 18

<210> 1056

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1056

gtcatcttta cataaaaa 18

<210> 1057

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1057

gtcacttatt cttcaaat 18

<210> 1058

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1058

atattatact ttcatttaa 19

<210> 1059

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1059

aatattatac tttcatttaa 20

<210> 1060

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1060

taatattata ctttcattta 20

<210> 1061

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1061

taatattata ctttcattt 19

<210> 1062

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1062

ttaatattat actttcattt 20

<210> 1063

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1063

gttaatatta tactttca 18

<210> 1064

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1064

ttcaaatata attatcacaa 20

<210> 1065

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1065

tattaaatc acacaacat 19

<210> 1066

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1066

tgttctataa ctaataat 18

<210> 1067

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1067

ttcatttaac tttcaacc 18

<210> 1068

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1068

ttttcatttaa ctttcaacc 19

<210> 1069

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1069

atttcattta actttcaacc 20

<210> 1070

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1070

atttcattta actttcaac 19

<210> 1071

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1071

catttcattt aactttcaac 20

<210> 1072

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1072

catttcattt aactttcaa 19

<210> 1073

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1073

gcatttcatt taactttca 19

<210> 1074

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1074

gcatttcatt taactttc 18

<210> 1075

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1075

aagcatttca tttaactt 18

<210> 1076

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1076

taattgtctt taactcc 17

<210> 1077

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1077

cttctcacat tcatcatatt 20

<210> 1078

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1078

ataatttttc ctatctcca 19

<210> 1079

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1079

aataattttt cctatctcca 20

<210> 1080

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1080

ataatttttc ctatctcc 18

<210> 1081

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1081

gaataatttttcctatctc 19

<210> 1082

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1082

tccccaataa acttcaa 17

<210> 1083

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1083

ttccccaata aacttcaa 18

<210> 1084

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1084

tattccccaa taaacttcaa 20

<210> 1085

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1085

attccccaat aaacttca 18

<210> 1086

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1086

ataattcccca ataaacttca 20

<210> 1087

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1087

aatattcccc aataaacttc 20

<210> 1088

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1088

caatattccc caataaac 18

<210> 1089

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1089

cttcacaatt taaattcaa 19

<210> 1090

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1090

acttcacaat ttaaattcaa 20

<210> 1091

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1091

cacttcacaa tttaaattca 20

<210> 1092

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1092

cacttcacaa tttaaattc 19

<210> 1093

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1093

acacttcaca atttaaattc 20

<210> 1094

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1094

acacttcaca atttaaatt 19

<210> 1095

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1095

acacttcaca atttaaat 18

<210> 1096

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1096

gacacttcac aatttaaat 19

<210> 1097

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1097

agacacttca caatttaaa 19

<210> 1098

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1098

tagacacttc acaatta 18

<210> 1099

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1099

atagacactt cacaattt 18

<210> 1100

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1100

ttgacataca aacccaaa 18

<210> 1101

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1101

cacttgacat acaaaccc 18

<210> 1102

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1102

cacttgacat acaaacc 17

<210> 1103

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1103

ccacttgaca tacaaac 17

<210> 1104

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1104

tatagagatg aagtta 16

<210> 1105

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1105

ctatagagat gaagtt 16

<210> 1106

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1106

ccttgaaaac ttccataa 18

<210> 1107

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1107

cagatattcc tttaaacc 18

<210> 1108

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1108

tcagatattc ctttaaac 18

<210> 1109

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1109

tattaatcaa atatttacta 20

<210> 1110

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1110

attattaatc aaatatttac 20

<210> 1111

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1111

tattattaat caaatattatta 20

<210> 1112

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1112

ctattattaa tcaaatattt 20

<210> 1113

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1113

ctattattaa tcaaatattt 19

<210> 1114

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1114

ctattattaa tcaaatat 18

<210> 1115

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1115

gctattatta atcaaata 18

<210> 1116

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1116

tgccattaac ttttttat 18

<210> 1117

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1117

catatcacct cctccaaaa 19

<210> 1118

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1118

tacagcatat cacctcct 18

<210> 1119

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1119

ctacagcata tcacctcc 18

<210> 1120

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1120

ctacagcata tcacctc 17

<210> 1121

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1121

ctctacagca tatcacc 17

<210> 1122

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1122

gacttctatt aaaaattca 19

<210> 1123

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1123

gacttctatt aaaaattc 18

<210> 1124

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1124

tttacttatt tactcataa 19

<210> 1125

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1125

accactaact ccatttaatt 20

<210> 1126

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1126

cactaactcc atttaatt 18

<210> 1127

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1127

ccactaactc catttaatt 19

<210> 1128

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1128

accactaact ccatttaat 19

<210> 1129

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1129

aaccactaac tccatttaat 20

<210> 1130

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1130

ccactaactc catttaat 18

<210> 1131

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1131

aaccactaac tccattaa 19

<210> 1132

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1132

aaaccactaa ctccatttaa 20

<210> 1133

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1133

accactaact ccattaa 18

<210> 1134

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1134

aaccactaac tccatta 18

<210> 1135

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1135

aaaccactaa ctccattta 19

<210> 1136

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1136

aaccactaac tccatt 17

<210> 1137

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1137

aaaccactaa ctccattt 18

<210> 1138

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1138

tgctatacaa atctacc 17

<210> 1139

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1139

tcaccacatt aattaaac 18

<210> 1140

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1140

atcaccacat taattaaac 19

<210> 1141

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1141

gatcaccaca ttaattaaa 19

<210> 1142

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1142

atcaccacat taattaaa 18

<210> 1143

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1143

gatcaccaca ttaattaa 18

<210> 1144

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1144

gatcaccaca ttaatta 17

<210> 1145

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1145

tagatcacca cattaat 17

<210> 1146

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1146

atagatcacc acattaat 18

<210> 1147

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1147

atagatcacc acattaa 17

<210> 1148

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1148

tattaaaatc cttcaact 18

<210> 1149

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1149

tatattaaaa tccttcaact 20

<210> 1150

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1150

tatattaaaa tccttcaac 19

<210> 1151

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1151

ttatattaaa atccttcaac 20

<210> 1152

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1152

ttatattaaa atccttcaa 19

<210> 1153

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1153

attatattaa aatccttcaa 20

<210> 1154

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1154

tattatatta aaatccttca 20

<210> 1155

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1155

tattatatta aaatccttc 19

<210> 1156

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1156

atattatatt aaaatccttc 20

<210> 1157

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1157

tatattatat taaaatcctt 20

<210> 1158

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1158

tatattatat taaaatcct 19

<210> 1159

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1159

ttctctattt atttctacct 20

<210> 1160

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1160

tctctattta tttctacc 18

<210> 1161

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1161

aatttctcta tttatttcta 20

<210> 1162

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1162

taaatttctc tatttatttc 20

<210> 1163

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1163

