IL322500A - Syf2 antisense oligonucleotides - Google Patents

Description

151421.02101/134342068v.

Docket No. 151421.021 SYF2 ANTISENSE OLIGONUCLEOTIDES id="p-1" id="p-1" id="p-1"

[0001] This application claims the benefit of U.S. provisional application no. 63/482,514, filed January 31, 2023, and U.S. provisional application no. 63/513,063, filed July 11, 2023, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION id="p-2" id="p-2" id="p-2"

[0002] The present invention relates to SYF2 antisense oligonucleotides (ASOs), pharmaceutical compositions containing them, and methods for treating, inhibiting, suppressing, and preventing neurological or neurodegenerative diseases with them.

BACKGROUND OF THE INVENTION id="p-3" id="p-3" id="p-3"

[0003] Many neurodegenerative disorders in patients are difficult to effectively treat, especially where the pathology of a neurodegenerative disorder in a particular patient is not completely understood. id="p-4" id="p-4" id="p-4"

[0004] International Publication No. WO 2021/150840 discloses a method of treating a neurodegenerative disease by administering a SYF2 inhibitor. id="p-5" id="p-5" id="p-5"

[0005] There remains a need for effective treatments for many neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). 151421.02101/134342068v.

SUMMARY OF THE INVENTION id="p-6" id="p-6" id="p-6"

[0006] The present invention relates to SYF2 antisense oligonucleotides (ASOs), pharmaceutical compositions containing them, and their use in the treatment of neurodegenerative disorders. id="p-7" id="p-7" id="p-7"

[0007] One embodiment is a single stranded ASO that suppresses the expression of SYF2, wherein the ASO has a nucleobase sequence that comprises at least 12 or 15 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-1052 (such as 1-266, 533- 573, and 615-833). The nucleobase sequence of the ASO can comprise up to 30, 25, 24, 23, 22, 21, 20, 18, 17, 16, or 15 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-1052 (such as 1-266, 533-573, and 615-833). The ASO can also be any of SEQ ID NOs: 1-1052 (such as 1-266, 533-573, and 615-833). id="p-8" id="p-8" id="p-8"

[0008] Another embodiment is a single stranded ASO comprising any one of the nucleobase sequences of SEQ ID NOs: 1-266, 533-573, and 615-833. Yet another embodiment is a single stranded ASO comprising any one of the nucleobase sequences of SEQ ID NOs: 1-50, 533-573, and 615-833. Yet another embodiment is a single stranded ASO comprising any one of the nucleobase sequences of SEQ ID NOs: 267-316, 574-614, and 834-1052. id="p-9" id="p-9" id="p-9"

[0009] Another embodiment is a single stranded ASO comprising a sequence of any one of SEQ ID NOs: 1-1052. Yet another embodiment is a single stranded ASO of any one of SEQ ID NOs: 1-1052. id="p-10" id="p-10" id="p-10"

[0010] Yet another embodiment is an oligonucleotide comprising or consisting of 12 to linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, 151421.02101/134342068v. at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-266, 533-573, and 615-833. The oligonucleotide can comprise up to 25, 24, 23, 22, 21, , 18, 17, 16, or 15 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-266, 533-573, and 615-833. id="p-11" id="p-11" id="p-11"

[0011] Yet another embodiment is an oligonucleotide comprising any one of the nucleobase sequences of SEQ ID NOs: 1-266, 533-573, and 615-833. In one embodiment, the oligonucleotide has 12 to 30 linked nucleosides. id="p-12" id="p-12" id="p-12"

[0012] In certain embodiments, at least one internucleoside linkage is a modified internucleoside linkage, and the modified internucleoside linkage may be a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage. At least one of the nucleosides may also be a modified nucleobase. id="p-13" id="p-13" id="p-13"

[0013] In other embodiments, at least one nucleoside of the ASO may be a modified sugar moiety, where that modified sugar moiety can be a bicyclic sugar moiety, or the modified sugar moiety may comprise a 2'-O-methoxyethyl group, 2’-F, or 2’-O-hexadecyl group. In certain aspects, the bicyclic sugar moiety comprises a 4'-CH(R)-O-2' bridge where the R group is, independently, H, C1-12 alkyl, or a protecting group. In one embodiment, the bicyclic sugar moiety comprises a 4-(CH2)2-O-2 bridge ("ENA" or ethylene-bridged nucleic acid). id="p-14" id="p-14" id="p-14"

[0014] In yet other embodiments, the ASO is a gapmer (e.g., a MOE gapmer), where a gap segment may consist of 8 to 12 linked deoxynucleosides, a 5' wing segment consisting of 3 to linked nucleosides, and a 3' wing segment consisting of 3 to 5 linked nucleosides. In certain aspects, the gap segment may be positioned between the 5' wing segment and the 3' wing 151421.02101/134342068v. segment, where a nucleoside of each wing segment comprises a modified sugar moiety (e.g., one with a 2'-O-methoxyethyl group). id="p-15" id="p-15" id="p-15"

[0015] In other embodiments, the oligonucleotide consists of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-266, 533-573, and 615-833. id="p-16" id="p-16" id="p-16"

[0016] Another embodiment is a pharmaceutical composition comprising a SYF2 ASO of the present invention and one or more pharmaceutically acceptable carriers, diluents, and/or excipients. In one embodiment, the pharmaceutical composition is suitable for parenteral administration, such as intracerebroventricular injection or intrathecal administration. id="p-17" id="p-17" id="p-17"

[0017] Yet another embodiment is a method of treating a subject having a neurological or neurodegenerative disease by administering a therapeutically effective amount of a SYF2 ASO or a pharmaceutical composition described herein. id="p-18" id="p-18" id="p-18"

[0018] Yet another embodiment is a method of treating a subject having a SYF2 disease or disorder by administering a therapeutically effective amount of a SYF2 ASO or a pharmaceutical composition described herein.

BRIEF DESCRIPTION OF THE DRAWINGS id="p-19" id="p-19" id="p-19"

[0019] FIG. 1 is a bar graph showing the expression levels of human SYF2 (normalized to GAPDH) in HeLa cells after transfection with a negative control (NC) ASO or one of ASO-1 to ASO-50 (25 nM) from Table 2B. ASO-20, ASO-21, and ASO-22 significantly reduced human 151421.02101/134342068v.

SYF2 expression. In figures 1-6, **** refers to p < 0.0001, *** refers to p < 0.001, ** refers to p < 0.01, and * refers to p < 0.05. id="p-20" id="p-20" id="p-20"

[0020] FIG. 2 is a bar graph showing the expression levels of human SYF2 (normalized to GAPDH) in HeLa cells after transfection with a NC ASO or one of ASO-51 to ASO-74 (25 nM) from Table 2B. ASO-53, ASO-58, and ASO-60 significantly reduced human SYF2 expression. id="p-21" id="p-21" id="p-21"

[0021] FIG. 3 is a bar graph showing the expression levels of human SYF2 (normalized to GAPDH) in HeLa cells after transfection with a NC ASO or one of ASO-75 to ASO-100 ( nM) from Table 2B. ASO-83, ASO-84, ASO-90, ASO-92, ASO-96, and ASO-97 significantly reduced human SYF2 expression. id="p-22" id="p-22" id="p-22"

[0022] FIG. 4 is a bar graph showing the expression levels of human SYF2 (normalized to GAPDH) in HeLa cells after transfection with a NC ASO or one of ASO-101 to ASO-121 ( nM) from Table 2B. ASO-120 significantly reduced human SYF2 expression. id="p-23" id="p-23" id="p-23"

[0023] FIG. 5 is a bar graph of the expression levels of SYF2 (normalized to HPRT) in iPSC- derived cortical neurons (Ngn2-induced neurons, Ngn2-iNs) after treatment via gymonsis with a NC ASO or ASO-19, ASO-24, ASO-25, ASO-32, ASO-35, ASO-42, ASO-43, ASO-63, ASO- 69, ASO-70, ASO-80, ASO-86, and ASO-120. id="p-24" id="p-24" id="p-24"

[0024] FIG. 6 is a bar graph of the human SYF2 expression levels (normalized to HPRT) in Ngn2-iN treated with 10 M of NC ASO or one of ASO-122 to ASO-219.

DETAILED DESCRIPTION OF THE INVENTION id="p-25" id="p-25" id="p-25"

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the 151421.02101/134342068v. present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Definitions id="p-26" id="p-26" id="p-26"

[0026] The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," "may" and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. id="p-27" id="p-27" id="p-27"

[0027] The singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. id="p-28" id="p-28" id="p-28"

[0028] The present disclosure also contemplates other embodiments "comprising," "consisting of" and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not. id="p-29" id="p-29" id="p-29"

[0029] As used herein, "2'-deoxynucleoside" means a nucleoside comprising a 2'-H(H) furanosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA) and a nucleobase. In certain embodiments, a 2'-deoxynucleoside may comprise a modified nucleobase and a furanosyl sugar moiety or may comprise an RNA nucleobase (uracil) and a furanosyl sugar moiety. 151421.02101/134342068v. id="p-30" id="p-30" id="p-30"

[0030] As used herein, "2'-substituted nucleoside" means a nucleoside comprising a 2'- substituted sugar moiety. As used herein, "2'-substituted" in reference to a sugar moiety means a sugar moiety comprising at least one 2'-substituent group other than H or OH. id="p-31" id="p-31" id="p-31"

[0031] As used herein, "antisense molecule" means an oligomeric nucleic acid or oligomeric duplex capable of achieving at least one antisense activity. id="p-32" id="p-32" id="p-32"

[0032] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." The term "about" may refer to plus or minus 10% of the indicated number. For example, "about %" may indicate a range of 9% to 11%, and "about 1" may mean from 0.9-1.1. Other meanings of "about" may be apparent from the context, such as rounding off, so, for example "about 1" may also mean from 0.5 to 1.4. id="p-33" id="p-33" id="p-33"

[0033] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. id="p-34" id="p-34" id="p-34"

[0034] As used herein, "bicyclic sugar" or "bicyclic sugar moiety" means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic 151421.02101/134342068v. sugar moiety does not comprise a furanosyl moiety. As used herein, "bicyclic nucleoside" or "BNA" means a nucleoside comprising a bicyclic sugar moiety. id="p-35" id="p-35" id="p-35"

[0035] As used herein, "chirally enriched population" means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides. id="p-36" id="p-36" id="p-36"

[0036] As used herein, "complementary" in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more regions thereof and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. Complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T); adenine (A) and uracil (U); cytosine (C) and guanine (G); and 5-methylcytosine (mC) and guanine (G). Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, "fully complementary" or "100% complementary" in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide. 151421.02101/134342068v. id="p-37" id="p-37" id="p-37"

[0037] As used herein, "gapmer" means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the "gap" and the external regions may be referred to as the "wings." Unless otherwise indicated, "gapmer" refers to a sugar motif.

Unless otherwise indicated, the sugar moieties of the nucleosides of the gap of a gapmer are unmodified 2'-deoxyfuranosyl. Thus, the term "MOE gapmer" indicates a gapmer having a sugar motif of 2'-MOE nucleosides in both wings and a gap of 2'-deoxynucleosides. Unless otherwise indicated, a MOE gapmer may comprise one or more modified internucleoside linkages and/or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications. Tables 2A and 2B, below, provide exemplary MOE- gapmers. id="p-38" id="p-38" id="p-38"

[0038] "Inhibit" as used herein refers to the ability to substantially antagonize, prohibit, prevent, suppress, restrain, slow, disrupt, alter, eliminate, stop, or reverse the progression or severity of the activity of a particular agent (e.g., infectious agent) or disease. id="p-39" id="p-39" id="p-39"

[0039] As used herein, the term "internucleoside linkage" is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein "modified internucleoside linkage" means any internucleoside linkage other than a phosphodiester internucleoside linkage.

"Phosphorothioate linkage" is a modified internucleoside linkage in which one of the non- bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom. 151421.02101/134342068v. id="p-40" id="p-40" id="p-40"

[0040] As used herein, "MOE" means methoxyethyl. "2'-MOE" means a -OCH 2CH2OCH group at the 2' position of a furanosyl ring. id="p-41" id="p-41" id="p-41"

[0041] A "neurological disease" is any disease that causes electrical, biochemical, or structural abnormalities in the brain, spine, or neurons. For example, a neurological disease may be a neurodegenerative disease. id="p-42" id="p-42" id="p-42"

[0042] As used herein, "non-bicyclic modified sugar moiety" means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring. id="p-43" id="p-43" id="p-43"

[0043] As used herein, "nucleobase" means an unmodified nucleobase or a modified nucleobase. As used herein, an "unmodified nucleobase" is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a "modified nucleobase" is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase or modified nucleobase. A "5-methylcytosine" or "mC" is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. As used herein, "nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification. id="p-44" id="p-44" id="p-44"

[0044] As used herein, "nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, "modified nucleoside" means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. "Linked nucleosides" are nucleosides that are connected in a continuous sequence (i.e., no additional nucleosides are presented between those that are linked). 151421.02101/134342068v. id="p-45" id="p-45" id="p-45"

[0045] As used herein, "oligomeric compound" means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired. A "singled stranded oligomeric compound" is an unpaired oligomeric compound. The term "oligomeric duplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a "duplexed oligomeric compound." id="p-46" id="p-46" id="p-46"

[0046] As used herein, "oligonucleotide" means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. The internucleoside linkages may be any described herein. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, "modified oligonucleotide" means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, "unmodified oligonucleotide" means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications. id="p-47" id="p-47" id="p-47"

[0047] "SYF2", also known in the art as "SYF2 Pre-MRNA Splicing Factor", encodes a nuclear protein that interacts with cyclin D-type binding-protein 1, which is thought to be a cell cycle regulator at the G1/S transition. SYF2 has been shown to reduce TDP-43 aggregation and mislocalization and cryptic exon inclusion, while also rescuing C9ORF72 and ensuring sporadic ALS neuron survival. TDP-43 has been shown to decrease the incorporation of cryptic exons that result in non-productive RNA transcripts. Consequently, a loss or decrease in nuclear TDP- 43 in motor neurons will result in a reduction of mRNA levels for many genes, including STMN2, which transcribes a microtubule-binding protein. The loss of STMN2 has been shown to compromise neurite outgrowth in motor neurons. 151421.02101/134342068v. id="p-48" id="p-48" id="p-48"

[0048] As used herein a "SYF2 disease or disorder" includes lysosomal degradation diseases and disorders mediated by SYF2. For example, the a SYF2 disease or disorder includes, but is not limited to, amyloid diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, type 2 diabetes, diabetic amyloidosis and chronic hemodialysis-related amyloid), multiple sclerosis, and an MPS disorder (such as MPS I, MPS II, MPS IIIA, MPS IIIB, MPS IIIC, MPS HID, MPS IVA, MPS IVB, MPS VI, MPS VII, or MPS IX). In some embodiments, the diseases are autoimmune disorders (such as multiple sclerosis, rheumatoid arthritis, juvenile chronic arthritis, Ankylosing spondylitis, psoriasis, psoriatic arthritis, adult still disease, Becet syndrome, familial Mediterranean fever, Crohn's disease, leprosy, osteomyelitis, tuberculosis, chronic bronchiectasis, Castleman disease), or CNS disorders (such as spongiform encephalopathies (Creutzfeld- Jakob, Kuru, Mad Cow)). The compositions and methods of the disclosure can be used to treat individuals with lysosomal storage diseases comprising administering to a subject in need of treatment a therapeutically effective amount of a SYF ASO or pharmaceutical composition described herein. In some embodiments, the ASOs and compositions of the disclosure decrease or inhibit the activity of SYF2 and alters the biogenesis, function or dynamics of the endosomal or lysosomal systems in a way that reduces the abundance of the material abnormally stored in the lysosome in lysosomal storage diseases. In some embodiments, the ASOs and compositions target, decrease or inhibit the activity of SYF thus altering the biogenesis, functions, or dynamics of the endoplasmic reticulum or Golgi apparatus in a way that reduces the abundance of the material abnormally stored in the lysosome in lysosomal storage diseases. In other embodiments, the disease is a neurological disorder. id="p-49" id="p-49" id="p-49"

[0049] As used herein, "sugar moiety" means an unmodified sugar moiety or a modified sugar moiety. The superscript prime symbol (') is used to describe the numbering of a sugar in a 151421.02101/134342068v. nucleoside or nucleotide (the nucleobase positions are numbered without the prime). When describing the sugar only, the prime symbol is not used. As used herein, "unmodified sugar moiety" means a 2-OH(H) furanosyl moiety, as found in RNA (an "unmodified RNA sugar moiety"), or a 2-H(H) moiety, as found in DNA (an "unmodified DNA sugar moiety").