tttctaaatt tctctattta 20

<210> 1164

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1164

caatgcttaa tacttat 17

<210> 1165

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1165

ccaatgctta atactta 17

<210> 1166

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1166

ttccataaaa tatttaacct 20

<210> 1167

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1167

atcatttcca taaaatattt 20

<210> 1168

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1168

aatcatttcc ataaaatatt 20

<210> 1169

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1169

ctgataaatc attataat 18

<210> 1170

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1170

tcaaattcct aaatcata 18

<210> 1171

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1171

tacattaact aaaaaccaa 19

<210> 1172

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1172

ttacattaac taaaaaccaa 20

<210> 1173

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1173

tacattaact aaaaacca 18

<210> 1174

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1174

ttacattaac taaaaacca 19

<210> 1175

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1175

ttacattaac taaaaacc 18

<210> 1176

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1176

gttacattaa ctaaaaacc 19

<210> 1177

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1177

catgttacat taactaaa 18

<210> 1178

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1178

tcatgttaca ttaacta 17

<210> 1179

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1179

gggatttgag tagatt 16

<210> 1180

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1180

caaagacaca atagtg 16

<210> 1181

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1181

gcaaagacac aatagt 16

<210> 1182

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1182

cataatatca aatatttact 20

<210> 1183

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1183

cataatatca aatatttac 19

<210> 1184

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1184

tcataatatc aaatatttac 20

<210> 1185

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1185

tcataatatc aaatattatta 19

<210> 1186

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1186

agaacaaaca aacaacacac 20

<210> 1187

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1187

atgttaaact atattcaa 18

<210> 1188

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1188

tttctatcaa cattttctac 20

<210> 1189

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1189

attttctatc aacattttc 19

<210> 1190

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1190

aattttctat caacattttc 20

<210> 1191

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1191

aattttctat caacatttt 19

<210> 1192

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1192

taatttttcta tcaacatttt 20

<210> 1193

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1193

taatttttcta tcaacattt 19

<210> 1194

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1194

ataatttttct atcaacattt 20

<210> 1195

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1195

atcaacatt 19

<210> 1196

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1196

tataattttc tatcaacatt 20

<210> 1197

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1197

tataattttc tatcaacat 19

<210> 1198

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1198

ctataatttt ctatcaacat 20

<210> 1199

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1199

ctataatttt ctatcaaca 19

<210> 1200

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1200

tctataattt tctatcaaca 20

<210> 1201

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1201

ctataatttt ctatcaac 18

<210> 1202

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1202

tctataattt tctatcaac 19

<210> 1203

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1203

atctataatt ttctatcaac 20

<210> 1204

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1204

tctataattt tctatcaa 18

<210> 1205

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1205

atctataatt ttctatcaa 19

<210> 1206

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1206

aatctataat tttctatcaa 20

<210> 1207

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1207

atctataatt ttctatca 18

<210> 1208

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1208

aatctataat tttctatca 19

<210> 1209

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1209

ctactaccaa atctataa 18

<210> 1210

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1210

tccttttcca attatatat 19

<210> 1211

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1211

ctccttttcc aattatatat 20

<210> 1212

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1212

ctccttttcc aattatata 19

<210> 1213

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1213

cctccttttc caattatata 20

<210> 1214

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1214

ctccttttcc aattatat 18

<210> 1215

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1215

cctccttttc caattatat 19

<210> 1216

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1216

acctcctttt ccaattatat 20

<210> 1217

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1217

attgtttaca tactct 16

<210> 1218

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1218

atgttattta atcatcaa 18

<210> 1219

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1219

gaatttacat aatctttt 18

<210> 1220

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1220

cagaatttac ataatctt 18

<210> 1221

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1221

acagaattta cataatct 18

<210> 1222

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1222

gttatcaaaa aattacaat 19

<210> 1223

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1223

aaaataccttttattctctc 20

<210> 1224

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1224

taaccca 17

<210> 1225

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1225

ttatttttac cacaaacaa 19

<210> 1226

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1226

tttattttta ccacaaacaa 20

<210> 1227

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1227

tttattttta ccacaaaca 19

<210> 1228

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1228

atttattttt accacaaaca 20

<210> 1229

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1229

atttattttt accacaaac 19

<210> 1230

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1230

tattatttt taccacaaac 20

<210> 1231

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1231

aatttcaact ccaattta 18

<210> 1232

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1232

aaatttcaac tccaattta 19

<210> 1233

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1233

taaatttcaa ctccaattta 20

<210> 1234

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1234

taaatttcaa ctccaattt 19

<210> 1235

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1235

aatttttcc ctatacct 18

<210> 1236

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1236

caatttttc cctatacct 19

<210> 1237

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1237

aatttttcc ctatacc 17

<210> 1238

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1238

caatttttc cctatacc 18

<210> 1239

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1239

acaattttat ccctatacc 19

<210> 1240

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1240

cacaatttta tccctatacc 20

<210> 1241

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1241

acaattttat ccctatac 18

<210> 1242

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1242

cacaatttta tccctatac 19

<210> 1243

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1243

cacaatttta tccctata 18

<210> 1244

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1244

aacaacaaac acttcatat 19

<210> 1245

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1245

taacaacaaa cacttcatat 20

<210> 1246

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1246

taacaacaaa cacttcata 19

<210> 1247

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1247

ataacaacaa acacttcata 20

<210> 1248

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1248

taacaacaaa cacttcat 18

<210> 1249

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1249

ataacaacaa acacttcat 19

<210> 1250

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1250

tataacaaca aacacttcat 20

<210> 1251

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1251

ataacaacaa acacttca 18

<210> 1252

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1252

tataacaaca aacacttc 18

<210> 1253

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1253

atataacaac aaacacttc 19

<210> 1254

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1254

aatataacaa caaacacttc 20

<210> 1255

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1255

atataacaac aaacactt 18

<210> 1256

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1256

gaatataaca acaaacact 19

<210> 1257

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1257

agaatataac aacaaacac 19

<210> 1258

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1258

cttaactttt acaaattaat 20

<210> 1259

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1259

cttaactttt acaaattaa 19

<210> 1260

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1260

tcttaacttt tacaaattaa 20

<210> 1261

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1261

tcttaacttt tacaaatta 19

<210> 1262

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1262

ttcttaactt ttacaaatta 20

<210> 1263

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1263

ttcttaactt ttacaaatt 19

<210> 1264

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1264

gttcttaact tttacaaa 18

<210> 1265

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1265

aagttcttaa cttttaca 18

<210> 1266

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1266

tgattaacat ttaactat 18

<210> 1267

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1267

aagtacatac acatcacca 19

<210> 1268

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1268

aagtacatac acatcacc 18

<210> 1269

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1269

actttctcat taatatta 19

<210> 1270

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1270

aactttctca ttaatattatta 20

<210> 1271

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1271

taactttctc attaatattt 20

<210> 1272

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1272

taactttctc attaatatt 19

<210> 1273

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1273

ttaactttct cattaatatt 20

<210> 1274

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1274

ttaactttct cattaatat 19

<210> 1275

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1275

attaactttc tcattaatat 20

<210> 1276

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1276

attaactttc tcattaata 19

<210> 1277

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1277

cattaacttt ctcattaata 20

<210> 1278

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1278

attaactttc tcattaat 18

<210> 1279

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1279

cattaacttt ctcattaat 19

<210> 1280

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1280

tcattaactt tctcattaat 20

<210> 1281

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1281

atcattaact ttctcattaa 20

<210> 1282

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1282

atcattaact ttctcatta 19

<210> 1283

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1283

acatcattaa ctttctcatt 20

<210> 1284

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1284

catcattaac tttctcat 18

<210> 1285

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1285

acatcattaa ctttctcat 19

<210> 1286

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1286

gacatcatta actttctca 19

<210> 1287

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1287

gacatcatta actttctc 18

<210> 1288

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1288

cgacatcatt aactttctc 19

<210> 1289

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1289

cgacatcatt aactttct 18

<210> 1290

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1290

cgacatcatt aactttc 17

<210> 1291

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1291

acgacatcat taacttt 17

<210> 1292

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1292

aacgacatca ttaacttt 18

<210> 1293

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1293

aacgacatca ttaactt 17

<210> 1294

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1294

gcatatacatat ttaacaca 18

<210> 1295

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1295

agcatacata tttaacaca 19

<210> 1296

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1296

agcatacata tttaacac 18

<210> 1297

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1297

cttcattcta atatttaaa 19

<210> 1298

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1298

tcttcattct aatattattaaa 20

<210> 1299

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1299

tcttcattct aatatttaa 19

<210> 1300

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1300

ccttcttcat tctaatatt 19

<210> 1301

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1301

ccttcttcat tctaatat 18

<210> 1302

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1302

tccttcttca ttctaatat 19

<210> 1303

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1303

caggatccac aggcat 16

<210> 1304

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1304

catttcataa gcctca 16

<210> 1305

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1305

gcatttcata agcctc 16

<210> 1306

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1306

ggcatttcat aagcct 16

<210> 1307

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1307

aggcatttca taagcc 16

<210> 1308

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1308

aaggcatttc ataagc 16

<210> 1309

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1309

ctaaaaatat attctctaat 20

<210> 1310

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1310

ctaaaaatat attctctaa 19

<210> 1311

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1311

tctaaaaata tattctctaa 20

<210> 1312

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1312

tctaaaaata tattctcta 19

<210> 1313

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1313

ttctaaaaat atattctcta 20

<210> 1314

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1314

ccctaacttt ccattta 17

<210> 1315

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1315

atttccctaa ctttccatt 19

<210> 1316

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1316

gatttcccta actttcca 18

<210> 1317

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1317

tgatttccct aactttcca 19

<210> 1318

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1318

gatacatttt ctattaaa 18

<210> 1319

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1319

tgatacattt tctattaa 18

<210> 1320

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1320

agttttttc atctaaca 18

<210> 1321

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1321

agtattaatt cccttta 18

<210> 1322

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1322

ttaatctcaa ttttctataa 19

<210> 1323

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1323

tttaatctca atttctataa 20

<210> 1324

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1324

aatttaatct caatttctat 20

<210> 1325

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1325

aatttaatct caatttcta 19

<210> 1326

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1326

caatttaatc tcaatttcta 20

<210> 1327

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1327

caatttaatc tcaatttct 19

<210> 1328

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1328

acaatttaat ctcaatttct 20

<210> 1329

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1329

caatttaatc tcaatttc 18

<210> 1330

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1330

acaatttaat ctcaatttc 19

<210> 1331

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1331

aacaatttaa tctcaatttc 20

<210> 1332

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1332

ttttcatcaa acctacca 18

<210> 1333

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1333

tttttcatca aacctacca 19

<210> 1334

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1334

ttttttcatc aaacctacca 20

<210> 1335

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1335

ttttttcatc aaacctacc 19

<210> 1336

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1336

tttttttcat caaacctacc 20

<210> 1337

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1337

ccagatcaac attacctc 18

<210> 1338

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1338

accagatca acattacc 18

<210> 1339

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1339

accagatca accattac 17

<210> 1340

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1340

cacccagatc aacatta 17

<210> 1341

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1341

cccaccagat caacatt 17

<210> 1342

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1342

aatctatcac cattttcctt 20

<210> 1343

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1343

tctatcacca ttttcctt 18

<210> 1344

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1344

aatctatcac cattttcct 19

<210> 1345

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1345

atctatcacc atttttcct 18

<210> 1346

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1346

tcaatctatc accattttc 19

<210> 1347

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1347

ttcaatctat caccattttc 20

<210> 1348

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1348

caatctatca ccattttc 18

<210> 1349

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1349

cctaatactc tataactt 18

<210> 1350

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1350

attatcctaa tactctataa 20

<210> 1351

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1351

tatcctaata ctctataa 18

<210> 1352

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1352

ttatcctaat actctata 18

<210> 1353

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1353

attatcctaa tactctat 18

<210> 1354

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1354

atatttctta ggcttcag 18

<210> 1355

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1355

gatattttctt aggcttca 18

<210> 1356

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1356

agatattttct taggcttc 18

<210> 1357

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1357

aagatatttc ttaggctt 18

<210> 1358

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1358

aaagatattt cttaggct 18

<210> 1359

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1359

aagatatttc ttaggc 16

<210> 1360

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1360

gcaaagatat ttcttaggg 18

<210> 1361

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1361

agcaaagata tttcttag 18

<210> 1362

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1362

gagcaaagat atttctta 18

<210> 1363

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1363

ggagcaaaga tatttctt 18

<210> 1364

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1364

ctgggagcaa agatatttct 20

<210> 1365

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1365

tgggagcaaa gatatttc 18

<210> 1366

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1366

ctgggagcaa agatattt 18

<210> 1367

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1367

tgggagcaaa gatatt 16

<210> 1368

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1368

ctgggagcaa agatat 16

<210> 1369

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1369

actgggagca aagata 16

<210> 1370

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1370

gaaactggga gcaaagat 18

<210> 1371

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1371

agaaactgggg agcaaaga 18

<210> 1372

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1372

aagaaactgg gagcaaag 18

<210> 1373

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1373

agatctcaag aaactgggg 18

<210> 1374

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1374

gatctcaaga aactgg 16

<210> 1375

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1375

gcagatctca agaaactg 18

<210> 1376

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1376

agcagatctc aagaaact 18

<210> 1377

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1377

gcagatctca agaaac 16

<210> 1378

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1378

tcagcagatc tcaagaaa 18