Unmodified sugar moieties have one hydrogen at each of the 1, 3, and 4 positions, an oxygen at the 3 position, and two hydrogens at the 5 position. As used herein, "modified sugar moiety" or "modified sugar" means a modified furanosyl sugar moiety or a sugar surrogate. As used herein, modified furanosyl sugar moiety means a furanosyl sugar comprising a non-hydrogen substituent in place of at least one hydrogen of an unmodified sugar moiety. In certain embodiments, a modified furanosyl sugar moiety is a 2-substituted sugar moiety. Such modified furanosyl sugar moieties include bicyclic sugars and nonbicyclic sugars. id="p-50" id="p-50" id="p-50"

[0050] "Subject" and "patient" as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc.) and a human). In some embodiments, the subject may be a human or a non-human. In a preferred embodiment, the subject or patient is a human. The subject or patient may be undergoing other forms of treatment. id="p-51" id="p-51" id="p-51"

[0051] A "therapeutically effective amount," or "effective dosage" or "effective amount" as used interchangeably herein unless otherwise defined, means a dosage of a drug effective for periods of time necessary, to achieve the desired therapeutic result. An effective dosage may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the drug to elicit a desired 151421.02101/134342068v. response in the individual. This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, mammal, or human, such as reducing and/or inhibiting the function of a receptor. A therapeutically effective amount may be administered in one or more administrations (e.g., the agent may be given as a preventative treatment or therapeutically at any stage of disease progression, before or after symptoms, and the like), applications or dosages and is not intended to be limited to a particular formulation, combination or administration route. It is within the scope of the present disclosure that the drug may be administered at various times during the course of treatment of the subject. The times of administration and dosages used will depend on several factors, such as the goal of treatment (e.g., treating v. preventing), condition of the subject, etc. and can be readily determined by one skilled in the art. id="p-52" id="p-52" id="p-52"

[0052] As used herein, the term "treat" or "treating" a subject, refers to administering a composition or agent described herein to the subject, such that at least one symptom of a disease or disorder is healed, alleviated, relieved, altered, remedied, reduced, ameliorated, or improved.

Treating includes administering an amount effective to alleviate, relieve, alter, remedy, reduce, ameliorate, and/or improve one or more symptoms associated with a disease or disorder. The treatment may inhibit deterioration or worsening of a symptom associated with the disease or disorder.

Antisense Oligonucleotides id="p-53" id="p-53" id="p-53"

[0053] In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined 151421.02101/134342068v. pattern or sugar motif. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modifications discussed herein. id="p-54" id="p-54" id="p-54"

[0054] In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which is defined by two external regions or "wings" and a central or internal region or "gap." The three regions of a gapmer motif include the "5’ wing", the "gap" and the "3’ wing" which form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3'-most nucleoside of the 5'-wing and the 5'-most nucleoside of the 3'-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5'-wing differs from the sugar motif of the 3'-wing (asymmetric gapmer). id="p-55" id="p-55" id="p-55"

[0055] In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside. id="p-56" id="p-56" id="p-56"

[0056] In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides (e.g., nucleosides). In certain embodiments, each nucleoside of the gap of a gapmer is an unmodified 2'-deoxy nucleoside. 151421.02101/134342068v. id="p-57" id="p-57" id="p-57"

[0057] In certain embodiments, the gapmer is a deoxy gapmer. In embodiments, the nucleosides on the gap side of each wing/gap junction are unmodified 2'-deoxy nucleosides and the nucleosides on the wing sides of each wing/gap junction are modified nucleosides. In certain embodiments, each nucleoside of the gap is an unmodified 2'-deoxy nucleoside. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside. id="p-58" id="p-58" id="p-58"

[0058] In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified oligonucleotide comprises the same 2'-modification. id="p-59" id="p-59" id="p-59"

[0059] In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include, but are not limited to, phosphates, which contain a phosphodiester bond (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates or other alkylphosphonates, phosphoramidates, and phosphorothioates, and phosphorodithioates. Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (-CH 2- 151421.02101/134342068v.

N(CH3)-O-CH2-), thiodiester, thionocarbamate (-O-C(=O)(NH)-S-); siloxane (-O-SiH 2-O-); and N,N'-dimethylhydrazine (-CH2-N(CH3)-N(CH3)-). Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. Methods of preparation of phosphorous-containing and non- phosphorous-containing internucleoside linkages are well known to those skilled in the art. id="p-60" id="p-60" id="p-60"

[0060] Representative internucleoside linkages having a chiral center include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereo-random internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereo-random. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the 151421.02101/134342068v. particular phosphorothioate linkage is present in at least 80% of the molecules in the population.

In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003); Wan et al., Nuc. Acid. Res. 42, 13456 (2014); Chapter 10 of Locked Nucleic Acid Aptamers in Nucleic Acid and Peptide Aptamers: Methods and Protocols v 535, 2009 by Barciszewski et al., editor Gunter Mayerand; and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In another embodiment, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Rp) configuration. id="p-61" id="p-61" id="p-61"

[0061] In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside. id="p-62" id="p-62" id="p-62"

[0062] In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2- 151421.02101/134342068v. thiothymine and 2-thiocytosine, 5-propynyl (-C≡C-CH 3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8- thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5- bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3- deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N- benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3- diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp).

Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Patent No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443. id="p-63" id="p-63" id="p-63"

[0063] In certain embodiments, modified sugar moieties are nonbicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2, 4, and/or positions. In certain embodiments one or more non-bridging substituent of nonbicyclic modified 151421.02101/134342068v. sugar moieties is branched. Examples of 2-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2-F, 2-OCH 3 ("OMe" or "O-methyl"), and 2- O(CH2)2OCH3 ("MOE"). In certain embodiments, 2-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF 3, OCF3, O-C1-10 alkoxy, O-C1-10 substituted alkoxy, O-C1-10 alkyl, O-C1-10 substituted alkyl, S-alkyl, N(Rm)-alkyl, O-alkenyl, S-alkenyl, N(Rm)-alkenyl, O-alkynyl, S-alkynyl, N(Rm)-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH2)2SCH3, O(CH2)2ON(Rm)(Rn) or OCH2C(=O)-N(Rm)(Rn), where each Rm and Rn is, independently, H, an amino protecting group, or substituted or unsubstituted C1-10 alkyl, and the 2-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl.

Examples of 4'-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), and alkyl. Examples of 5-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5-methyl (R or S), 5- vinyl, and 5-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2-F-5-methyl sugar moieties and the like. id="p-64" id="p-64" id="p-64"

[0064] In certain embodiments, a 2'-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a nonbridging 2'-substituent group selected from: F, NH 2, N3, OCF3, OCH3, O(CH2)3NH2, CH2CH=CH2, OCH2CH=CH2, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2)2ON(Rm)(Rn), O(CH2)2O(CH2)2N(CH3)2, -O-(CH2)nCH3 (where n is 13-17, and in one preferred embodiment, 15), and N-substituted acetamide (OCH 2C(=O)-N(Rm)(Rn)), where each 151421.02101/134342068v.

Rm and Rn is, independently, H, an amino protecting group, or substituted or unsubstituted C 1- alkyl. In one embodiment, the 2’-substituent is -O-hexadecyl (C16). id="p-65" id="p-65" id="p-65"

[0065] In certain embodiments, a 2'-substituted nucleoside nonbicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2'-substituent group selected from: F, OCF3, OCH3, OCH2CH2OCH3, O(CH2)2SCH3, O(CH2)2ON(CH3)2, O(CH2)2O(CH2)2N(CH3)2, and OCH2C(=O)-N(H)CH3 ("NMA"). id="p-66" id="p-66" id="p-66"

[0066] In certain embodiments, a 2'-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a nonbridging 2'-substituent group selected from: F, OCH 3, and OCH2CH2OCH3. In one embodiment, the 2’-substituent is F. In another embodiment, the 2’- substituent is OCH3 (methoxy). id="p-67" id="p-67" id="p-67"

[0067] Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4 and the 2 furanose ring atoms. Examples of such 4 to 2 bridging sugar substituents include but are not limited to: 4- CH2-2, 4-(CH2)2-2, 4-(CH2)3-2, 4-CH2-O-2 ("LNA"), 4-CH2-S-2, 4-(CH2)2-O-2 ("ENA"), 4- CH(CH3)-O-2 (referred to as "constrained ethyl" or "cEt"), 4-CH 2-O-CH2-2, 4-CH2-N(R)-2, 4- CH(CH2OCH3)-O-2 ("constrained MOE" or "cMOE") and analogs thereof, 4-C(CH 3)(CH3)-O- and analogs thereof, 4-CH2-N(OCH3)-2 and analogs thereof, 4-CH2-O-N(CH3)-2, 4-CH2- C(H)(CH3)-2, 4-CH2-C(=CH2)-2 and analogs thereof, 4-C(RaRb)-N(R)-O-2, 4-C(RaRb)-O-N(R)- 2, 4-CH2-O-N(R)-2, and 4-CH2-N(R)-O-2, wherein each R, R a, and Rb, is, independently, H, a protecting group, or C1-12 alkyl. In one embodiment, the modified sugar moiety comprises a 4- (CH2)2-O-2 bridge (where the "4" represents the 4 furanose ring atom and the "2" represents the 2 furanose ring atom) ("ENA" or ethylene-bridged nucleic acid). 151421.02101/134342068v. id="p-68" id="p-68" id="p-68"

[0068] In certain embodiments, such 4 to 2 bridges independently comprise from 1 to 4 linked groups independently selected from: -[C(R a)(Rb)]n-, -[C(Ra)(Rb)]n-O-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -C(=NRa)-, -C(=O)-, -C(=S)-, -O-, -Si(Ra)2-, -S(=O)x-, and - N(Ra)-; wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; each Ra and Rb is, independently, H, a protecting group, hydroxyl, C 1-12 alkyl, substituted C1-12 alkyl, C1-12 alkenyl, substituted C2-12 alkenyl, C2-12 alkynyl, substituted C2- alkynyl, C5-20 aryl, substituted C5-20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-7 alicyclic radical, substituted C5-7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H), substituted acyl, CN, sulfonyl (S(=O) 2-J1), or sulfoxyl (S(=O)-J1); and each J1 and J2 is, independently, H, C1-12 alkyl, substituted C1-12 alkyl, C2-12 alkenyl, substituted C2-12 alkenyl, C2-12 alkynyl, substituted C2-12 alkynyl, C5-20 aryl, substituted C5-20 aryl, acyl (C(=O)-H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C1-12 aminoalkyl, substituted C1-12 aminoalkyl, or a protecting group. id="p-69" id="p-69" id="p-69"

[0069] Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731- 7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org.

Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 20017, 129, 8362-8379; Wengel et a., U.S. Pat. No. 7,053,207; Imanishi et al., U.S. Pat. No. 6,268,490; Imanishi et al.

U.S. Pat. No. 6,770,748; Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499; Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133; Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191; Torsten et al., WO 2004/106356; Wengel et al., WO 1999/014226; Seth et al., WO 151421.02101/134342068v. 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; and U.S. Patent Publication Nos. Allerson et al., US2008/0039618 and Migawa et al., US2015/0191727. id="p-70" id="p-70" id="p-70"

[0070] Another modification of the ASO involves chemically linking to the ASO one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the ASO. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), a thioether, e.g., beryl-S- tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg.

Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651- 3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol.

Exp. Ther., 1996, 277:923-937). 151421.02101/134342068v. id="p-71" id="p-71" id="p-71"

[0071] The disclosure provides oligonucleotides (modified or unmodified) that can be used to modulate SYF2 expression. Tables 1A and 1B provide (5' to 3') generic sequences of bases for the SYF2 antisense oligonucleotides or inhibitory nucleic acids. The ASO sequences SEQ ID NOs: 1-37 are predicted to skip exon 5 of SYF2 efficiently, and generate a stop codon to cause early-termination of SYF2 translation. The ASO sequences SEQ ID NOs: 38-50 are predicted to skip exon 2 of SYF2 efficiently, and make a major structural change to the protein rendering it non-functional. The ASO sequences SEQ ID NOs: 51-139 have low acute neurotoxicity scores as determined by the method described in Hagedorn et al., Nucleic Acid Therapeutics, 2022, 32(3):151-162 (DOI: 10.1089/nat/2021/0071). The ASO sequences SEQ ID NOs: 140-266 have low numbers of predicted off-target binding sites as determined by the GGGenome search tool using 2 mismatches/gaps.

TABLE 1A SEQ ID NO. Sequence GACCATCCTTAGACAACT GTATACACACACACACAC ATACACACACACACACAC TACACACACACACACACA ATACATCCACATCACCTC TACATCCACATCACCTCA ACATCCACATCACCTCAG CATCCACATCACCTCAGG ATCCACATCACCTCAGGT TCCACATCACCTCAGGTT CCACATCACCTCAGGTTG CACATCACCTCAGGTTGA ACATCACCTCAGGTTGAA CATCACCTCAGGTTGAAA CACCTCAGGTTGAAAAAG ACCTCAGGTTGAAAAAGG 151421.02101/134342068v. 17 CCTCAGGTTGAAAAAGGA CTCAGGTTGAAAAAGGAC GTTTCCATGTCAGGTTTG TCCATGTCAGGTTTGATC CCATGTCAGGTTTGATCT CATGTCAGGTTTGATCTG ATGTCAGGTTTGATCTGC TGTCAGGTTTGATCTGCT GTCAGGTTTGATCTGCTT TCAGGTTTGATCTGCTTG CAGGTTTGATCTGCTTGG AGGTTTGATCTGCTTGGT GGTTTGATCTGCTTGGTC GTTTGATCTGCTTGGTCA TTGATCTGCTTGGTCAAC TGATCTGCTTGGTCAACC GGCAGCAGCATAATCTAA TTCCTTGTTTGGACCTTC TCCTTGTTTGGACCTTCC CCTTGTTTGGACCTTCCT CTTGTTTGGACCTTCCTA GCCTCCAAGACTACTCAC CCTCCAAGACTACTCACC CTCCAAGACTACTCACCC GACAAGGAGAACTGGCTT ACAAGGAGAACTGGCTTC CAAGGAGAACTGGCTTCA AAGGAGAACTGGCTTCAG AGGAGAACTGGCTTCAGG GAGAACTGGCTTCAGGCA AGAACTGGCTTCAGGCAG GAACTGGCTTCAGGCAGA AACTGGCTTCAGGCAGAG TCAGCTTCTCCCAGGACT CACACACACACACAAATACA ACACACACACACACAAATAC CACACACACACACACAAATA TACACACACACACACACAAA 151421.02101/134342068v. 55 ACACACACACACACACAAAT ATACACACACACACACACAA ACACACACAAATACATCCAC CACACACAAATACATCCACA CACACACACAAATACATCCA ACACACACACAAATACATCC CACACACACACAAATACATC TATACACACACACACACACA ACAAATACATCCACATCACC CACAAATACATCCACATCAC CACACAAATACATCCACATC AATACATCCACATCACCTCA AAATACATCCACATCACCTC CAAATACATCCACATCACCT ATACTCCTCCCAACTACCAT CATCAACATTCTTCATCTCC CTTCATCTCCATTCCAAATC GTATACACACACACACACAC GAACCCTCACCAACAAAACC TACTCCTCCCAACTACCATC ACTCCTCCCAACTACCATCC CCTCCCAACTACCATCCCTA TATCTTCTTCCACAACTTCC CATCACAACCTTTCTCTCTT ATCACAACCTTTCTCTCTTC ATCTTCTTCCACAACTTCCT ACATTCTTCATCTCCATTCC CATTCTTCATCTCCATTCCA GAAACCCCATCTCTACTAAA CCATCACAACCTTTCTCTCT ACAACCTTTCTCTCTTCCCA TCCTCCCAACTACCATCCCT GACTCTATCAAATTCCACAC CTCCTCCCAACTACCATCCC GATACCCCATCTCTACTAAA TCACAACCTTTCTCTCTTCC AACCTTTCTCTCTTCCCACT AGACTCCCAAACCTAACCCA 151421.02101/134342068v. 93 CAACCTTTCTCTCTTCCCAC CACAACCTTTCTCTCTTCCC CAGATATATTCAACCCACAC TGAAACCCCATCTCTACTAA GATACTCCTCCCAACTACCA TGATACCCCATCTCTACTAA GTTCCTTACACAATCACTCT 100 CTTTTTCCTCTCCCATCTTT 101 TTTTTCCTCTCCCATCTTTC 102 TCTTTTTCCTCTCCCATCTT 103 TTTTCCTCTCCCATCTTTCT 104 TCTTCTTTTTCCTCTCCCAT 105 TTCTTTTTCCTCTCCCATCT 106 CTTCTTTTTCCTCTCCCATC 107 AGATACTCCTCCCAACTACC 108 GGAACCCTCACCAACAAAAC 109 TGTTCCTTACACAATCACTC 110 AGACCTTTCCCCTTCAATAT 111 GCCATCACAACCTTTCTCTC 112 TAGACCTTTCCCCTTCAATA 113 CTGACCCCATTTTATCCTAA 114 CAGCAACTTCACTTTCTCAT 115 GGCTCACACCAATAATCCCA 116 CCAGCAACTTCACTTTCTCA 117 GGACTCTTATCCCTAATACA 118 ACATCAGATTCCCTATCAAC 119 ACACCTGTAATCTCAACCAT 120 CATCAGATTCCCTATCAACT 121 GAGACTCCCAAACCTAACCC 122 TTAGACCTTTCCCCTTCAAT 123 CTAGCTCTACATATTTCCCT 124 CCTGTAATCCCACTACTTTT 125 CTGTTCCTCTTTCCAAATTC 126 CCATCTCAGCTAAAACTACA 127 AGAGATACTCCTCCCAACTA 128 ACTGCCATCTTCCTCATCAC 129 GTGAAACCCCATCTCTACTA 130 CTGCCATCTTCCTCATCACT 151421.02101/134342068v. 131 CACACCTGTAATCTCAACCA 132 AAGCAAGACTCCATCTCAAA 133 GAGATACTCCTCCCAACTAC 134 TGGCTCACACCAATAATCCC 135 TCTAGCTCTACATATTTCCC 136 TTTAGACCTTTCCCCTTCAA 137 CTCAGCTCATTTCAACTTTC 138 CTTTAGTTCCCACTCCAAAC 139 GAAAAAGTTCACCAACCCCA 140 TCTGCCTCAGCCTCCCAAAG 141 CTGCCTCAGCCTCCCAAAGT 142 CCTGAGCAACACAGTGAGAC 143 CTGAGCAACACAGTGAGACC 144 TGAGCAACACAGTGAGACCC 145 CAGCCCAGTCAATAAGGTTC 146 GCCTAAGAGCCAGTGTATAC 147 TATCAACTGGCTGAACTACC 148 ATCAACTGGCTGAACTACCA 149 GCCCAGTCAATAAGGTTCAA 150 AGAGATACTCCTCCCAACTA 151 ATCCCCAAGCCACTATAGAC 152 GTCAGGTTTGATCTGCTTGG 153 ACAGCCCAGTCAATAAGGTT 154 AGCCCAGTCAATAAGGTTCA 155 CTACTACATGAGGCACCCCC 156 CAGATTCCCTATCAACTGGC 157 GCCACTATAGACAGGTCAAA 158 AACCCCAGCACTAAAGCATT 159 CCATACCTTAGCATTAAAGC 160 TCACCTCAGGTTGAAAAAGG 161 CTAACAGCCCAGTCAATAAG 162 GCCTCTATTGAGTTGTGTGG 163 TGGACTCTTATCCCTAATAC 164 GGACTCTTATCCCTAATACA 165 GGTGTCACCTACTACATGAG 166 TACATGAGGCACCCCCTGGA 167 TCCCTATCAACTGGCTGAAC 168 GAACTACCACACTGTAGACT 151421.02101/134342068v. 169 ACCAACCCCAGCACTAAAGC 170 CAACCAGTCTTAGAATGCCC 171 TAACAGCCCAGTCAATAAGG 172 GCTGGACTCTTATCCCTAAT 173 ACAGTAGTTTAGGTGTCACC 174 TACTACATGAGGCACCCCCT 175 GTCTCTTACTGACACTAGAC 176 TCAACCCACACTTGCTATCC 177 AACCTGGCTAACTGAAGTAC 178 GCTAACTGAAGTACAGCCTT 179 GACTAACAGCCCAGTCAATA 180 ATCAGGTGTCAGACCTTGTT 181 AAATCCAGATACACCTTGCC 182 GGTCCCTTTTTATTGGATCA 183 GTCATAAGCTGGTGGCAGTT 184 ACTACATGAGGCACCCCCTG 185 ACATCAGATTCCCTATCAAC 186 GATTCCCTATCAACTGGCTG 187 GGAGACTCCCAAACCTAACC 188 GTCCTTAGCTTTGGAGTACA 189 TTAGCTTTGGAGTACACAAC 190 GGCATGGACTACTAAATTCT 191 CCAAGCCACTATAGACAGGT 192 GTACAGATCAAAGAGCCAAC 193 GAGAGGCTCCAGGACTTATC 194 CAACCCCAGCACTAAAGCAT 195 ACCTGGCTAACTGAAGTACA 196 GGCACATCCTTTCTTGAAAC 197 ATGACTAACAGCCCAGTCAA 198 TGTTTATCAGGTGTCAGACC 199 TATCAGGTGTCAGACCTTGT 200 GTCCCTTTTTATTGGATCAG 201 GGTTTGTATCAGGTGACTGA 202 AACAGTCACTGGTGTTAGTC 203 TTGCTGGACTCTTATCCCTA 204 AAGTGAACCAGGTCTCTTAC 205 GGTTGTTAGTAATGGAGACT 206 GAAGGATAGCTCCACTCCTC 151421.02101/134342068v. 207 TAGCTTTGGAGTACACAACT 208 AGCAGCCCACCACCTGTTTA 209 GGTTTGATCTGCTTGGTCAA 210 TGTTTGGACCTTCCTATTGA 211 ACTAACAGCCCAGTCAATAA 212 CCCAGTCAATAAGGTTCAAT 213 AACCACCATGTTGTAGTGTC 214 TAAATCCAGATACACCTTGC 215 GTGTGGTCCCTTTTTATTGG 216 GCAGTATTGGAGACCATACT 217 GAGTTAGACATTCCTTAGGT 218 TCCTTAGGTCATAAGCTGGT 219 TTAGGTCATAAGCTGGTGGC 220 GCCTAGCTGTCAGGTCACTC 221 ACTGGCTGAACTACCACACT 222 AGTAATGGAGACTCCCAAAC 223 TCCTTAGCTTTGGAGTACAC 224 CATCCCCAAGCCACTATAGA 225 CAAGCCACTATAGACAGGTC 226 GTCAAGCTGCTCTACTGAAT 227 TAACCAATCAACAACCAGTC 228 GAGCATCATAGCACCATGTT 229 GTTTATCAGGTGTCAGACCT 230 CAGTATTGGAGACCATACTA 231 CTTAGGTCATAAGCTGGTGG 232 CATCCCTAGTATATTCTTGG 233 ATCCCTAGTATATTCTTGGC 234 CTAGCTGTCAGGTCACTCCA 235 CTGGACTCTTATCCCTAATA 236 CCTATCAACTGGCTGAACTA 237 TCAACTGGCTGAACTACCAC 238 GGCTGAACTACCACACTGTA 239 GGTCTCTTACTGACACTAGA 240 GCCTCCAAGACTACTCACCC 241 GATCATGGAAGGATAGCTCC 242 CCTTAGCTTTGGAGTACACA 243 AGCTTTGGAGTACACAACTC 244 GAGTACACAACTCCAAGTGG 151421.02101/134342068v. 245 CAACCCACACTTGCTATCCA 246 AAGCCACTATAGACAGGTCA 247 AGCCACTATAGACAGGTCAA 248 CTATGACCATCCTGTCAATT 249 CAATCAACAACCAGTCTTAG 250 TGTCAGGTTTGATCTGCTTG 251 GTTTGATCTGCTTGGTCAAC 252 TTGTTTGGACCTTCCTATTG 253 TGAGTTAGACATTCCTTAGG 254 AGTTAGACATTCCTTAGGTC 255 TAGGTCATAAGCTGGTGGCA 256 CATAAGCTGGTGGCAGTTTG 257 CCAACTACCATCCCTAGTAT 258 GGTCAACAAAGTTGAGTCTG 259 GTTTGTATCAGGTGACTGAG 260 ACCTACTACATGAGGCACCC 261 ATCAGATTCCCTATCAACTG 262 ATTCCCTATCAACTGGCTGA 263 GCTGAACTACCACACTGTAG 264 AGGTCTCTTACTGACACTAG 265 GACTCCCAAACCTAACCCAG 266 GAATGATCCCAATGTGCTGC 533 GTTTGGACCTTCCTATTG 534 CTAACAGCCCAGTCAATA 535 AACAGCCCAGTCAATAAG 536 ACAGCCCAGTCAATAAGG 537 CAGCCCAGTCAATAAGGT 538 AGCCCAGTCAATAAGGTT 539 GCCCAGTCAATAAGGTTC 540 CCCAGTCAATAAGGTTCA 541 ATCTGACCTGAAAATCCC 542 TCTGACCTGAAAATCCCA 543 CTGACCTGAAAATCCCAG 544 TGACCTGAAAATCCCAGA 545 GACCTGAAAATCCCAGAT 546 ACCTGAAAATCCCAGATC 547 CCTGAAAATCCCAGATCA 548 CTGAAAATCCCAGATCAG 151421.02101/134342068v. 549 TGAAAATCCCAGATCAGG 550 GCACTGATCTCCAGCAAC 551 CACTGATCTCCAGCAACT 552 ACTGATCTCCAGCAACTT 553 CTGATCTCCAGCAACTTC 554 TGATCTCCAGCAACTTCA 555 GATCTCCAGCAACTTCAC 556 ATCTCCAGCAACTTCACT 557 TCTCCAGCAACTTCACTT 558 CTCCAGCAACTTCACTTT 559 TCCAGCAACTTCACTTTC 560 CATAGTCTTCTCCTCTTG 561 ATAGTCTTCTCCTCTTGC 562 GAGCTTTTTTGGCTTCCC 563 AGCTTTTTTGGCTTCCCA 564 TCTTCCACAACTTCCTGG 565 CTTCCACAACTTCCTGGT 566 TTCCACAACTTCCTGGTG 567 TCCACAACTTCCTGGTGA 568 CCACAACTTCCTGGTGAT 569 CACAACTTCCTGGTGATT 570 ACACAAGAAGTCTGTCAG 571 CACAAGAAGTCTGTCAGC 572 ACAAGAAGTCTGTCAGCT 573 CAAGAAGTCTGTCAGCTA TABLE 1B SEQ ID NO. Sequence 615 ATAACAACCTTTCCCTCTGG 616 CCTTTCCCTCTGGAGTTTTA 617 GGAAATAAAGATGAAGCAGG 618 GCGTCAAAATAAGAGTCATG 619 GGCCATGAGTTAATGATTGT 620 GGTGTATGGAATTTCCCATA 621 CTCACCAGGGGTATTGGGTG 622 TAATCCCAAGCATTTATTGC 623 GGAACTGTACATGATCAGAT 151421.02101/134342068v. 624 GATCAGATCATGGAAGGATA 625 AGATCATGGAAGGATAGCTC 626 GTGGCCACTGCCATCTTCCT 627 TCATCACTGTCCTTAGCTTT 628 TGTCCTTAGCTTTGGAGTAC 629 GTACACAACTCCAAGTGGCC 630 CAAATTCCACACTGATAGCA 631 CCACACTGATAGCAACAATG 632 GACTGCATCTGATGTGTGCT 633 GCTGGCAATCTTAAGCCCAA 634 GCTGAGTGAGAAGGCATGGA 635 GAGTGAGAAGGCATGGACTA 636 CATGGACTACTAAATTCTGG 637 TTACAAAACAACTTCACTAC 638 CGCCATCACAACCTTTCTCT 639 CTAGCAGAAATTTTTACCCC 640 CCCATAGAATCTTTCAGCTT 641 CCAGATCTATGACCATCCTG 642 GATCTATGACCATCCTGTCA 643 CCATCCTGTCAATTTCCTCT 644 ATGAAGAAGACTATTGGATG 645 CTCTTCTCCATGTTTTTCTC 646 GTTGGGAAAAACTCTTCTCC 647 GTTTCCATGTCAGGTTTGAT 648 CCATGTCAGGTTTGATCTGC 649 GATGATACTGGCGTAACTGG 650 GGCAGCAGCATAATCTGAAA 651 CCAGCAACTTCACTTTCTCA 652 GCATCTTCTGCACTGATCTC 653 TAGTCTTCTCCTCTTGCCGC 654 CTCATAGTCTTCTCCTCTTG 655 TTCCCACTTCCGGCAACAAG 656 CTCTTCCCACTTCCGGCAAC 657 AGCCGCCATCACAACCTTTC 658 GTATATGCGTCAAAATAAGA 659 GTTAGAAATTCTAATCCCAA 660 TACATCTTATATCCAAGCAC 661 GGATTAGACAGCTGTTCCTC 151421.02101/134342068v. 662 GATATCTGCATCATCATTAT 663 TCTGCATCATCATTATAAGG 664 GTAACTGGGCAGCAGCATAA 665 TAACAACCTTTCCCTCTGGA 666 AGGCATGGACTACTAAATTC 667 GAAGGCATGGACTACTAAAT 668 CTGAGTGAGAAGGCATGGAC 669 TGAGTGAGAAGGCATGGACT 670 AGAAGGCATGGACTACTAAA 671 GAGAAGGCATGGACTACTAA 672 TGAGAAGGCATGGACTACTA 673 GTGAGAAGGCATGGACTACT 674 AGTGAGAAGGCATGGACTAC 675 AATCTTTCAGCTTTCTTGTT 676 AGAATCTTTCAGCTTTCTTG 677 CTACTAAATTCTGGATTACT 678 CACACTGATAGCAACAATGA 679 ACACTGATAGCAACAATGAC 680 CACTGATAGCAACAATGACT 681 ACTGATAGCAACAATGACTG 682 CTGATAGCAACAATGACTGC 683 TGATAGCAACAATGACTGCA 684 GGCAATCTTAAGCCCAAAAT 685 GCAATCTTAAGCCCAAAATG 686 CAATCTTAAGCCCAAAATGC 687 ATGCTTCAAAGATTAAACAG 688 CTTCAAAGATTAAACAGCCA 689 CATCTTATATCCAAGCACAA 690 ATCTTATATCCAAGCACAAA 691 CTTATATCCAAGCACAAAAA 692 CATGAAAGGATATACGTTTA 693 ATTTCTAAATGCTGAGTGAG 694 CTAAATGCTGAGTGAGAAGG 695 TAAATGCTGAGTGAGAAGGC 696 AAATGCTGAGTGAGAAGGCA 697 AATGCTGAGTGAGAAGGCAT 698 ATGCTGAGTGAGAAGGCATG 699 TGCTGAGTGAGAAGGCATGG 151421.02101/134342068v. 700 CATGAAGAAGACTATTGGAT 701 TACACAACTCCAAGTGGCCC 702 ACACAACTCCAAGTGGCCCG 703 CATCACTGTCCTTAGCTTTG 704 ATCACTGTCCTTAGCTTTGG 705 TCACTGTCCTTAGCTTTGGA 706 CACTGTCCTTAGCTTTGGAG 707 ACTGTCCTTAGCTTTGGAGT 708 CTGTCCTTAGCTTTGGAGTA 709 GATCATGGAAGGATAGCTCC 710 ATCATGGAAGGATAGCTCCA 711 TCATGGAAGGATAGCTCCAC 712 CTCCCCGACCTTGGTCACAG 713 ATGGAAGGATAGCTCCACTC 714 GGAAGGATAGCTCCACTCCT 715 CAGCCCAGTCAATAAGGTTC 716 GCCTCTATTGAGTTGTGTGG 717 TATCAACTGGCTGAACTACC 718 ATCAACTGGCTGAACTACCA 719 GTCAGGTTTGATCTGCTTGG 720 AACCCCAGCACTAAAGCATT 721 GGACTCTTATCCCTAATACA 722 TCCCTATCAACTGGCTGAAC 723 GCTGGACTCTTATCCCTAAT 724 ACAGTAGTTTAGGTGTCACC 725 GACTAACAGCCCAGTCAATA 726 ACTACATGAGGCACCCCCTG 727 GAGAGGCTCCAGGACTTATC 728 TTGCTGGACTCTTATCCCTA 729 GGTTGTTAGTAATGGAGACT 730 GGTTTGATCTGCTTGGTCAA 731 TGTTTGGACCTTCCTATTGA 732 TTAGGTCATAAGCTGGTGGC 733 ATCCCTAGTATATTCTTGGC 734 CTACCATCCCTAGTATATTC 735 GGTCAGGCAGGACATATTAA 736 CAACCAGTCTTAGAATGCCC 737 GTCATAAGCTGGTGGCAGTT 151421.02101/134342068v. 738 TGGACTCTTATCCCTAATAC 739 GATTCCCTATCAACTGGCTG 740 TCAACTGGCTGAACTACCAC 741 AACCACCATGTTGTAGTGTC 742 GGTCCCTTTTTATTGGATCA 743 AAGTGAACCAGGTCTCTTAC 744 CCAACTACCATCCCTAGTAT 745 ATCAGGTGTCAGACCTTGTT 746 GTCCCTTTTTATTGGATCAG 747 TAGGTCATAAGCTGGTGGCA 748 GGTCAACAAAGTTGAGTCTG 749 GTGTGGTCCCTTTTTATTGG 750 CTTAGGTCATAAGCTGGTGG 751 AGAGATACTCCTCCCAACTA 752 CCCAACTACCATCCCTAGTA 753 CTGGACTCTTATCCCTAATA 754 GCTCTGTTGGTCTGTCAGAC 755 CAATCAACAACCAGTCTTAG 756 ACAACCAGTCTTAGAATGCC 757 CCTATCAACTGGCTGAACTA 758 CCCATACCTTAGCATTAAAG 759 TGGTCCCTTTTTATTGGATC 760 AGATACTCCTCCCAACTACC 761 ACCAACCCCAGCACTAAAGC 762 TTGTTTGGACCTTCCTATTG 763 CCCTATCAACTGGCTGAACT 764 GGCACATCCTTTCTTGAAAC 765 ATTCCCTATCAACTGGCTGA 766 GAGAGATACTCCTCCCAACT 767 GAGATACTCCTCCCAACTAC 768 TCCCAACTACCATCCCTAGT 769 CAAACAGTAGTTTAGGTGTC 770 GCTGACACCTACAATTATGA 771 CAACTACCATCCCTAGTATA 772 AGCAGCCCACCACCTGTTTA 773 CTCTATTGAGTTGTGTGGTC 774 TGCTGGACTCTTATCCCTAA 775 CTATCAACTGGCTGAACTAC 151421.02101/134342068v. 776 GAACCCTCACCAACAAAACC 777 CTATGACCATCCTGTCAATT 778 TGACTAACAGCCCAGTCAAT 779 GGTCATAAGCTGGTGGCAGT 780 CATAAGCTGGTGGCAGTTTG 781 GATACTCCTCCCAACTACCA 782 CATCCCTAGTATATTCTTGG 783 CCAATCAACAACCAGTCTTA 784 AGTCTTAGAATGCCCAGTTA 785 GTGTGAAGTAATATATGCCC 786 TCTATGACCATCCTGTCAAT 787 TAACCAATCAACAACCAGTC 788 AACAACCAGTCTTAGAATGC 789 CAATCTGACCTGAAAATCCC 790 CAAACCTAACCCAGATACAT 791 GCCTCCAAGACTACTCACCC 792 AGAGGCTCCAGGACTTATCA 793 TCTTAGAATGCCCAGTTAAG 794 ACTAACAGCCCAGTCAATAA 795 TCAATCTGACCTGAAAATCC 796 CAACCCCAGCACTAAAGCAT 797 GTCTGGCTTTCAAACAGTAG 798 GATGATCCTGCTCTGTTGGT 799 GAGGCTCCAGGACTTATCAG 800 CAACCACCATGTTGTAGTGT 801 GTGGTCCCTTTTTATTGGAT 802 CAACAACCAGTCTTAGAATG 803 ACCAGTCTTAGAATGCCCAG 804 TCCTTGTTTGGACCTTCCTA 805 GCATAGCTTCTATCCTGAAG 806 AATGACTAACAGCCCAGTCA 807 GTTGTTAGTAATGGAGACTC 808 GGAACCCTCACCAACAAAAC 809 TCAGGTGTCAGACCTTGTTT 810 GTCAACAAAGTTGAGTCTGT 811 AACTCCTTTAGTTGTCTGGC 812 CCCCTGGAGACCCACAAACT 813 GTCTTAGAATGCCCAGTTAA 151421.02101/134342068v. 814 CCTTGTTTGGACCTTCCTAT 815 GCACATCCTTTCTTGAAACC 816 TAAGCTGGTGGCAGTTTGTC 817 AACAGTAGTTTAGGTGTCAC 818 GCACAAGAGGCACATCCTTT 819 GTCAATCTGACCTGAAAATC 820 CCTCTATTGAGTTGTGTGGT 821 CCATCCCTAGTATATTCTTG 822 GTTTGGACCTTCCTATTGAG 823 GACCTTCCTATTGAGAGAAA 824 GCACTGGTTTGCTGTTCCAG 825 GAGTTGTGTGGTCCCTTTTT 826 CATGTGTTCCTTACACAATC 827 GTTTTGTCTCACTACAACAG 828 AGCTATTTGCTGGACTCTTA 829 TTTCCATGTCAGGTTTGATC 830 CATGTCAGGTTTGATCTGCT 831 TCCATGTCAGGTTTGATCTG 832 CACCTGTTTATGAAAAGAGG 833 TCTAAGCATAGCTTCTATCC id="p-72" id="p-72" id="p-72"