<210> 1379

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1379

gtcagcagat ctcaagaa 18

<210> 1380

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1380

tcagcagatc tcaaga 16

<210> 1381

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1381

gaactgagca cttgtaca 18

<210> 1382

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1382

ggaactgagc acttgtac 18

<210> 1383

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1383

tggaactgag cacttgta 18

<210> 1384

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1384

ggaactgagc acttgt 16

<210> 1385

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1385

attggaactg agcacttg 18

<210> 1386

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1386

ttggaactga gcactt 16

<210> 1387

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1387

acattggaac tgagcact 18

<210> 1388

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1388

cattggaact gagcac 16

<210> 1389

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1389

cacattggaa ctgagcac 18

<210> 1390

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1390

aactttgaga aatgtcat 18

<210> 1391

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1391

aaactttgag aaatgtca 18

<210> 1392

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1392

tgctgatgga agactt 16

<210> 1393

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1393

ctgctgatgg aagact 16

<210> 1394

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1394

actgctgatg gaagac 16

<210> 1395

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1395

atcactgctg atggaaga 18

<210> 1396

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1396

ggcaggtaca gatact 16

<210> 1397

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1397

aatccacagc acacaaagac 20

<210> 1398

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1398

atccacagca cacaaaga 18

<210> 1399

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1399

aatccacagc acacaaag 18

<210> 1400

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1400

aaatccacag cacacaaa 18

<210> 1401

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1401

gaaataagtg gtagtcac 18

<210> 1402

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1402

agaaataagt ggtagtca 18

<210> 1403

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1403

gaaataagtg gtagtc 16

<210> 1404

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1404

agaaataagt ggtagt 16

<210> 1405

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1405

ttagaaataa gtggtagt 18

<210> 1406

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1406

tagaaataag tggtag 16

<210> 1407

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1407

tttagaaata agtggtag 18

<210> 1408

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1408

ggatttagaa ataagtggta 20

<210> 1409

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1409

gattagaaa taagtggt 18

<210> 1410

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1410

ggatttagaa ataagtgg 18

<210> 1411

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1411

tgaggattta gaaataagtg 20

<210> 1412

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1412

gtgaggattt agaaataagt 20

<210> 1413

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1413

tgaggattta gaaataag 18

<210> 1414

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1414

gtgaggattt agaaataa 18

<210> 1415

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1415

agtgaggatt tagaaata 18

<210> 1416

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1416

tagtgaggat ttagaaat 18

<210> 1417

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1417

atagtgagga tttagaaa 18

<210> 1418

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1418

aatagtgagg atttagaa 18

<210> 1419

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1419

aatagtgagg atttag 16

<210> 1420

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1420

ttctgaacaa cagcaacaaa 20

<210> 1421

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1421

aacttctgaa caacagcaac 20

<210> 1422

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1422

caacttctga acaacagcaa 20

<210> 1423

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1423

aacttctgaa caacagca 18

<210> 1424

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1424

caacttctga acaacagca 19

<210> 1425

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1425

acaacttctg aacaacagca 20

<210> 1426

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1426

caacttctga acaacagc 18

<210> 1427

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1427

aacttctgaa caacagc 17

<210> 1428

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1428

acaacttctg aacaacagc 19

<210> 1429

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1429

aacaacttct gaacaacagc 20

<210> 1430

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1430

acaacttctg aacaacag 18

<210> 1431

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1431

aacaacttct gaacaacag 19

<210> 1432

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1432

taacaacttc tgaacaacag 20

<210> 1433

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1433

aacaacttct gaacaaca 18

<210> 1434

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1434

acaacttctg aacaaca 17

<210> 1435

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1435

taacaacttc tgaacaaca 19

<210> 1436

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1436

ctaacaactt ctgaacaaca 20

<210> 1437

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1437

acaacttctg aacaac 16

<210> 1438

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1438

ctaacaactt ctgaacaac 19

<210> 1439

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1439

actaacaact tctgaacaac 20

<210> 1440

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1440

aacaacttct gaacaac 17

<210> 1441

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1441

taacaacttc tgaacaac 18

<210> 1442

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1442

ctaacaactt ctgaacaa 18

<210> 1443

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1443

actaacaact tctgaacaa 19

<210> 1444

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1444

cactaacaac ttctgaacaa 20

<210> 1445

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1445

ctaacaactt ctgaaca 17

<210> 1446

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1446

actaacaact tctgaaca 18

<210> 1447

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1447

cactaacaac ttctgaaca 19

<210> 1448

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1448

tcactaacaa cttctgaaca 20

<210> 1449

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1449

ctaacaactt ctgaac 16

<210> 1450

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1450

cactaacaac ttctgaac 18

<210> 1451

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1451

tcactaacaa cttctgaac 19

<210> 1452

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1452

atcactaaca acttctgaac 20

<210> 1453

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1453

tcactaacaa cttctgaa 18

<210> 1454

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1454

atcactaaca acttctgaa 19

<210> 1455

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1455

aatcactaac aacttctgaa 20

<210> 1456

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1456

cactaacaac ttctga 16

<210> 1457

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1457

tcactaacaa cttctga 17

<210> 1458

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1458

atcactaaca acttctga 18

<210> 1459

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1459

aatcactaac aacttctga 19

<210> 1460

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1460

aaatcactaa caacttctga 20

<210> 1461

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1461

tcactaacaa cttctg 16

<210> 1462

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1462

atcactaaca acttctg 17

<210> 1463

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1463

aatcactaac aacttctg 18

<210> 1464

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1464

aaatcactaa caacttctg 19

<210> 1465

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1465

caaatcacta acaacttctg 20

<210> 1466

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1466

aaatcactaa caacttct 18

<210> 1467

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1467

caaatcacta acaacttct 19

<210> 1468

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1468

aatcactaac aacttct 17

<210> 1469

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1469

gcaaatcact aacaacttct 20

<210> 1470

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1470

caaatcacta acaacttc 18

<210> 1471

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1471

gcaaatcact aacaacttc 19

<210> 1472

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1472

agcaaatcac taacaacttc 20

<210> 1473

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1473

gcaaatcact aacaactt 18

<210> 1474

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1474

agcaaatcac taacaactt 19

<210> 1475

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1475

tagcaaatca ctaacaactt 20

<210> 1476

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1476

agcaaatcac taacaact 18

<210> 1477

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1477

tagcaaatca ctaacaact 19

<210> 1478

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1478

atagcaaatc actaacaact 20

<210> 1479

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1479

gcaaatcact aacaact 17

<210> 1480

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1480

tagcaaatca ctaacaac 18

<210> 1481

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1481

atagcaaatc actaacaac 19

<210> 1482

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1482

agcaaatcac taacaac 17

<210> 1483

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1483

atagcaaatc actaacaa 18

<210> 1484

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1484

tagcaaatca ctaacaa 17

<210> 1485

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1485

aaaaatctta taatatat 18

<210> 1486

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1486

taaaaatctt ataatata 18