[0072] In one embodiment, the disclosure provides modified oligonucleotides consisting of 12- linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least , at least 11 at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 or at least 20 consecutive nucleotide bases of any of the nucleobase sequences of SEQ ID NO:1-266, 533-573, and 615-833 in Tables 1A and 1B. In some embodiments, the modified oligonucleotide is at least 80% to 100% (i.e., 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98% or 100%; or any numerical range or value between any of the foregoing values) identical to any of the sequences comprising or consisting of SEQ ID NO:1-266, 533-573, and 615-833. id="p-73" id="p-73" id="p-73"

[0073] The sequences provided in Tables 1A and 1B can be used to design antisense molecules for inhibition of SYF2 expression. For example, gapmer oligonucleotides can be designed using 151421.02101/134342068v. the sequences in Tables 1A and 1B and can comprise a 5'-wing of about 3-5 nucleotides, a 3'- wing of about 3-5 nucleotides and a gap region comprising 8-12 consecutive deoxyribonucleosides of any one of the sequences of Tables 1A and 1B. In one embodiment, an oligonucleotide of the disclosure comprises a gapmer having a gap segment of at least 8, at least 9, at least 10, at least 11 at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19 or at least 20 consecutive nucleotide bases of any of the nucleobase sequences of SEQ ID NO:1-266, 533-573, and 615-833 in Tables 1A and 1B; flanked by a 5' and 3' wing segments, wherein the gap segment is located between the 5' and 3' wing segments and wherein each of the wing segments comprises a modified sugar. In one embodiment, the gap segment is 8-10 nucleosides in length and each wing segment is 3-5 modified nucleosides in length. In yet another embodiment, an oligonucleotide of the disclosure comprises a 5' wing segment comprising modified sugars and having the nucleobase sequence of the first 3- nucleobases of any of SEQ ID NO:1-266, 533-573, and 615-833, followed by a gap of the next 8-12 unmodified nucleotides of the same sequence corresponding to SEQ ID NO:1-266, 533- 573, and 615-833, followed by a 3' wing segment comprising modified sugars and having the nucleobase sequence of the last 3-5 nucleobases of the same sequence corresponding to SEQ ID NO:1-266, 533-573, and 615-833. Tables 2A and 2B provide MOE gapmers of the disclosure. id="p-74" id="p-74" id="p-74"

[0074] The 5' and/or 3' wings can comprise the following chemistries: 2'-OMe, 2'-MOE, LNA or DNA, by themselves or used in combination with one another. The backbone linkage of the 5' and/or 3' wings can be phosphorothioate or a mixture of phosphodiester and phosphorothioate.

Linkages in the gap region can be phosphorothioate. 151421.02101/134342068v. id="p-75" id="p-75" id="p-75"

[0075] In some embodiments, the oligonucleotide is single stranded. In some embodiments the oligonucleotide comprises or is complexed with a moiety that neutralizes charge on the oligonucleotide to promote uptake and transfer across a cell membrane. id="p-76" id="p-76" id="p-76"

[0076] In one embodiment, every nucleobase in each 18-mer listed in Table 1A is a 2MOE nucleobase and each internucleotide linkage is a phosphorothioate linkage. The ASO may be a splice switching ASO. id="p-77" id="p-77" id="p-77"

[0077] In one embodiment, each of the 20-mer ASOs in Tables 1A and 1B have the following -10-5 motif: 2MOE*2MOE-2MOE-2MOE-2MOE-N*N*N*N*N*N*N*N*N*N*2MOE- 2MOE-2MOE*2MOE*2MOE where (i) 2MOE is a nucleobase with a 2'-OCH 2CH2-OCH3 group (i.e., 2'-MOE), (ii) N is a nucleobase, (iii) the asterisk (*) refers to a phosphorothioate linkage, and (iv) the dash (-) refers to a phosphodiester linkage. The ASO may be a RNase H dependent ASO. id="p-78" id="p-78" id="p-78"

[0078] In another embodiment, each of the 20-mer ASOs in Tables 1A and 1B have the following 5-10-5 motif: 2MOE*2MOE-2MOE-2MOE-2MOE- N*N*N*N*N*N*N*N*N*N*2MOE-2MOE-2MOE*2MOE*2MOE where (i) 2MOE is a nucleobase with a 2'-OCH2CH2-OCH3 group (i.e., 2'-MOE), (ii) N is a nucleobase except each cytosine (C) is present as 5-methyl deoxycytidine (Me-dC), (iii) the asterisk (*) refers to a phosphorothioate linkage, and (iv) the dash (-) refers to a phosphodiester linkage. The ASO may be a RNase H dependent ASO. id="p-79" id="p-79" id="p-79"

[0079] Table 2A below shows SEQ ID NOs: 1-266 and 533-573 with certain motifs, including certain modified 2MOE nucleobases and phosphorothioate linkages (referred to as SEQ ID NOs: 267-532 and 574-614). SEQ ID NOs: 1-37, 38-50, 51-139, 140-266, 533-573 correspond, with a 151421.02101/134342068v. particular motif, to SEQ ID NOs: 267-303, 304-316, 317-405, 406-532, and 574-614, respectively. id="p-80" id="p-80" id="p-80"

[0080] Table 2A: The Sequence of Bases in SYF2 Antisense Oligonucleotides - (ASOs).

(Gapmer design: 5'- five 2'-methoxyethylribose nucleotides – ten DNA nucleotides – five 2'- methoxyethylribose nucleotides – 3'; Capital letters are 2'-methoxyethylribose nucleosides; lower case are DNA nucleosides; asterisks (*) are phosphorothioate linkages; linkages which do not have an asterisk are phosphodiester linkages) (Note that the following table provides 2'MOE wings; however, alternative wings comprising 2'-OMe or LNA (locked nucleic acid) are contemplated).

TABLE 2A SEQ ID NO. Sequence 267 G*A*C*C*A*T*C*C*T*T*A*G*A*C*A*A*C*T 268 G*T*A*T*A*C*A*C*A*C*A*C*A*C*A*C*A*C 269 A*T*A*C*A*C*A*C*A*C*A*C*A*C*A*C*A*C 270 T*A*C*A*C*A*C*A*C*A*C*A*C*A*C*A*C*A 271 A*T*A*C*A*T*C*C*A*C*A*T*C*A*C*C*T*C 272 T*A*C*A*T*C*C*A*C*A*T*C*A*C*C*T*C*A 273 A*C*A*T*C*C*A*C*A*T*C*A*C*C*T*C*A*G 274 C*A*T*C*C*A*C*A*T*C*A*C*C*T*C*A*G*G 275 A*T*C*C*A*C*A*T*C*A*C*C*T*C*A*G*G*T 276 T*C*C*A*C*A*T*C*A*C*C*T*C*A*G*G*T*T 277 C*C*A*C*A*T*C*A*C*C*T*C*A*G*G*T*T*G 278 C*A*C*A*T*C*A*C*C*T*C*A*G*G*T*T*G*A 279 A*C*A*T*C*A*C*C*T*C*A*G*G*T*T*G*A*A 280 C*A*T*C*A*C*C*T*C*A*G*G*T*T*G*A*A*A 281 C*A*C*C*T*C*A*G*G*T*T*G*A*A*A*A*A*G 282 A*C*C*T*C*A*G*G*T*T*G*A*A*A*A*A*G*G 283 C*C*T*C*A*G*G*T*T*G*A*A*A*A*A*G*G*A 284 C*T*C*A*G*G*T*T*G*A*A*A*A*A*G*G*A*C 285 G*T*T*T*C*C*A*T*G*T*C*A*G*G*T*T*T*G 286 T*C*C*A*T*G*T*C*A*G*G*T*T*T*G*A*T*C 151421.02101/134342068v. 287 C*C*A*T*G*T*C*A*G*G*T*T*T*G*A*T*C*T 288 C*A*T*G*T*C*A*G*G*T*T*T*G*A*T*C*T*G 289 A*T*G*T*C*A*G*G*T*T*T*G*A*T*C*T*G*C 290 T*G*T*C*A*G*G*T*T*T*G*A*T*C*T*G*C*T 291 G*T*C*A*G*G*T*T*T*G*A*T*C*T*G*C*T*T 292 T*C*A*G*G*T*T*T*G*A*T*C*T*G*C*T*T*G 293 C*A*G*G*T*T*T*G*A*T*C*T*G*C*T*T*G*G 294 A*G*G*T*T*T*G*A*T*C*T*G*C*T*T*G*G*T 295 G*G*T*T*T*G*A*T*C*T*G*C*T*T*G*G*T*C 296 G*T*T*T*G*A*T*C*T*G*C*T*T*G*G*T*C*A 297 T*T*G*A*T*C*T*G*C*T*T*G*G*T*C*A*A*C 298 T*G*A*T*C*T*G*C*T*T*G*G*T*C*A*A*C*C 299 G*G*C*A*G*C*A*G*C*A*T*A*A*T*C*T*A*A 300 T*T*C*C*T*T*G*T*T*T*G*G*A*C*C*T*T*C 301 T*C*C*T*T*G*T*T*T*G*G*A*C*C*T*T*C*C 302 C*C*T*T*G*T*T*T*G*G*A*C*C*T*T*C*C*T 303 C*T*T*G*T*T*T*G*G*A*C*C*T*T*C*C*T*A 304 G*C*C*T*C*C*A*A*G*A*C*T*A*C*T*C*A*C 305 C*C*T*C*C*A*A*G*A*C*T*A*C*T*C*A*C*C 306 C*T*C*C*A*A*G*A*C*T*A*C*T*C*A*C*C*C 307 G*A*C*A*A*G*G*A*G*A*A*C*T*G*G*C*T*T 308 A*C*A*A*G*G*A*G*A*A*C*T*G*G*C*T*T*C 309 C*A*A*G*G*A*G*A*A*C*T*G*G*C*T*T*C*A 310 A*A*G*G*A*G*A*A*C*T*G*G*C*T*T*C*A*G 311 A*G*G*A*G*A*A*C*T*G*G*C*T*T*C*A*G*G 312 G*A*G*A*A*C*T*G*G*C*T*T*C*A*G*G*C*A 313 A*G*A*A*C*T*G*G*C*T*T*C*A*G*G*C*A*G 314 G*A*A*C*T*G*G*C*T*T*C*A*G*G*C*A*G*A 315 A*A*C*T*G*G*C*T*T*C*A*G*G*C*A*G*A*G 316 T*C*A*G*C*T*T*C*T*C*C*C*A*G*G*A*C*T 317 C*ACACa*c*a*c*a*c*a*c*a*a*ATA*C*A 318 A*CACAc*a*c*a*c*a*c*a*c*a*AAT*A*C 319 C*ACACa*c*a*c*a*c*a*c*a*c*AAA*T*A 320 T*ACACa*c*a*c*a*c*a*c*a*c*ACA*A*A 321 A*CACAc*a*c*a*c*a*c*a*c*a*CAA*A*T 322 A*TACAc*a*c*a*c*a*c*a*c*a*CAC*A*A 323 A*CACAc*a*c*a*a*a*t*a*c*a*TCC*A*C 324 C*ACACa*c*a*a*a*t*a*c*a*t*CCA*C*A 151421.02101/134342068v. 325 C*ACACa*c*a*c*a*a*a*t*a*c*ATC*C*A 326 A*CACAc*a*c*a*c*a*a*a*t*a*CAT*C*C 327 C*ACACa*c*a*c*a*c*a*a*a*t*ACA*T*C 328 T*ATACa*c*a*c*a*c*a*c*a*c*ACA*C*A 329 A*CAAAt*a*c*a*t*c*c*a*c*a*TCA*C*C 330 C*ACAAa*t*a*c*a*t*c*c*a*c*ATC*A*C 331 C*ACACa*a*a*t*a*c*a*t*c*c*ACA*T*C 332 A*ATACa*t*c*c*a*c*a*t*c*a*CCT*C*A 333 A*AATAc*a*t*c*c*a*c*a*t*c*ACC*T*C 334 C*AAATa*c*a*t*c*c*a*c*a*t*CAC*C*T 335 A*TACTc*c*t*c*c*c*a*a*c*t*ACC*A*T 336 C*ATCAa*c*a*t*t*c*t*t*c*a*TCT*C*C 337 C*TTCAt*c*t*c*c*a*t*t*c*c*AAA*T*C 338 G*TATAc*a*c*a*c*a*c*a*c*a*CAC*A*C 339 G*AACCc*t*c*a*c*c*a*a*c*a*AAA*C*C 340 T*ACTCc*t*c*c*c*a*a*c*t*a*CCA*T*C 341 A*CTCCt*c*c*c*a*a*c*t*a*c*CAT*C*C 342 C*CTCCc*a*a*c*t*a*c*c*a*t*CCC*T*A 343 T*ATCTt*c*t*t*c*c*a*c*a*a*CTT*C*C 344 C*ATCAc*a*a*c*c*t*t*t*c*t*CTC*T*T 345 A*TCACa*a*c*c*t*t*t*c*t*c*TCT*T*C 346 A*TCTTc*t*t*c*c*a*c*a*a*c*TTC*C*T 347 A*CATTc*t*t*c*a*t*c*t*c*c*ATT*C*C 348 C*ATTCt*t*c*a*t*c*t*c*c*a*TTC*C*A 349 G*AAACc*c*c*a*t*c*t*c*t*a*CTA*A*A 350 C*CATCa*c*a*a*c*c*t*t*t*c*TCT*C*T 351 A*CAACc*t*t*t*c*t*c*t*c*t*TCC*C*A 352 T*CCTCc*c*a*a*c*t*a*c*c*a*TCC*C*T 353 G*ACTCt*a*t*c*a*a*a*t*t*c*CAC*A*C 354 C*TCCTc*c*c*a*a*c*t*a*c*c*ATC*C*C 355 G*ATACc*c*c*a*t*c*t*c*t*a*CTA*A*A 356 T*CACAa*c*c*t*t*t*c*t*c*t*CTT*C*C 357 A*ACCTt*t*c*t*c*t*c*t*t*c*CCA*C*T 358 A*GACTc*c*c*a*a*a*c*c*t*a*ACC*C*A 359 C*AACCt*t*t*c*t*c*t*c*t*t*CCC*A*C 360 C*ACAAc*c*t*t*t*c*t*c*t*c*TTC*C*C 361 C*AGATa*t*a*t*t*c*a*a*c*c*CAC*A*C 362 T*GAAAc*c*c*c*a*t*c*t*c*t*ACT*A*A 151421.02101/134342068v. 363 G*ATACt*c*c*t*c*c*c*a*a*c*TAC*C*A 364 T*GATAc*c*c*c*a*t*c*t*c*t*ACT*A*A 365 G*TTCCt*t*a*c*a*c*a*a*t*c*ACT*C*T 366 C*TTTTt*c*c*t*c*t*c*c*c*a*TCT*T*T 367 T*TTTTc*c*t*c*t*c*c*c*a*t*CTT*T*C 368 T*CTTTt*t*c*c*t*c*t*c*c*c*ATC*T*T 369 T*TTTCc*t*c*t*c*c*c*a*t*c*TTT*C*T 370 T*CTTCt*t*t*t*t*c*c*t*c*t*CCC*A*T 371 T*TCTTt*t*t*c*c*t*c*t*c*c*CAT*C*T 372 C*TTCTt*t*t*t*c*c*t*c*t*c*CCA*T*C 373 A*GATAc*t*c*c*t*c*c*c*a*a*CTA*C*C 374 G*GAACc*c*t*c*a*c*c*a*a*c*AAA*A*C 375 T*GTTCc*t*t*a*c*a*c*a*a*t*CAC*T*C 376 A*GACCt*t*t*c*c*c*c*t*t*c*AAT*A*T 377 G*CCATc*a*c*a*a*c*c*t*t*t*CTC*T*C 378 T*AGACc*t*t*t*c*c*c*c*t*t*CAA*T*A 379 C*TGACc*c*c*a*t*t*t*t*a*t*CCT*A*A 380 C*AGCAa*c*t*t*c*a*c*t*t*t*CTC*A*T 381 G*GCTCa*c*a*c*c*a*a*t*a*a*TCC*C*A 382 C*CAGCa*a*c*t*t*c*a*c*t*t*TCT*C*A 383 G*GACTc*t*t*a*t*c*c*c*t*a*ATA*C*A 384 A*CATCa*g*a*t*t*c*c*c*t*a*TCA*A*C 385 A*CACCt*g*t*a*a*t*c*t*c*a*ACC*A*T 386 C*ATCAg*a*t*t*c*c*c*t*a*t*CAA*C*T 387 G*AGACt*c*c*c*a*a*a*c*c*t*AAC*C*C 388 T*TAGAc*c*t*t*t*c*c*c*c*t*TCA*A*T 389 C*TAGCt*c*t*a*c*a*t*a*t*t*TCC*C*T 390 C*CTGTa*a*t*c*c*c*a*c*t*a*CTT*T*T 391 C*TGTTc*c*t*c*t*t*t*c*c*a*AAT*T*C 392 C*CATCt*c*a*g*c*t*a*a*a*a*CTA*C*A 393 A*GAGAt*a*c*t*c*c*t*c*c*c*AAC*T*A 394 A*CTGCc*a*t*c*t*t*c*c*t*c*ATC*A*C 395 G*TGAAa*c*c*c*c*a*t*c*t*c*TAC*T*A 396 C*TGCCa*t*c*t*t*c*c*t*c*a*TCA*C*T 397 C*ACACc*t*g*t*a*a*t*c*t*c*AAC*C*A 398 A*AGCAa*g*a*c*t*c*c*a*t*c*TCA*A*A 399 G*AGATa*c*t*c*c*t*c*c*c*a*ACT*A*C 400 T*GGCTc*a*c*a*c*c*a*a*t*a*ATC*C*C 151421.02101/134342068v. 401 T*CTAGc*t*c*t*a*c*a*t*a*t*TTC*C*C 402 T*TTAGa*c*c*t*t*t*c*c*c*c*TTC*A*A 403 C*TCAGc*t*c*a*t*t*t*c*a*a*CTT*T*C 404 C*TTTAg*t*t*c*c*c*a*c*t*c*CAA*A*C 405 G*AAAAa*g*t*t*c*a*c*c*a*a*CCC*C*A 406 T*CTGCc*t*c*a*g*c*c*t*c*c*CAA*A*G 407 C*TGCCt*c*a*g*c*c*t*c*c*c*AAA*G*T 408 C*CTGAg*c*a*a*c*a*c*a*g*t*GAG*A*C 409 C*TGAGc*a*a*c*a*c*a*g*t*g*AGA*C*C 410 T*GAGCa*a*c*a*c*a*g*t*g*a*GAC*C*C 411 C*AGCCc*a*g*t*c*a*a*t*a*a*GGT*T*C 412 G*CCTAa*g*a*g*c*c*a*g*t*g*TAT*A*C 413 T*ATCAa*c*t*g*g*c*t*g*a*a*CTA*C*C 414 A*TCAAc*t*g*g*c*t*g*a*a*c*TAC*C*A 415 G*CCCAg*t*c*a*a*t*a*a*g*g*TTC*A*A 416 A*GAGAt*a*c*t*c*c*t*c*c*c*AAC*T*A 417 A*TCCCc*a*a*g*c*c*a*c*t*a*TAG*A*C 418 G*TCAGg*t*t*t*g*a*t*c*t*g*CTT*G*G 419 A*CAGCc*c*a*g*t*c*a*a*t*a*AGG*T*T 420 A*GCCCa*g*t*c*a*a*t*a*a*g*GTT*C*A 421 C*TACTa*c*a*t*g*a*g*g*c*a*CCC*C*C 422 C*AGATt*c*c*c*t*a*t*c*a*a*CTG*G*C 423 G*CCACt*a*t*a*g*a*c*a*g*g*TCA*A*A 424 A*ACCCc*a*g*c*a*c*t*a*a*a*GCA*T*T 425 C*CATAc*c*t*t*a*g*c*a*t*t*AAA*G*C 426 T*CACCt*c*a*g*g*t*t*g*a*a*AAA*G*G 427 C*TAACa*g*c*c*c*a*g*t*c*a*ATA*A*G 428 G*CCTCt*a*t*t*g*a*g*t*t*g*TGT*G*G 429 T*GGACt*c*t*t*a*t*c*c*c*t*AAT*A*C 430 G*GACTc*t*t*a*t*c*c*c*t*a*ATA*C*A 431 G*GTGTc*a*c*c*t*a*c*t*a*c*ATG*A*G 432 T*ACATg*a*g*g*c*a*c*c*c*c*CTG*G*A 433 T*CCCTa*t*c*a*a*c*t*g*g*c*TGA*A*C 434 G*AACTa*c*c*a*c*a*c*t*g*t*AGA*C*T 435 A*CCAAc*c*c*c*a*g*c*a*c*t*AAA*G*C 436 C*AACCa*g*t*c*t*t*a*g*a*a*TGC*C*C 437 T*AACAg*c*c*c*a*g*t*c*a*a*TAA*G*G 438 G*CTGGa*c*t*c*t*t*a*t*c*c*CTA*A*T 151421.02101/134342068v. 439 A*CAGTa*g*t*t*t*a*g*g*t*g*TCA*C*C 440 T*ACTAc*a*t*g*a*g*g*c*a*c*CCC*C*T 441 G*TCTCt*t*a*c*t*g*a*c*a*c*TAG*A*C 442 T*CAACc*c*a*c*a*c*t*t*g*c*TAT*C*C 443 A*ACCTg*g*c*t*a*a*c*t*g*a*AGT*A*C 444 G*CTAAc*t*g*a*a*g*t*a*c*a*GCC*T*T 445 G*ACTAa*c*a*g*c*c*c*a*g*t*CAA*T*A 446 A*TCAGg*t*g*t*c*a*g*a*c*c*TTG*T*T 447 A*AATCc*a*g*a*t*a*c*a*c*c*TTG*C*C 448 G*GTCCc*t*t*t*t*t*a*t*t*g*GAT*C*A 449 G*TCATa*a*g*c*t*g*g*t*g*g*CAG*T*T 450 A*CTACa*t*g*a*g*g*c*a*c*c*CCC*T*G 451 A*CATCa*g*a*t*t*c*c*c*t*a*TCA*A*C 452 G*ATTCc*c*t*a*t*c*a*a*c*t*GGC*T*G 453 G*GAGAc*t*c*c*c*a*a*a*c*c*TAA*C*C 454 G*TCCTt*a*g*c*t*t*t*g*g*a*GTA*C*A 455 T*TAGCt*t*t*g*g*a*g*t*a*c*ACA*A*C 456 G*GCATg*g*a*c*t*a*c*t*a*a*ATT*C*T 457 C*CAAGc*c*a*c*t*a*t*a*g*a*CAG*G*T 458 G*TACAg*a*t*c*a*a*a*g*a*g*CCA*A*C 459 G*AGAGg*c*t*c*c*a*g*g*a*c*TTA*T*C 460 C*AACCc*c*a*g*c*a*c*t*a*a*AGC*A*T 461 A*CCTGg*c*t*a*a*c*t*g*a*a*GTA*C*A 462 G*GCACa*t*c*c*t*t*t*c*t*t*GAA*A*C 463 A*TGACt*a*a*c*a*g*c*c*c*a*GTC*A*A 464 T*GTTTa*t*c*a*g*g*t*g*t*c*AGA*C*C 465 T*ATCAg*g*t*g*t*c*a*g*a*c*CTT*G*T 466 G*TCCCt*t*t*t*t*a*t*t*g*g*ATC*A*G 467 G*GTTTg*t*a*t*c*a*g*g*t*g*ACT*G*A 468 A*ACAGt*c*a*c*t*g*g*t*g*t*TAG*T*C 469 T*TGCTg*g*a*c*t*c*t*t*a*t*CCC*T*A 470 A*AGTGa*a*c*c*a*g*g*t*c*t*CTT*A*C 471 G*GTTGt*t*a*g*t*a*a*t*g*g*AGA*C*T 472 G*AAGGa*t*a*g*c*t*c*c*a*c*TCC*T*C 473 T*AGCTt*t*g*g*a*g*t*a*c*a*CAA*C*T 474 A*GCAGc*c*c*a*c*c*a*c*c*t*GTT*T*A 475 G*GTTTg*a*t*c*t*g*c*t*t*g*GTC*A*A 476 T*GTTTg*g*a*c*c*t*t*c*c*t*ATT*G*A 151421.02101/134342068v. 477 A*CTAAc*a*g*c*c*c*a*g*t*c*AAT*A*A 478 C*CCAGt*c*a*a*t*a*a*g*g*t*TCA*A*T 479 A*ACCAc*c*a*t*g*t*t*g*t*a*GTG*T*C 480 T*AAATc*c*a*g*a*t*a*c*a*c*CTT*G*C 481 G*TGTGg*t*c*c*c*t*t*t*t*t*ATT*G*G 482 G*CAGTa*t*t*g*g*a*g*a*c*c*ATA*C*T 483 G*AGTTa*g*a*c*a*t*t*c*c*t*TAG*G*T 484 T*CCTTa*g*g*t*c*a*t*a*a*g*CTG*G*T 485 T*TAGGt*c*a*t*a*a*g*c*t*g*GTG*G*C 486 G*CCTAg*c*t*g*t*c*a*g*g*t*CAC*T*C 487 A*CTGGc*t*g*a*a*c*t*a*c*c*ACA*C*T 488 A*GTAAt*g*g*a*g*a*c*t*c*c*CAA*A*C 489 T*CCTTa*g*c*t*t*t*g*g*a*g*TAC*A*C 490 C*ATCCc*c*a*a*g*c*c*a*c*t*ATA*G*A 491 C*AAGCc*a*c*t*a*t*a*g*a*c*AGG*T*C 492 G*TCAAg*c*t*g*c*t*c*t*a*c*TGA*A*T 493 T*AACCa*a*t*c*a*a*c*a*a*c*CAG*T*C 494 G*AGCAt*c*a*t*a*g*c*a*c*c*ATG*T*T 495 G*TTTAt*c*a*g*g*t*g*t*c*a*GAC*C*T 496 C*AGTAt*t*g*g*a*g*a*c*c*a*TAC*T*A 497 C*TTAGg*t*c*a*t*a*a*g*c*t*GGT*G*G 498 C*ATCCc*t*a*g*t*a*t*a*t*t*CTT*G*G 499 A*TCCCt*a*g*t*a*t*a*t*t*c*TTG*G*C 500 C*TAGCt*g*t*c*a*g*g*t*c*a*CTC*C*A 501 C*TGGAc*t*c*t*t*a*t*c*c*c*TAA*T*A 502 C*CTATc*a*a*c*t*g*g*c*t*g*AAC*T*A 503 T*CAACt*g*g*c*t*g*a*a*c*t*ACC*A*C 504 G*GCTGa*a*c*t*a*c*c*a*c*a*CTG*T*A 505 G*GTCTc*t*t*a*c*t*g*a*c*a*CTA*G*A 506 G*CCTCc*a*a*g*a*c*t*a*c*t*CAC*C*C 507 G*ATCAt*g*g*a*a*g*g*a*t*a*GCT*C*C 508 C*CTTAg*c*t*t*t*g*g*a*g*t*ACA*C*A 509 A*GCTTt*g*g*a*g*t*a*c*a*c*AAC*T*C 510 G*AGTAc*a*c*a*a*c*t*c*c*a*AGT*G*G 511 C*AACCc*a*c*a*c*t*t*g*c*t*ATC*C*A 512 A*AGCCa*c*t*a*t*a*g*a*c*a*GGT*C*A 513 A*GCCAc*t*a*t*a*g*a*c*a*g*GTC*A*A 514 C*TATGa*c*c*a*t*c*c*t*g*t*CAA*T*T 151421.02101/134342068v. 515 C*AATCa*a*c*a*a*c*c*a*g*t*CTT*A*G 516 T*GTCAg*g*t*t*t*g*a*t*c*t*GCT*T*G 517 G*TTTGa*t*c*t*g*c*t*t*g*g*TCA*A*C 518 T*TGTTt*g*g*a*c*c*t*t*c*c*TAT*T*G 519 T*GAGTt*a*g*a*c*a*t*t*c*c*TTA*G*G 520 A*GTTAg*a*c*a*t*t*c*c*t*t*AGG*T*C 521 T*AGGTc*a*t*a*a*g*c*t*g*g*TGG*C*A 522 C*ATAAg*c*t*g*g*t*g*g*c*a*GTT*T*G 523 C*CAACt*a*c*c*a*t*c*c*c*t*AGT*A*T 524 G*GTCAa*c*a*a*a*g*t*t*g*a*GTC*T*G 525 G*TTTGt*a*t*c*a*g*g*t*g*a*CTG*A*G 526 A*CCTAc*t*a*c*a*t*g*a*g*g*CAC*C*C 527 A*TCAGa*t*t*c*c*c*t*a*t*c*AAC*T*G 528 A*TTCCc*t*a*t*c*a*a*c*t*g*GCT*G*A 529 G*CTGAa*c*t*a*c*c*a*c*a*c*TGT*A*G 530 A*GGTCt*c*t*t*a*c*t*g*a*c*ACT*A*G 531 G*ACTCc*c*a*a*a*c*c*t*a*a*CCC*A*G 532 G*AATGa*t*c*c*c*a*a*t*g*t*GCT*G*C 574 G*T*T*T*G*G*A*C*C*T*T*C*C*T*A*T*T*G 575 C*T*A*A*C*A*G*C*C*C*A*G*T*C*A*A*T*A 576 A*A*C*A*G*C*C*C*A*G*T*C*A*A*T*A*A*G 577 A*C*A*G*C*C*C*A*G*T*C*A*A*T*A*A*G*G 578 C*A*G*C*C*C*A*G*T*C*A*A*T*A*A*G*G*T 579 A*G*C*C*C*A*G*T*C*A*A*T*A*A*G*G*T*T 580 G*C*C*C*A*G*T*C*A*A*T*A*A*G*G*T*T*C 581 C*C*C*A*G*T*C*A*A*T*A*A*G*G*T*T*C*A 582 A*T*C*T*G*A*C*C*T*G*A*A*A*A*T*C*C*C 583 T*C*T*G*A*C*C*T*G*A*A*A*A*T*C*C*C*A 584 C*T*G*A*C*C*T*G*A*A*A*A*T*C*C*C*A*G 585 T*G*A*C*C*T*G*A*A*A*A*T*C*C*C*A*G*A 586 G*A*C*C*T*G*A*A*A*A*T*C*C*C*A*G*A*T 587 A*C*C*T*G*A*A*A*A*T*C*C*C*A*G*A*T*C 588 C*C*T*G*A*A*A*A*T*C*C*C*A*G*A*T*C*A 589 C*T*G*A*A*A*A*T*C*C*C*A*G*A*T*C*A*G 590 T*G*A*A*A*A*T*C*C*C*A*G*A*T*C*A*G*G 591 G*C*A*C*T*G*A*T*C*T*C*C*A*G*C*A*A*C 592 C*A*C*T*G*A*T*C*T*C*C*A*G*C*A*A*C*T 593 A*C*T*G*A*T*C*T*C*C*A*G*C*A*A*C*T*T 151421.02101/134342068v. 594 C*T*G*A*T*C*T*C*C*A*G*C*A*A*C*T*T*C 595 T*G*A*T*C*T*C*C*A*G*C*A*A*C*T*T*C*A 596 G*A*T*C*T*C*C*A*G*C*A*A*C*T*T*C*A*C 597 A*T*C*T*C*C*A*G*C*A*A*C*T*T*C*A*C*T 598 T*C*T*C*C*A*G*C*A*A*C*T*T*C*A*C*T*T 599 C*T*C*C*A*G*C*A*A*C*T*T*C*A*C*T*T*T 600 T*C*C*A*G*C*A*A*C*T*T*C*A*C*T*T*T*C 601 C*A*T*A*G*T*C*T*T*C*T*C*C*T*C*T*T*G 602 A*T*A*G*T*C*T*T*C*T*C*C*T*C*T*T*G*C 603 G*A*G*C*T*T*T*T*T*T*G*G*C*T*T*C*C*C 604 A*G*C*T*T*T*T*T*T*G*G*C*T*T*C*C*C*A 605 T*C*T*T*C*C*A*C*A*A*C*T*T*C*C*T*G*G 606 C*T*T*C*C*A*C*A*A*C*T*T*C*C*T*G*G*T 607 T*T*C*C*A*C*A*A*C*T*T*C*C*T*G*G*T*G 608 T*C*C*A*C*A*A*C*T*T*C*C*T*G*G*T*G*A 609 C*C*A*C*A*A*C*T*T*C*C*T*G*G*T*G*A*T 610 C*A*C*A*A*C*T*T*C*C*T*G*G*T*G*A*T*T 611 A*C*A*C*A*A*G*A*A*G*T*C*T*G*T*C*A*G 612 C*A*C*A*A*G*A*A*G*T*C*T*G*T*C*A*G*C 613 A*C*A*A*G*A*A*G*T*C*T*G*T*C*A*G*C*T 614 C*A*A*G*A*A*G*T*C*T*G*T*C*A*G*C*T*A id="p-81" id="p-81" id="p-81"