<210> 1487

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1487

ctaaaaatct tataatata 19

<210> 1488

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1488

cctaaaaatc ttataatata 20

<210> 1489

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1489

ctaaaaatct tataatat 18

<210> 1490

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1490

cctaaaaatc ttataata 18

<210> 1491

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1491

acctaaaaat cttataata 19

<210> 1492

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1492

acacctaaaa atcttataat 20

<210> 1493

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1493

cacctaaaaa tcttataa 18

<210> 1494

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1494

acacctaaaa atcttata 18

<210> 1495

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1495

gacacctaaa aatcttata 19

<210> 1496

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1496

gacacctaaa aatcttat 18

<210> 1497

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1497

agacacctaa aaatcttat 19

<210> 1498

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1498

gacacctaaa aatctta 17

<210> 1499

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1499

ttagacagta tcattaaa 18

<210> 1500

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1500

tagacagtat cattaa 16

<210> 1501

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1501

ttagacagta tcatta 16

<210> 1502

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1502

cttagacagt atcatt 16

<210> 1503

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1503

attcttagac agtatcat 18

<210> 1504

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1504

tattcttaga cagtatca 18

<210> 1505

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1505

attcttagac agtatc 16

<210> 1506

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1506

attattctta gacagtat 18

<210> 1507

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1507

ttatctcttag acagta 16

<210> 1508

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1508

cattattctt agacag 16

<210> 1509

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1509

caatacgtca ttattc 16

<210> 1510

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1510

cacaatacgt cattat 16

<210> 1511

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1511

tcacaatacg tcatta 16

<210> 1512

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1512

ttcacaatac gtcatt 16

<210> 1513

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1513

atttcacaat acgtcatt 18

<210> 1514

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1514

tttcacaata cgtcat 16

<210> 1515

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1515

atttcacaat acgtcat 17

<210> 1516

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1516

atttcacaat acgtca 16

<210> 1517

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1517

aatttcacaa tacgtc 16

<210> 1518

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1518

caaatttcac aatacg 16

<210> 1519

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1519

attaacaaat ttcacaatac 20

<210> 1520

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1520

atatattaac aaatttcaca 20

<210> 1521

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1521

tatatattaa caaatttcac 20

<210> 1522

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1522

atatattaac aaatttcac 19

<210> 1523

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1523

atatattaac aaatttca 18

<210> 1524

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1524

tatatattaa caaatttca 19

<210> 1525

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1525

atatatatta acaaatttca 20

<210> 1526

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1526

tatatattaa caaatttc 18

<210> 1527

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1527

atatatatta acaaatttc 19

<210> 1528

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1528

tatatatatt aacaaatttc 20

<210> 1529

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1529

atatatatta acaaattt 18

<210> 1530

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1530

tatatatatt aacaaatt 18

<210> 1531

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1531

ttatatatat taacaaat 18

<210> 1532

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1532

attatatata ttaacaaa 18

<210> 1533

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1533

tattatatat attaacaa 18

<210> 1534

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1534

gtattatata tattaaca 18

<210> 1535

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1535

agtattatat atattaac 18

<210> 1536

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1536

aagtattata tatattaa 18

<210> 1537

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1537

tttaagtatt atatatatta 20

<210> 1538

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1538

catagtttca tgctca 16

<210> 1539

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1539

tttataggtg catagt 16

<210> 1540

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1540

tattatagg tgcata 16

<210> 1541

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1541

ttatatacaa acacaagt 18

<210> 1542

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1542

tttatataca aacacaag 18

<210> 1543

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1543

atttatatac aaacacaa 18

<210> 1544

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1544

catttata caaacacaa 19

<210> 1545

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1545

ccatttatat acaaacacaa 20

<210> 1546

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1546

catttata caaacaca 18

<210> 1547

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1547

acaaacaca 19

<210> 1548

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1548

accatttata tacaaacaca 20

<210> 1549

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1549

caccatttat atacaaacac 20

<210> 1550

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1550

ccatttatat acaaacac 18

<210> 1551

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1551

accatttata tacaaacac 19

<210> 1552

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1552

ctcaccattt atatacaaac 20

<210> 1553

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1553

tctcaccatt tatatacaaa 20

<210> 1554

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1554

ttctcaccat ttatatacaa 20

<210> 1555

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1555

attctcacca tttatataca 20

<210> 1556

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1556

tctcaccatt tatataca 18

<210> 1557

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1557

ttctcaccat ttatatac 18

<210> 1558

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1558

attctcacca tttatata 18

<210> 1559

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1559

taattctcac catttatata 20

<210> 1560

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1560

ttaattctca ccattattat 20

<210> 1561

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1561

tttaattctc accatttata 20

<210> 1562

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1562

ttttaattct caccatttat 20

<210> 1563

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1563

attttaattc tcaccattta 20

<210> 1564

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1564

tattttaatt ctcaccattt 20

<210> 1565

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1565

ttattttaat tctcaccatt 20

<210> 1566

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1566

aaagtgagat gggata 16

<210> 1567

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1567

cagttcttaa ttcatg 16

<210> 1568

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1568

ttctaaaatt ccttccttc 18

<210> 1569

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1569

cttctaaaat tcctcctt 18

<210> 1570

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1570

tcttctaaaa ttcctcct 18

<210> 1571

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1571

ctcttctaaa attcctcc 18

<210> 1572

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1572

tacctcttct aaaattcctc 20

<210> 1573

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1573

cctcttctaa aattcctc 18

<210> 1574

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1574

acctcttcta aaattcct 18

<210> 1575

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1575

tacctcttct aaaattcc 18

<210> 1576

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1576

tctacctctt ctaaaattcc 20

<210> 1577

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1577

ctacctcttc taaaattc 18

<210> 1578

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1578

ctctacctct tctaaaattc 20

<210> 1579

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1579

tccattttct ctacctct 18

<210> 1580

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1580

ttccattttc tctacctc 18

<210> 1581

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1581

agggttaatg ttccattt 18

<210> 1582

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1582

attattctta gacagt 16

<210> 1583

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1583

tagggttaat gttccatt 18

<210> 1584

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1584

agggttaatg ttccat 16

<210> 1585

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1585

tagggttaat gttcca 16

<210> 1586

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1586

gtagggttaa tgttcc 16

<210> 1587

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1587

tgtagggtta atgttc 16

<210> 1588

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1588

gtgtagggtt aatgtt 16

<210> 1589

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1589

agtgtagggt taatgt 16

<210> 1590

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1590

caataattaa tcacag 16

<210> 1591

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1591

gattgaaggg agaaat 16

<210> 1592

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1592

atcttctaca ctgctt 16

<210> 1593

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1593

aatgtgtctt atggct 16

<210> 1594

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1594

gctaatgtgt cttatg 16

<210> 1595

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1595