[0081] Table 2B below shows SEQ ID NOs: 615-833 with a particular motif, including modified 2MOE nucleobases and phosphorothioate linkages (referred to as SEQ ID NOs: 834- 1052). SEQ ID NOs: 615-833 correspond, with the motif, to SEQ ID NOs: 834-1052, respectively. id="p-82" id="p-82" id="p-82"

[0082] Table 2B shows examples of antisense oligonucleotides of the invention that incorporate modified bases and other modifications as described herein. These monomer units are described using known oligonucleotide synthesis nomenclature to indicate the non-standard monomer units, for example as set forth by Integrated DNA Technologies (Iowa, US). For example, in the sequences provided in Table 2B, the non-standard monomer units are enclosed in 151421.02101/134342068v. forward slashes "/" and an asterisk "*" between units indicates a PS linkage, while a lack of an asterisk indicates a PO linkage. The format "/i2MOErN/" (and "/2MOErN/" in the first and last nucleotides) refers to a 2′-methoxyethylribose nucleotide, where N refers to the particular nucleobase. The "5" in the first nucleotide refers to the 5’ end, while the "3" in the last nucleotide refers to the 3’ end. "iMe-dC" refers to 5-methyl deoxycytidine.

TABLE 2B SEQ ID NO. ASO code Sequence 834 ASO-1 /52MOErA/*/i2MOErT//i2MOErA//i2MOErA//i2MOErC/A*A*/iMe-dC/*/iMe-dC/*T*T*T*/iMe-dC/*/iMe-dC/*/iMe-dC/*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErG/*/32MOErG/ 835 ASO-2 /52MOErC/*/i2MOErC//i2MOErT//i2MOErT//i2MOErT//iMe-dC/*/iMe-dC/*/iMe-dC/*T*/iMe-dC/*T*G*G*A*G*/i2MOErT//i2MOErT//i2MOErT/*/i2MOErT/*/32MOErA/ 836 ASO-3 /52MOErG/*/i2MOErG//i2MOErA//i2MOErA//i2MOErA/T*A*A*A*G*A*T*G*A*A*/i2MOErG//i2MOErC//i2MOErA/*/i2MOErG/*/32MOErG/ 837 ASO-4 /52MOErG/*/i2MOErC//i2MOErG//i2MOErT//i2MOErC/A*A*A*A*T*A*A*G*A*G*/i2MOErT//i2MOErC//i2MOErA/*/i2MOErT/*/32MOErG/ 838 ASO-5 /52MOErG/*/i2MOErG//i2MOErC//i2MOErC//i2MOErA/T*G*A*G*T*T*A*A*T*G*/i2MOErA//i2MOErT//i2MOErT/*/i2MOErG/*/32MOErT/ 839 ASO-6 /52MOErG/*/i2MOErG//i2MOErT//i2MOErG//i2MOErT/A*T*G*G*A*A*T*T*T*/iMe-dC/*/i2MOErC//i2MOErC//i2MOErA/*/i2MOErT/*/32MOErA/ 840 ASO-7 /52MOErC/*/i2MOErT//i2MOErC//i2MOErA//i2MOErC//iMe-dC/*A*G*G*G*G*T*A*T*T*/i2MOErG//i2MOErG//i2MOErG/*/i2MOErT/*/32MOErG/ 151421.02101/134342068v. 841 ASO-8 /52MOErT/*/i2MOErA//i2MOErA//i2MOErT//i2MOErC//iMe-dC/*/iMe-dC/*A*A*G*/iMe-dC/*A*T*T*T*/i2MOErA//i2MOErT//i2MOErT/*/i2MOErG/*/32MOErC/ 842 ASO-9 /52MOErG/*/i2MOErG//i2MOErA//i2MOErA//i2MOErC/T*G*T*A*/iMe-dC/*A*T*G*A*T*/i2MOErC//i2MOErA//i2MOErG/*/i2MOErA/*/32MOErT/ 843 ASO-10 /52MOErG/*/i2MOErA//i2MOErT//i2MOErC//i2MOErA/G*A*T*/iMe-dC/*A*T*G*G*A*A*/i2MOErG//i2MOErG//i2MOErA/*/i2MOErT/*/32MOErA/ 844 ASO-11 /52MOErA/*/i2MOErG//i2MOErA//i2MOErT//i2MOErC/A*T*G*G*A*A*G*G*A*T*/i2MOErA//i2MOErG//i2MOErC/*/i2MOErT/*/32MOErC/ 845 ASO-12 /52MOErG/*/i2MOErT//i2MOErG//i2MOErG//i2MOErC//iMe-dC/*A*/iMe-dC/*T*G*/iMe-dC/*/iMe-dC/*A*T*/iMe-dC/*/i2MOErT//i2MOErT//i2MOErC/*/i2MOErC/*/32MOErT/ 846 ASO-13 /52MOErT/*/i2MOErC//i2MOErA//i2MOErT//i2MOErC/A*/iMe-dC/*T*G*T*/iMe-dC/*/iMe-dC/*T*T*A*/i2MOErG//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErT/ 847 ASO-14 /52MOErT/*/i2MOErG//i2MOErT//i2MOErC//i2MOErC/T*T*A*G*/iMe-dC/*T*T*T*G*G*/i2MOErA//i2MOErG//i2MOErT/*/i2MOErA/*/32MOErC/ 848 ASO-15 /52MOErG/*/i2MOErT//i2MOErA//i2MOErC//i2MOErA//iMe-dC/*A*A*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*A*A*G*/i2MOErT//i2MOErG//i2MOErG/*/i2MOErC/*/32MOErC/ 849 ASO-16 /52MOErC/*/i2MOErA//i2MOErA//i2MOErA//i2MOErT/T*/iMe-dC/*/iMe-dC/*A*/iMe-dC/*A*/iMe-dC/*T*G*A*/i2MOErT//i2MOErA//i2MOErG/*/i2MOErC/*/32MOErA/ 850 ASO-17 /52MOErC/*/i2MOErC//i2MOErA//i2MOErC//i2MOErA//iMe-dC/*T*G*A*T*A*G*/iMe-dC/*A*A*/i2MOErC//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErG/ 151421.02101/134342068v. 851 ASO-18 /52MOErG/*/i2MOErA//i2MOErC//i2MOErT//i2MOErG//iMe-dC/*A*T*/iMe-dC/*T*G*A*T*G*T*/i2MOErG//i2MOErT//i2MOErG/*/i2MOErC/*/32MOErT/ 852 ASO-19 /52MOErG/*/i2MOErC//i2MOErT//i2MOErG//i2MOErG//iMe-dC/*A*A*T*/iMe-dC/*T*T*A*A*G*/i2MOErC//i2MOErC//i2MOErC/*/i2MOErA/*/32MOErA/ 853 ASO-20 /52MOErG/*/i2MOErC//i2MOErT//i2MOErG//i2MOErA/G*T*G*A*G*A*A*G*G*/iMe-dC/*/i2MOErA//i2MOErT//i2MOErG/*/i2MOErG/*/32MOErA/ 854 ASO-21 /52MOErG/*/i2MOErA//i2MOErG//i2MOErT//i2MOErG/A*G*A*A*G*G*/iMe-dC/*A*T*G*/i2MOErG//i2MOErA//i2MOErC/*/i2MOErT/*/32MOErA/ 855 ASO-22 /52MOErC/*/i2MOErA//i2MOErT//i2MOErG//i2MOErG/A*/iMe-dC/*T*A*/iMe-dC/*T*A*A*A*T*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErG/*/32MOErG/ 856 ASO-23 /52MOErT/*/i2MOErT//i2MOErA//i2MOErC//i2MOErA/A*A*A*/iMe-dC/*A*A*/iMe-dC/*T*T*/iMe-dC/*/i2MOErA//i2MOErC//i2MOErT/*/i2MOErA/*/32MOErC/ 857 ASO-24 /52MOErC/*/i2MOErG//i2MOErC//i2MOErC//i2MOErA/T*/iMe-dC/*A*/iMe-dC/*A*A*/iMe-dC/*/iMe-dC/*T*T*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErC/*/32MOErT/ 858 ASO-25 /52MOErC/*/i2MOErT//i2MOErA//i2MOErG//i2MOErC/A*G*A*A*A*T*T*T*T*T*/i2MOErA//i2MOErC//i2MOErC/*/i2MOErC/*/32MOErC/ 859 ASO-26 /52MOErC/*/i2MOErC//i2MOErC//i2MOErA//i2MOErT/A*G*A*A*T*/iMe-dC/*T*T*T*/iMe-dC/*/i2MOErA//i2MOErG//i2MOErC/*/i2MOErT/*/32MOErT/ 860 ASO-27 /52MOErC/*/i2MOErC//i2MOErA//i2MOErG//i2MOErA/T*/iMe-dC/*T*A*T*G*A*/iMe-dC/*/iMe-dC/*A*/i2MOErT//i2MOErC//i2MOErC/*/i2MOErT/*/32MOErG/ 151421.02101/134342068v. 861 ASO-28 /52MOErG/*/i2MOErA//i2MOErT//i2MOErC//i2MOErT/A*T*G*A*/iMe-dC/*/iMe-dC/*A*T*/iMe-dC/*/iMe-dC/*/i2MOErT//i2MOErG//i2MOErT/*/i2MOErC/*/32MOErA/ 862 ASO-29 /52MOErC/*/i2MOErC//i2MOErA//i2MOErT//i2MOErC//iMe-dC/*T*G*T*/iMe-dC/*A*A*T*T*T*/i2MOErC//i2MOErC//i2MOErT/*/i2MOErC/*/32MOErT/ 863 ASO-30 /52MOErA/*/i2MOErT//i2MOErG//i2MOErA//i2MOErA/G*A*A*G*A*/iMe-dC/*T*A*T*T*/i2MOErG//i2MOErG//i2MOErA/*/i2MOErT/*/32MOErG/ 864 ASO-31 /52MOErC/*/i2MOErT//i2MOErC//i2MOErT//i2MOErT//iMe-dC/*T*/iMe-dC/*/iMe-dC/*A*T*G*T*T*T*/i2MOErT//i2MOErT//i2MOErC/*/i2MOErT/*/32MOErC/ 865 ASO-32 /52MOErG/*/i2MOErT//i2MOErT//i2MOErG//i2MOErG/G*A*A*A*A*A*/iMe-dC/*T*/iMe-dC/*T*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErC/*/32MOErC/ 866 ASO-33 /52MOErG/*/i2MOErT//i2MOErT//i2MOErT//i2MOErC//iMe-dC/*A*T*G*T*/iMe-dC/*A*G*G*T*/i2MOErT//i2MOErT//i2MOErG/*/i2MOErA/*/32MOErT/ 867 ASO-34 /52MOErC/*/i2MOErC//i2MOErA//i2MOErT//i2MOErG/T*/iMe-dC/*A*G*G*T*T*T*G*A*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErG/*/32MOErC/ 868 ASO-35 /52MOErG/*/i2MOErA//i2MOErT//i2MOErG//i2MOErA/T*A*/iMe-dC/*T*G*G*/iMe-dC/*G*T*A*/i2MOErA//i2MOErC//i2MOErT/*/i2MOErG/*/32MOErG/ 869 ASO-36 /52MOErG/*/i2MOErG//i2MOErC//i2MOErA//i2MOErG//iMe-dC/*A*G*/iMe-dC/*A*T*A*A*T*/iMe-dC/*/i2MOErT//i2MOErG//i2MOErA/*/i2MOErA/*/32MOErA/ 151421.02101/134342068v. 870 ASO-37 /52MOErC/*/i2MOErC//i2MOErA//i2MOErG//i2MOErC/A*A*/iMe-dC/*T*T*/iMe-dC/*A*/iMe-dC/*T*T*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErC/*/32MOErA/ 871 ASO-38 /52MOErG/*/i2MOErC//i2MOErA//i2MOErT//i2MOErC/T*T*/iMe-dC/*T*G*/iMe-dC/*A*/iMe-dC/*T*G*/i2MOErA//i2MOErT//i2MOErC/*/i2MOErT/*/32MOErC/ 872 ASO-39 /52MOErT/*/i2MOErA//i2MOErG//i2MOErT//i2MOErC/T*T*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*T*/iMe-dC/*T*T*/i2MOErG//i2MOErC//i2MOErC/*/i2MOErG/*/32MOErC/ 873 ASO-40 /52MOErC/*/i2MOErT//i2MOErC//i2MOErA//i2MOErT/A*G*T*/iMe-dC/*T*T*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErG/ 874 ASO-41 /52MOErT/*/i2MOErT//i2MOErC//i2MOErC//i2MOErC/A*/iMe-dC/*T*T*/iMe-dC/*/iMe-dC/*G*G*/iMe-dC/*A*/i2MOErA//i2MOErC//i2MOErA/*/i2MOErA/*/32MOErG/ 875 ASO-42 /52MOErC/*/i2MOErT//i2MOErC//i2MOErT//i2MOErT//iMe-dC/*/iMe-dC/*/iMe-dC/*A*/iMe-dC/*T*T*/iMe-dC/*/iMe-dC/*G*/i2MOErG//i2MOErC//i2MOErA/*/i2MOErA/*/32MOErC/ 876 ASO-43 /52MOErA/*/i2MOErG//i2MOErC//i2MOErC//i2MOErG//iMe-dC/*/iMe-dC/*A*T*/iMe-dC/*A*/iMe-dC/*A*A*/iMe-dC/*/i2MOErC//i2MOErT//i2MOErT/*/i2MOErT/*/32MOErC/ 877 ASO-44 /52MOErG/*/i2MOErT//i2MOErA//i2MOErT//i2MOErA/T*G*/iMe-dC/*G*T*/iMe-dC/*A*A*A*A*/i2MOErT//i2MOErA//i2MOErA/*/i2MOErG/*/32MOErA/ 878 ASO-45 /52MOErG/*/i2MOErT//i2MOErT//i2MOErA//i2MOErG/A*A*A*T*T*/iMe-dC/*T*A*A*T*/i2MOErC//i2MOErC//i2MOErC/*/i2MOErA/*/32MOErA/ 151421.02101/134342068v. 879 ASO-46 /52MOErT/*/i2MOErA//i2MOErC//i2MOErA//i2MOErT//iMe-dC/*T*T*A*T*A*T*/iMe-dC/*/iMe-dC/*A*/i2MOErA//i2MOErG//i2MOErC/*/i2MOErA/*/32MOErC/ 880 ASO-47 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151421.02101/134342068v. 907 ASO-74 /52MOErC/*/i2MOErT//i2MOErT//i2MOErC//i2MOErA/A*A*G*A*T*T*A*A*A*/iMe-dC/*/i2MOErA//i2MOErG//i2MOErC/*/i2MOErC/*/32MOErA/ 908 ASO-75 /52MOErC/*/i2MOErA//i2MOErT//i2MOErC//i2MOErT/T*A*T*A*T*/iMe-dC/*/iMe-dC/*A*A*G*/i2MOErC//i2MOErA//i2MOErC/*/i2MOErA/*/32MOErA/ 909 ASO-76 /52MOErA/*/i2MOErT//i2MOErC//i2MOErT//i2MOErT/A*T*A*T*/iMe-dC/*/iMe-dC/*A*A*G*/iMe-dC/*/i2MOErA//i2MOErC//i2MOErA/*/i2MOErA/*/32MOErA/ 910 ASO-77 /52MOErC/*/i2MOErT//i2MOErT//i2MOErA//i2MOErT/A*T*/iMe-dC/*/iMe-dC/*A*A*G*/iMe-dC/*A*/iMe-dC/*/i2MOErA//i2MOErA//i2MOErA/*/i2MOErA/*/32MOErA/ 911 ASO-78 /52MOErC/*/i2MOErA//i2MOErT//i2MOErG//i2MOErA/A*A*G*G*A*T*A*T*A*/iMe-dC/*/i2MOErG//i2MOErT//i2MOErT/*/i2MOErT/*/32MOErA/ 912 ASO-79 /52MOErA/*/i2MOErT//i2MOErT//i2MOErT//i2MOErC/T*A*A*A*T*G*/iMe-dC/*T*G*A*/i2MOErG//i2MOErT//i2MOErG/*/i2MOErA/*/32MOErG/ 913 ASO-80 /52MOErC/*/i2MOErT//i2MOErA//i2MOErA//i2MOErA/T*G*/iMe-dC/*T*G*A*G*T*G*A*/i2MOErG//i2MOErA//i2MOErA/*/i2MOErG/*/32MOErG/ 914 ASO-81 /52MOErT/*/i2MOErA//i2MOErA//i2MOErA//i2MOErT/G*/iMe-dC/*T*G*A*G*T*G*A*G*/i2MOErA//i2MOErA//i2MOErG/*/i2MOErG/*/32MOErC/ 915 ASO-82 /52MOErA/*/i2MOErA//i2MOErA//i2MOErT//i2MOErG//iMe-dC/*T*G*A*G*T*G*A*G*A*/i2MOErA//i2MOErG//i2MOErG/*/i2MOErC/*/32MOErA/ 916 ASO-83 /52MOErA/*/i2MOErA//i2MOErT//i2MOErG//i2MOErC/T*G*A*G*T*G*A*G*A*A*/i2MOErG//i2MOErG//i2MOErC/*/i2MOErA/*/32MOErT/ 151421.02101/134342068v. 917 ASO-84 /52MOErA/*/i2MOErT//i2MOErG//i2MOErC//i2MOErT/G*A*G*T*G*A*G*A*A*G*/i2MOErG//i2MOErC//i2MOErA/*/i2MOErT/*/32MOErG/ 918 ASO-85 /52MOErT/*/i2MOErG//i2MOErC//i2MOErT//i2MOErG/A*G*T*G*A*G*A*A*G*G*/i2MOErC//i2MOErA//i2MOErT/*/i2MOErG/*/32MOErG/ 919 ASO-86 /52MOErC/*/i2MOErA//i2MOErT//i2MOErG//i2MOErA/A*G*A*A*G*A*/iMe-dC/*T*A*T*/i2MOErT//i2MOErG//i2MOErG/*/i2MOErA/*/32MOErT/ 920 ASO-87 /52MOErT/*/i2MOErA//i2MOErC//i2MOErA//i2MOErC/A*A*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*A*A*G*T*/i2MOErG//i2MOErG//i2MOErC/*/i2MOErC/*/32MOErC/ 921 ASO-88 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941 ASO-108 /52MOErT/*/i2MOErC//i2MOErC//i2MOErC//i2MOErT/A*T*/iMe-dC/*A*A*/iMe-dC/*T*G*G*/iMe-dC/*/i2MOErT//i2MOErG//i2MOErA/*/i2MOErA/*/32MOErC/ 942 ASO-109 /52MOErG/*/i2MOErC//i2MOErT//i2MOErG//i2MOErG/A*/iMe-dC/*T*/iMe-dC/*T*T*A*T*/iMe-dC/*/iMe-dC/*/i2MOErC//i2MOErT//i2MOErA/*/i2MOErA/*/32MOErT/ 943 ASO-110 /52MOErA/*/i2MOErC//i2MOErA//i2MOErG//i2MOErT/A*G*T*T*T*A*G*G*T*G*/i2MOErT//i2MOErC//i2MOErA/*/i2MOErC/*/32MOErC/ 944 ASO-111 /52MOErG/*/i2MOErA//i2MOErC//i2MOErT//i2MOErA/A*/iMe-dC/*A*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*G*T*/i2MOErC//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErA/ 945 ASO-112 /52MOErA/*/i2MOErC//i2MOErT//i2MOErA//i2MOErC/A*T*G*A*G*G*/iMe-dC/*A*/iMe-dC/*/iMe-dC/*/i2MOErC//i2MOErC//i2MOErC/*/i2MOErT/*/32MOErG/ 151421.02101/134342068v. 946 ASO-113 /52MOErG/*/i2MOErA//i2MOErG//i2MOErA//i2MOErG/G*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*A*G*G*A*/iMe-dC/*/i2MOErT//i2MOErT//i2MOErA/*/i2MOErT/*/32MOErC/ 947 ASO-114 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/52MOErC/*/i2MOErT//i2MOErA//i2MOErT//i2MOErG/A*/iMe-dC/*/iMe-dC/*A*T*/iMe-dC/*/iMe-dC/*T*G*T*/i2MOErC//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErT/ 997 ASO-164 /52MOErT/*/i2MOErG//i2MOErA//i2MOErC//i2MOErT/A*A*/iMe-dC/*A*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*G*/i2MOErT//i2MOErC//i2MOErA/*/i2MOErA/*/32MOErT/ 998 ASO-165 /52MOErG/*/i2MOErG//i2MOErT//i2MOErC//i2MOErA/T*A*A*G*/iMe-dC/*T*G*G*T*G*/i2MOErG//i2MOErC//i2MOErA/*/i2MOErG/*/32MOErT/ 999 ASO-166 /52MOErC/*/i2MOErA//i2MOErT//i2MOErA//i2MOErA/G*/iMe-dC/*T*G*G*T*G*G*/iMe-dC/*A*/i2MOErG//i2MOErT//i2MOErT/*/i2MOErT/*/32MOErG/ 1000 ASO-167 /52MOErG/*/i2MOErA//i2MOErT//i2MOErA//i2MOErC/T*/iMe-dC/*/iMe-dC/*T*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*A*/iMe-dC/*/i2MOErT//i2MOErA//i2MOErC/*/i2MOErC/*/32MOErA/ 1001 ASO-168 /52MOErC/*/i2MOErA//i2MOErT//i2MOErC//i2MOErC//iMe-dC/*T*A*G*T*A*T*A*T*T*/i2MOErC//i2MOErT//i2MOErT/*/i2MOErG/*/32MOErG/ 151421.02101/134342068v. 1002 ASO-169 /52MOErC/*/i2MOErC//i2MOErA//i2MOErA//i2MOErT//iMe-dC/*A*A*/iMe-dC/*A*A*/iMe-dC/*/iMe-dC/*A*G*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErA/ 1003 ASO-170 /52MOErA/*/i2MOErG//i2MOErT//i2MOErC//i2MOErT/T*A*G*A*A*T*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*/i2MOErA//i2MOErG//i2MOErT/*/i2MOErT/*/32MOErA/ 1004 ASO-171 /52MOErG/*/i2MOErT//i2MOErG//i2MOErT//i2MOErG/A*A*G*T*A*A*T*A*T*A*/i2MOErT//i2MOErG//i2MOErC/*/i2MOErC/*/32MOErC/ 1005 ASO-172 /52MOErT/*/i2MOErC//i2MOErT//i2MOErA//i2MOErT/G*A*/iMe-dC/*/iMe-dC/*A*T*/iMe-dC/*/iMe-dC/*T*G*/i2MOErT//i2MOErC//i2MOErA/*/i2MOErA/*/32MOErT/ 1006 ASO-173 /52MOErT/*/i2MOErA//i2MOErA//i2MOErC//i2MOErC/A*A*T*/iMe-dC/*A*A*/iMe-dC/*A*A*/iMe-dC/*/i2MOErC//i2MOErA//i2MOErG/*/i2MOErT/*/32MOErC/ 1007 ASO-174 /52MOErA/*/i2MOErA//i2MOErC//i2MOErA//i2MOErA//iMe-dC/*/iMe-dC/*A*G*T*/iMe-dC/*T*T*A*G*/i2MOErA//i2MOErA//i2MOErT/*/i2MOErG/*/32MOErC/ 1008 ASO-175 /52MOErC/*/i2MOErA//i2MOErA//i2MOErT//i2MOErC/T*G*A*/iMe-dC/*/iMe-dC/*T*G*A*A*A*/i2MOErA//i2MOErT//i2MOErC/*/i2MOErC/*/32MOErC/ 1009 ASO-176 /52MOErC/*/i2MOErA//i2MOErA//i2MOErA//i2MOErC//iMe-dC/*T*A*A*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*G*A*/i2MOErT//i2MOErA//i2MOErC/*/i2MOErA/*/32MOErT/ 1010 ASO-177 /52MOErG/*/i2MOErC//i2MOErC//i2MOErT//i2MOErC//iMe-dC/*A*A*G*A*/iMe-dC/*T*A*/iMe-dC/*T*/i2MOErC//i2MOErA//i2MOErC/*/i2MOErC/*/32MOErC/ 1011 ASO-178 /52MOErA/*/i2MOErG//i2MOErA//i2MOErG//i2MOErG//iMe-dC/*T*/iMe-dC/*/iMe-dC/*A*G*G*A*/iMe-dC/*T*/i2MOErT//i2MOErA//i2MOErT/*/i2MOErC/*/32MOErA/ 151421.02101/134342068v. 1012 ASO-179 /52MOErT/*/i2MOErC//i2MOErT//i2MOErT//i2MOErA/G*A*A*T*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*G*/i2MOErT//i2MOErT//i2MOErA/*/i2MOErA/*/32MOErG/ 1013 ASO-180 /52MOErA/*/i2MOErC//i2MOErT//i2MOErA//i2MOErA//iMe-dC/*A*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*G*T*/iMe-dC/*/i2MOErA//i2MOErA//i2MOErT/*/i2MOErA/*/32MOErA/ 1014 ASO-181 /52MOErT/*/i2MOErC//i2MOErA//i2MOErA//i2MOErT//iMe-dC/*T*G*A*/iMe-dC/*/iMe-dC/*T*G*A*A*/i2MOErA//i2MOErA//i2MOErT/*/i2MOErC/*/32MOErC/ 1015 ASO-182 /52MOErC/*/i2MOErA//i2MOErA//i2MOErC//i2MOErC//iMe-dC/*/iMe-dC/*A*G*/iMe-dC/*A*/iMe-dC/*T*A*A*/i2MOErA//i2MOErG//i2MOErC/*/i2MOErA/*/32MOErT/ 1016 ASO-183 /52MOErG/*/i2MOErT//i2MOErC//i2MOErT//i2MOErG/G*/iMe-dC/*T*T*T*/iMe-dC/*A*A*A*/iMe-dC/*/i2MOErA//i2MOErG//i2MOErT/*/i2MOErA/*/32MOErG/ 1017 ASO-184 /52MOErG/*/i2MOErA//i2MOErT//i2MOErG//i2MOErA/T*/iMe-dC/*/iMe-dC/*T*G*/iMe-dC/*T*/iMe-dC/*T*G*/i2MOErT//i2MOErT//i2MOErG/*/i2MOErG/*/32MOErT/ 1018 ASO-185 /52MOErG/*/i2MOErA//i2MOErG//i2MOErG//i2MOErC/T*/iMe-dC/*/iMe-dC/*A*G*G*A*/iMe-dC/*T*T*/i2MOErA//i2MOErT//i2MOErC/*/i2MOErA/*/32MOErG/ 1019 ASO-186 /52MOErC/*/i2MOErA//i2MOErA//i2MOErC//i2MOErC/A*/iMe-dC/*/iMe-dC/*A*T*G*T*T*G*T*/i2MOErA//i2MOErG//i2MOErT/*/i2MOErG/*/32MOErT/ 1020 ASO-187 /52MOErG/*/i2MOErT//i2MOErG//i2MOErG//i2MOErT//iMe-dC/*/iMe-dC/*/iMe-dC/*T*T*T*T*T*A*T*/i2MOErT//i2MOErG//i2MOErG/*/i2MOErA/*/32MOErT/ 151421.02101/134342068v. 1021 ASO-188 /52MOErC/*/i2MOErA//i2MOErA//i2MOErC//i2MOErA/A*/iMe-dC/*/iMe-dC/*A*G*T*/iMe-dC/*T*T*A*/i2MOErG//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErG/ 1022 ASO-189 /52MOErA/*/i2MOErC//i2MOErC//i2MOErA//i2MOErG/T*/iMe-dC/*T*T*A*G*A*A*T*G*/i2MOErC//i2MOErC//i2MOErC/*/i2MOErA/*/32MOErG/ 1023 ASO-190 /52MOErT/*/i2MOErC//i2MOErC//i2MOErT//i2MOErT/G*T*T*T*G*G*A*/iMe-dC/*/iMe-dC/*T*/i2MOErT//i2MOErC//i2MOErC/*/i2MOErT/*/32MOErA/ 1024 ASO-191 /52MOErG/*/i2MOErC//i2MOErA//i2MOErT//i2MOErA/G*/iMe-dC/*T*T*/iMe-dC/*T*A*T*/iMe-dC/*/iMe-dC/*/i2MOErT//i2MOErG//i2MOErA/*/i2MOErA/*/32MOErG/ 1025 ASO-192 /52MOErA/*/i2MOErA//i2MOErT//i2MOErG//i2MOErA//iMe-dC/*T*A*A*/iMe-dC/*A*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*/i2MOErA//i2MOErG//i2MOErT/*/i2MOErC/*/32MOErA/ 1026 ASO-193 /52MOErG/*/i2MOErT//i2MOErT//i2MOErG//i2MOErT/T*A*G*T*A*A*T*G*G*A*/i2MOErG//i2MOErA//i2MOErC/*/i2MOErT/*/32MOErC/ 1027 ASO-194 /52MOErG/*/i2MOErG//i2MOErA//i2MOErA//i2MOErC//iMe-dC/*/iMe-dC/*T*/iMe-dC/*A*/iMe-dC/*/iMe-dC/*A*A*/iMe-dC/*/i2MOErA//i2MOErA//i2MOErA/*/i2MOErA/*/32MOErC/ 1028 ASO-195 /52MOErT/*/i2MOErC//i2MOErA//i2MOErG//i2MOErG/T*G*T*/iMe-dC/*A*G*A*/iMe-dC/*/iMe-dC/*T*/i2MOErT//i2MOErG//i2MOErT/*/i2MOErT/*/32MOErT/ 1029 ASO-196 /52MOErG/*/i2MOErT//i2MOErC//i2MOErA//i2MOErA//iMe-dC/*A*A*A*G*T*T*G*A*G*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErG/*/32MOErT/ 151421.02101/134342068v. 1030 ASO-197 /52MOErA/*/i2MOErA//i2MOErC//i2MOErT//i2MOErC//iMe-dC/*T*T*T*A*G*T*T*G*T*/i2MOErC//i2MOErT//i2MOErG/*/i2MOErG/*/32MOErC/ 1031 ASO-198 /52MOErC/*/i2MOErC//i2MOErC//i2MOErC//i2MOErT/G*G*A*G*A*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*/iMe-dC/*/i2MOErA//i2MOErA//i2MOErA/*/i2MOErC/*/32MOErT/ 1032 ASO-199 /52MOErG/*/i2MOErT//i2MOErC//i2MOErT//i2MOErT/A*G*A*A*T*G*/iMe-dC/*/iMe-dC/*/iMe-dC/*A*/i2MOErG//i2MOErT//i2MOErT/*/i2MOErA/*/32MOErA/ 1033 ASO-200 /52MOErC/*/i2MOErC//i2MOErT//i2MOErT//i2MOErG/T*T*T*G*G*A*/iMe-dC/*/iMe-dC/*T*T*/i2MOErC//i2MOErC//i2MOErT/*/i2MOErA/*/32MOErT/ 1034 ASO-201 /52MOErG/*/i2MOErC//i2MOErA//i2MOErC//i2MOErA/T*/iMe-dC/*/iMe-dC/*T*T*T*/iMe-dC/*T*T*G*/i2MOErA//i2MOErA//i2MOErA/*/i2MOErC/*/32MOErC/ 1035 ASO-202 /52MOErT/*/i2MOErA//i2MOErA//i2MOErG//i2MOErC/T*G*G*T*G*G*/iMe-dC/*A*G*T*/i2MOErT//i2MOErT//i2MOErG/*/i2MOErT/*/32MOErC/ 1036 ASO-203 /52MOErA/*/i2MOErA//i2MOErC//i2MOErA//i2MOErG/T*A*G*T*T*T*A*G*G*T*/i2MOErG//i2MOErT//i2MOErC/*/i2MOErA/*/32MOErC/ 1037 ASO-204 /52MOErG/*/i2MOErC//i2MOErA//i2MOErC//i2MOErA/A*G*A*G*G*/iMe-dC/*A*/iMe-dC/*A*T*/i2MOErC//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErT/ 1038 ASO-205 /52MOErG/*/i2MOErT//i2MOErC//i2MOErA//i2MOErA/T*/iMe-dC/*T*G*A*/iMe-dC/*/iMe-dC/*T*G*A*/i2MOErA//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErC/ 1039 ASO-206 /52MOErC/*/i2MOErC//i2MOErT//i2MOErC//i2MOErT/A*T*T*G*A*G*T*T*G*T*/i2MOErG//i2MOErT//i2MOErG/*/i2MOErG/*/32MOErT/ 151421.02101/134342068v. 1040 ASO-207 /52MOErC/*/i2MOErC//i2MOErA//i2MOErT//i2MOErC//iMe-dC/*/iMe-dC/*T*A*G*T*A*T*A*T*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErG/ 1041 ASO-208 /52MOErG/*/i2MOErT//i2MOErT//i2MOErT//i2MOErG/G*A*/iMe-dC/*/iMe-dC/*T*T*/iMe-dC/*/iMe-dC/*T*A*/i2MOErT//i2MOErT//i2MOErG/*/i2MOErA/*/32MOErG/ 1042 ASO-209 /52MOErG/*/i2MOErA//i2MOErC//i2MOErC//i2MOErT/T*/iMe-dC/*/iMe-dC/*T*A*T*T*G*A*G*/i2MOErA//i2MOErG//i2MOErA/*/i2MOErA/*/32MOErA/ 1043 ASO-210 /52MOErG/*/i2MOErC//i2MOErA//i2MOErC//i2MOErT/G*G*T*T*T*G*/iMe-dC/*T*G*T*/i2MOErT//i2MOErC//i2MOErC/*/i2MOErA/*/32MOErG/ 1044 ASO-211 /52MOErG/*/i2MOErA//i2MOErG//i2MOErT//i2MOErT/G*T*G*T*G*G*T*/iMe-dC/*/iMe-dC/*/iMe-dC/*/i2MOErT//i2MOErT//i2MOErT/*/i2MOErT/*/32MOErT/ 1045 ASO-212 /52MOErC/*/i2MOErA//i2MOErT//i2MOErG//i2MOErT/G*T*T*/iMe-dC/*/iMe-dC/*T*T*A*/iMe-dC/*A*/i2MOErC//i2MOErA//i2MOErA/*/i2MOErT/*/32MOErC/ 1046 ASO-213 /52MOErG/*/i2MOErT//i2MOErT//i2MOErT//i2MOErT/G*T*/iMe-dC/*T*/iMe-dC/*A*/iMe-dC/*T*A*/iMe-dC/*/i2MOErA//i2MOErA//i2MOErC/*/i2MOErA/*/32MOErG/ 1047 ASO-214 /52MOErA/*/i2MOErG//i2MOErC//i2MOErT//i2MOErA/T*T*T*G*/iMe-dC/*T*G*G*A*/iMe-dC/*/i2MOErT//i2MOErC//i2MOErT/*/i2MOErT/*/32MOErA/ 1048 ASO-215 /52MOErT/*/i2MOErT//i2MOErT//i2MOErC//i2MOErC/A*T*G*T*/iMe-dC/*A*G*G*T*T*/i2MOErT//i2MOErG//i2MOErA/*/i2MOErT/*/32MOErC/ 151421.02101/134342068v. 1049 ASO-216 /52MOErC/*/i2MOErA//i2MOErT//i2MOErG//i2MOErT//iMe-dC/*A*G*G*T*T*T*G*A*T*/i2MOErC//i2MOErT//i2MOErG/*/i2MOErC/*/32MOErT/ 1050 ASO-217 /52MOErT/*/i2MOErC//i2MOErC//i2MOErA//i2MOErT/G*T*/iMe-dC/*A*G*G*T*T*T*G*/i2MOErA//i2MOErT//i2MOErC/*/i2MOErT/*/32MOErG/ 1051 ASO-218 /52MOErC/*/i2MOErA//i2MOErC//i2MOErC//i2MOErT/G*T*T*T*A*T*G*A*A*A*/i2MOErA//i2MOErG//i2MOErA/*/i2MOErG/*/32MOErG/ 1052 ASO-219 /52MOErT/*/i2MOErC//i2MOErT//i2MOErA//i2MOErA/G*/iMe-dC/*A*T*A*G*/iMe-dC/*T*T*/iMe-dC/*/i2MOErT//i2MOErA//i2MOErT/*/i2MOErC/*/32MOErC/ id="p-83" id="p-83" id="p-83"