aatatgtgct aatgtg 16

<210> 1596

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1596

taatatgtgc taatgt 16

<210> 1597

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1597

atgtgctaat atgtgc 16

<210> 1598

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1598

tgaatgtgct aatatgtg 18

<210> 1599

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1599

gaatgtgcta atatgt 16

<210> 1600

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1600

cttgaatgtg ctaatatg 18

<210> 1601

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1601

ccttgaatgt gctaatat 18

<210> 1602

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1602

cttgaatgtg ctaata 16

<210> 1603

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1603

ttaaccacat tctctc 16

<210> 1604

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1604

gtttaaaggc atttcctg 18

<210> 1605

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1605

tgtttaaagg catttcct 18

<210> 1606

<211> 9

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1606

agagaattg 9

<210> 1607

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1607

tatatttggc aacatttaaa 20

<210> 1608

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1608

atatttggca acatttaa 18

<210> 1609

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1609

tatatttggc aacattta 18

<210> 1610

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1610

atatatttgg caacattt 18

<210> 1611

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1611

catatatttg gcaacatt 18

<210> 1612

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1612

tcatatattt ggcaacat 18

<210> 1613

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1613

aattcatata tttggcaaca 20

<210> 1614

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1614

gaattcatat atttggcaac 20

<210> 1615

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1615

aattcatata tttggcaa 18

<210> 1616

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1616

gaattcatat atttggca 18

<210> 1617

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1617

agaattcata tatttggc 18

<210> 1618

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1618

tagaattcat atatttgg 18

<210> 1619

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1619

ctagaattca tatatttg 18

<210> 1620

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1620

cctagaattc atatattt 18

<210> 1621

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1621

tcctagaatt catatatt 18

<210> 1622

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1622

atcctagaat tcatatat 18

<210> 1623

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1623

taatagatct tccctgaa 18

<210> 1624

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1624

ttaatagatc ttccctga 18

<210> 1625

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1625

gttaatagat cttccctg 18

<210> 1626

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1626

agttaataga tcttccct 18

<210> 1627

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1627

gttaatagat cttccc 16

<210> 1628

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1628

agttaataga tcttcc 16

<210> 1629

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1629

gagttaatag atcttc 16

<210> 1630

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1630

tcaccatcaa gtttattt 18

<210> 1631

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1631

ttcaccatca agtttatt 18

<210> 1632

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1632

tcaccatcaa gtttat 16

<210> 1633

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1633

ttcaccatca agttta 16

<210> 1634

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1634

ctttctacta gtgacttt 18

<210> 1635

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1635

tttctactatag tgactt 16

<210> 1636

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1636

gtgact 16

<210> 1637

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1637

actttctact agtgac 16

<210> 1638

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1638

tactttctac tagtga 16

<210> 1639

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1639

atactttcta ctagtg 16

<210> 1640

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1640

tatactttct actagt 16

<210> 1641

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1641

ttatactttc tactag 16

<210> 1642

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1642

aaattatact ttctacta 18

<210> 1643

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1643

ttgaaattat actttctact 20

<210> 1644

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1644

tgaaattata ctttctac 18

<210> 1645

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1645

ttgaaattat actttcta 18

<210> 1646

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1646

cttgaaatta tactttct 18

<210> 1647

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1647

tgtcttgaaa ttatactttc 20

<210> 1648

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1648

ctgtcttgaa attachacttt 20

<210> 1649

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1649

tgtcttgaaa ttatactt 18

<210> 1650

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1650

ctgtcttgaa attack 18

<210> 1651

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1651

tctgtcttga aattatac 18

<210> 1652

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1652

tagcatgtct agaata 16

<210> 1653

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1653

cattactcat gaatac 16

<210> 1654

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1654

acattactca tgaata 16

<210> 1655

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1655

cacattactc atgaat 16

<210> 1656

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1656

atatcacatt actcat 16

<210> 1657

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1657

atatatcaca ttactcat 18

<210> 1658

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1658

tatatatcac attactcat 19

<210> 1659

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1659

atatatatca cattactcat 20

<210> 1660

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1660

tatatcacat tactca 16

<210> 1661

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1661

atatatatca cattactca 19

<210> 1662

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1662

aatatatatc acattactca 20

<210> 1663

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1663

atatatatca cattactc 18

<210> 1664

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1664

caatatatat cacattactc 20

<210> 1665

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1665

aatatatatc acattactc 19

<210> 1666

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1666

ccaatatata tcacattact 20

<210> 1667

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1667

caatatatat cacattact 19

<210> 1668

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1668

cccaatatat atcacattac 20

<210> 1669

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1669

caatatatat cacattac 18

<210> 1670

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1670

ccaatatata tcacattac 19

<210> 1671

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1671

ccaatata tcacatta 18

<210> 1672

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1672

cccaatatat atcacatta 19

<210> 1673

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1673

cccaatatat atcacatt 18

<210> 1674

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1674

gcccaatata tatcacatt 19

<210> 1675

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1675

gcccaatata tatcacat 18

<210> 1676

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1676

cccaatatat atcaca 16

<210> 1677

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1677

gcccaatata tatcaca 17

<210> 1678

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1678

atagtcactc attcctcc 18

<210> 1679

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1679

tatagtcact cattcctc 18

<210> 1680

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1680

ccttatagtc actcattc 18

<210> 1681

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1681

ccttatagtc actcat 16

<210> 1682

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1682

catccttata gtcactca 18

<210> 1683

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1683

ccatccttat agtcactc 18

<210> 1684

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1684

catccttata gtcact 16

<210> 1685

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1685

ccatccttat agtcac 16

<210> 1686

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1686

accatcctta tagtca 16

<210> 1687

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1687

aaccatcctt atagtc 16

<210> 1688

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1688

gtaaccatcc ttatag 16

<210> 1689

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1689

gcactctgta gtagtc 16

<210> 1690

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1690

agcactctgt agtagt 16

<210> 1691

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1691

cttagcactc tgtagtag 18

<210> 1692

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1692

gcttagcact ctgtagta 18

<210> 1693

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1693

cttagcactc tgtagt 16

<210> 1694

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1694

gcttagcact ctgtag 16

<210> 1695

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1695

agcttagcac tctgta 16

<210> 1696

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1696

cagcttagca ctctgt 16

<210> 1697

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1697

gcagcttagc actctg 16

<210> 1698

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1698

tgcagcttag cactct 16

<210> 1699

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1699

atgcagctta gcactc 16

<210> 1700

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1700

cttaccattt ctctctag 18

<210> 1701

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1701

acttaccatt tctctcta 18

<210> 1702

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1702

aacttaccat ttctctct 18

<210> 1703

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1703

aaacttacca tttctctc 18

<210> 1704

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1704

acataactta aataaaac 18

<210> 1705

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1705

ttaaacataa cttaaataaa 20

<210> 1706

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1706

taaacataac ttaaataa 18

<210> 1707

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1707

ttaaacataa cttaaata 18

<210> 1708

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1708

tgcttaaaca taacttaaat 20

<210> 1709

<211> 19

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1709

gcttaaacat aacttaaat 19

<210> 1710

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1710

gcttaaacat aacttaaa 18

<210> 1711

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1711

tgcttaaaca taacttaa 18

<210> 1712

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1712

gcttaaacat aactta 16

<210> 1713

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1713

ttgcttaaac ataactta 18

<210> 1714

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1714

cttgcttaaa cataactt 18

<210> 1715

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1715

ttgcttaaac ataact 16

<210> 1716

<211> 17

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1716

cttgcttaaa cataact 17

<210> 1717

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1717

cttgcttaaa cataac 16

<210> 1718

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1718

ttccttgctt aaacataa 18

<210> 1719

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1719

tttccttgct taaacata 18

<210> 1720

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1720

tccttttcctt gcttaaacat 20

<210> 1721

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1721

ccttttccttg cttaaaca 18

<210> 1722

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1722

tccttttcctt gcttaaac 18

<210> 1723

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1723

ataacaaatc ctttcctt 18

<210> 1724

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1724

aataacaaat ccttttcct 18

<210> 1725

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1725

caataacaaa tccttttcc 18

<210> 1726

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1726

tcaataacaa atccttttc 18

<210> 1727

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1727

ttcaataaca aatccttt 18

<210> 1728

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1728

gttcaataac aaatcc 16

<210> 1729

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1729

tatactgttc aataac 16

<210> 1730

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1730

aaatatactg ttcaataa 18

<210> 1731

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1731

gaaatatact gttcaata 18

<210> 1732

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1732

tgaaatatac tgttcaat 18

<210> 1733

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1733

ctgaaatata ctgttcaa 18

<210> 1734

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1734

cctgaaatat actgttca 18

<210> 1735

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1735

ctgaaatata ctgttc 16

<210> 1736

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1736

ttcctgaaat atactgtt 18

<210> 1737

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1737

cttcctgaaa tatactgt 18

<210> 1738

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1738

ccttcctgaa atatactg 18

<210> 1739

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1739

accttcctga aatatact 18

<210> 1740

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1740

ctaaccttcc tgaaatatac 20

<210> 1741

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1741

ttctaacctt cctgaaatat 20

<210> 1742

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1742

tctaaccttc ctgaaata 18

<210> 1743

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1743

ttctaacctt cctgaaat 18

<210> 1744

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1744

tttctaacct tcctgaaa 18

<210> 1745

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1745

attataaaata tatcctaa 18

<210> 1746

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1746

gctttaggta gattaaaa 18

<210> 1747

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1747

ctttaggtag attaaa 16

<210> 1748

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1748

aatatgctgc tttaggta 18

<210> 1749

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1749

aaatatgctg ctttaggt 18

<210> 1750

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1750

aatatgctgc tttaggg 16

<210> 1751

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1751

tctatttctt aatttaat 18

<210> 1752

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1752

ctctatttct taattttaa 18

<210> 1753

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1753

cctctatttc ttaattta 18

<210> 1754

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1754

tcctctattt cttaattt 18

<210> 1755

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1755

aactttccta atctcaaa 18

<210> 1756

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1756

caactttcct aatctcaa 18

<210> 1757

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1757

acaactttcc taatctca 18

<210> 1758

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1758

caactttcct aatctc 16

<210> 1759

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1759

tcacaacttt cctaatct 18

<210> 1760

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1760

cacaactttc ctaatc 16

<210> 1761

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1761

tcacaacttt cctaat 16

<210> 1762

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1762

gtcacaactt tcctaa 16

<210> 1763

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1763

ataaatcctt aaattcat 18

<210> 1764

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1764

cacataaatc cttaaattca 20

<210> 1765

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1765

ccacataaat ccttaaattc 20

<210> 1766

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1766

tccacataaa tccttaaatt 20

<210> 1767

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1767

ccacataaat ccttaaat 18

<210> 1768

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1768

tccacataaa tccttaaa 18

<210> 1769

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1769

tatccacata aatcctta 18

<210> 1770

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1770

tatccacata aatcct 16

<210> 1771

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1771

tttgtatcca cataaatc 18

<210> 1772

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1772

aatttgtatc cacataaa 18

<210> 1773

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1773

ggagaatttg tatccacata 20

<210> 1774

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1774

gagaatttgt atccacat 18

<210> 1775

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1775

ggagaatttg tatccaca 18

<210> 1776

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1776

gagaatttgt atccac 16

<210> 1777

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1777

ggagaatttg tatcca 16

<210> 1778

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1778

ttaaaggaga atttgtatcc 20

<210> 1779

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1779

tttaaaggag aatttgtatc 20

<210> 1780

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1780

ttaaaggaga atttgtat 18

<210> 1781

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1781

cactttaaag gagaattt 18

<210> 1782

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1782

acactttaaa ggagaatt 18

<210> 1783

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1783

aatattaagg gaagaaac 18

<210> 1784

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1784

ataaatatta agggaagaaa 20

<210> 1785

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1785

taaatattaa gggaagaa 18

<210> 1786

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1786

agataaatat taagggaaga 20

<210> 1787

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1787

gataaattt aagggaag 18

<210> 1788

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1788

cagataaata ttaaggga 18

<210> 1789

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1789

actattaaga tatataaa 18

<210> 1790

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1790

aactattaag atatataa 18

<210> 1791

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1791

aaactattaa gatatata 18

<210> 1792

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1792

taaactatta agatatat 18

<210> 1793

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1793

ataaactatt 18

<210> 1794

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1794

aataaactat taagatat 18

<210> 1795

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1795

aaataaacta ttaagata 18

<210> 1796

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1796

caaataaact attaagat 18

<210> 1797

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1797

ccaaataaac tattaaga 18

<210> 1798

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1798

cccaaataaa ctattaag 18

<210> 1799

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1799

tcccaaataa actattaa 18

<210> 1800

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1800

gtcccaaata aactatta 18

<210> 1801

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1801

ggtcccaaat aaactatt 18

<210> 1802

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1802

gtcccaaata aactat 16

<210> 1803

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1803

ttggtcccaa ataaacta 18

<210> 1804

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1804

tggtcccaaa taaact 16

<210> 1805

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1805

ttggtcccaa ataaac 16

<210> 1806

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1806

ataacttggg agaatgta 18

<210> 1807

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1807

tgaataactt gggagaatgt 20

<210> 1808

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1808

gaataacttg ggagaatg 18

<210> 1809

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1809

tgaataactt gggagaat 18

<210> 1810

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1810

ctgaataact tgggagaa 18

<210> 1811

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1811

gctgaataac ttgggaga 18

<210> 1812

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1812

ctgaataact tgggag 16

<210> 1813

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1813

gctgaataac ttggga 16

<210> 1814

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1814

atgaggctga ataacttgggg 20

<210> 1815

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1815

tgaggctgaa taacttgg 18

<210> 1816

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1816

atgaggctga ataacttg 18

<210> 1817

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1817

tatgaggctg aataactt 18

<210> 1818

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1818

atgaggctga ataact 16

<210> 1819

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1819

tatgaggctg aataac 16

<210> 1820

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1820

atatgaggct gaataa 16

<210> 1821

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1821

catatgaggc tgaata 16

<210> 1822

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1822

gtcatatgag gctgaa 16

<210> 1823

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1823

tggagtcata tgaggc 16

<210> 1824

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1824

gtggagtcat atgagg 16

<210> 1825

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1825

acacattaga ttgttctg 18

<210> 1826

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1826

acacattaga ttgttc 16

<210> 1827

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1827

ataccaaacc acacatta 18

<210> 1828

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1828

aataccaaac cacacatt 18

<210> 1829

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1829

gaataccaaa ccacac 16

<210> 1830

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1830

caaatagcta catact 16

<210> 1831

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1831

attatgtcac aaatagctac 20

<210> 1832

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1832

tattatgtca caaaatagcta 20

<210> 1833

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1833

attatgtcac aaatagct 18

<210> 1834

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1834

ttattatgtc acaaatagct 20

<210> 1835

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1835

tattatgtca caaaatagc 18

<210> 1836

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1836

tttattatgt cacaaaatagc 20

<210> 1837

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1837

attatgtcac aaatag 16

<210> 1838

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1838

atttattatg tcacaaatag 20

<210> 1839

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1839

ttattatgtc acaaatag 18

<210> 1840

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1840

tttattatgt cacaaata 18

<210> 1841

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1841

tattatgtca caaata 16

<210> 1842

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1842

atttattatg tcacaaat 18

<210> 1843

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1843

tattattat gtcacaaa 18

<210> 1844

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1844

atatatttat tatgtcacaa 20

<210> 1845

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1845

tatatttatt atgtcaca 18

<210> 1846

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1846

atatatttat tatgtcac 18

<210> 1847

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1847

gtatatatttattatgtc 18

<210> 1848

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1848

acactgtcgt cgaatg 16

<210> 1849

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1849

ttacaccaca ctgtcg 16

<210> 1850

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1850

tttacaccac actgtc 16

<210> 1851

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1851

ttggagccta cataga 16

<210> 1852

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1852

agccactgtt gccaca 16

<210> 1853

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1853

cagccactgt tgccac 16

<210> 1854

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1854

cttctcagcc actgtt 16

<210> 1855

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1855

cttcattctt gcccaa 16

<210> 1856

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1856

tcttcattct tgccca 16

<210> 1857

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1857

ttcttcattc ttgccc 16

<210> 1858

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1858

tccttcttca ttcttg 16

<210> 1859

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1859

ttcctcagaa ggcatt 16

<210> 1860

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1860

gatacccttc ctcaga 16

<210> 1861

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1861

tgataccctt cctcag 16

<210> 1862

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1862

ttgataccct tcctca 16

<210> 1863

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1863

ctttacacca cactgtcgtc 20

<210> 1864

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1864

cttgataccc ttcctc 16

<210> 1865

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1865

tttacaccac actgtcgt 18

<210> 1866

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1866

cctttacacc acactgtc 18

<210> 1867

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1867

tttacaccac actgtcgtcg 20

<210> 1868

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1868

cttgataccc ttcctt 16

<210> 1869

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1869

tcctttacac cacactga 18

<210> 1870

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1870

aattccttta caccacactc 20

<210> 1871

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1871

attccttttac accacactct 20

<210> 1872

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1872

cctttacacc acactc 16

<210> 1873

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1873

ctttacacca cactcttt 18

<210> 1874

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1874

ctttacacca cactctttca 20

<210> 1875

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1875

tcctttacac cacactct 18

<210> 1876

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1876

tcctttacac cacactgt 18

<210> 1877

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1877

ttcctttaca ccacactc 18

<210> 1878

<211> 18

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1878

aattccttta caccatac 18

<210> 1879

<211> 15

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1879

tctgtcttgg ctttg 15

<210> 1880

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1880

atttccaaat tcactt 16

<210> 1881

<211> 20

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1881

ccaaatctta taataactac 20

<210> 1882

<211> 16

<212> DNA

<213> Artificial Sequence

<220>

<223> Antisense Oligonucleotide

<400> 1882

ttcctttaca ccacac 16

<---

Claims (19)

1. Antisense oligonucleotide targeting the transcript of alpha-synuclein (SNCA) and having a sequence selected from the group consisting of SEQ ID NO: 276; 278; 325; 328; 326; 329; 330; 327; 332; 333 and 559. 2. Antisense oligonucleotide according to claim 1, in which the nucleotide sequence consists of a sequence selected from the group consisting of SEQ ID NO: 276; 278; 325; 328; 326; 329; 330; 327; 332; 333 and 559 with a structure selected from the group consisting of the structures in FIG. 1A-1C, where the capital letter is the sugar-modified nucleoside and the lowercase letter is DNA. 3. Antisense oligonucleotide according to any one of paragraphs. 1-2, wherein the nucleotide sequence is selected from the group consisting of: TTCtctatataacatCACT (SEQ ID NO: 276) TTTCtctatataacaTCAC (SEQ ID NO: 278); ATTAttcatcacaatCCA (SEQ ID NO: 325); ATTAttcatcacaATCC (SEQ ID NO:328); CattattcatcacaaTCCA (SEQ ID NO:326); CATtattcatcacaATCC (SEQ ID NO:329); ACattattcatcacaaTCC (SEQ ID NO: 330); AcattattcatcacaaTCCA (SEQ ID NO: 327); ACATtattcatcacAATC (SEQ ID NO: 332); TACAttattcatcacAATC (SEQ ID NO: 333); and GTCAaaatattcttaCTTC (SEQ ID NO:559), where uppercase letters denote the 2'-sugar modified nucleoside analogue and lowercase letters denote DNA. 4. Antisense oligonucleotide according to any one of paragraphs. 1-3, in which the nucleotide sequence has a chemical structure selected from the group consisting of: OxyTs OxyTs OxyMCs DNAts DNAcs DNAts DNAas DNAts DNAas DNAts DNAas DNAas DNAcs DNAas DNAts OxyMCs OxyAs OxyMCs OxyT; OxyTs OxyTs OxyTs OxyMCs DNAts DNAcs DNAts DNAas DNAts DNAas DNAts DNAas DNAas DNAcs DNAas OxyTs OxvMCs OxvAs OxvMC; OxyAs OxyTs OxyTs OxyAs DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas DNAas DNAts OxyMCs OxyMCs OxyA; OxyAs OxyTs OxyTs OxyAs DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas OxyAs OxyTs OxyMCs OxyMC; OxyMCs DNAas DNAts DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas DNAas OxyTs OxvMCs OxvMCs OxvA; OxyMCs OxyAs OxyTs DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas OxyAs OxyTs OxvMCs OxvMC; OxyAs OxyMCs OxyAs DNAts DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas DNAas OxyTs OxyMCs OxyMC; OxyAs DNAcs DNAas DNAts DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs DNAas DNAas OxyTs OxyMCs OxyMCs OxyA; OxyAs OxyMCs OxyAs OxyTs DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs OxyAs OxyAs OxyTs OxyMC; OxyTs OxyAs OxyMCs OxyAs DNAts DNAts DNAas DNAts DNAts DNAcs DNAas DNAts DNAcs DNAas DNAcs OxyAs OxvAs OxvTs OxvMC; and OxyGs OxyTs OxyMCs OxyAs DNAas DNAas DNAas DNAts DNAas DNAts DNAts DNAcs DNAts DNAts DNAas OxyMCs OxyTs OxyTs OxyMC. 5. Pharmaceutical composition for the treatment of synucleinopathy, containing an effective amount of antisense oligonucleotide according to any one of paragraphs. 1-4 and a pharmaceutically acceptable carrier. 6. The use of an antisense oligonucleotide according to any one of paragraphs. 1-4 or a composition according to claim 5 for the manufacture of a medicament for the treatment of synucleinopathy in a subject in need thereof. 7. Antisense oligonucleotide according to any one of paragraphs. 1-4 or a composition according to claim 5 for use in the treatment of synucleinopathy. 8. The antisense oligonucleotide or composition of claim 7 wherein the synucleinopathy is selected from the group consisting of Parkinson's disease, Parkinson's disease dementia (PDD), multiple system atrophy, Lewy body dementia, and any combinations thereof.

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