[0083] The SYF2 antisense or inhibitory nucleic acids of the disclosure can inhibit the expression and thus the activity associate with SYF2. The SYF2 antisense or inhibitory nucleic acids can include any combination of the oligonucleotides set forth in Tables 2A and 2B and sequences that are 98%-99% identical thereto.

Treatment Methods id="p-84" id="p-84" id="p-84"

[0084] Yet another embodiment is a method of treating a subject having a SYF2 disease or disorder by administering a therapeutically effective amount of a SYF2 ASO or a pharmaceutical composition described herein. id="p-85" id="p-85" id="p-85"

[0085] One embodiment is a method of treating a subject having a neurological or neurodegenerative disease by administering a therapeutically effective amount of a SYF2 ASO or a pharmaceutical composition described herein. The neurological disease may be a neurodegenerative disease. The neurodegenerative disease may result in motor neuron 151421.02101/134342068v. degeneration, for example. The neurological disease may be amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, or frontotemporal dementia, for example.

Further examples of neurological diseases include, but are not limited to, Parkinson’s disease, multiple sclerosis, peripheral myopathy, Rasmussen’s encephalitis, attention deficit hyperactivity disorder, autism, central pain syndromes, anxiety, and/or depression, for example. id="p-86" id="p-86" id="p-86"

[0086] The neurological disease may be associated with aberrant endosomal trafficking. For example, endosomal pathways and endosomes are necessary components for the recycling or breakdown of membrane-bound proteins, trafficking of Golgi-associated proteins, and the extracellular release of proteins in exosomes. These processes aid neurotransmission and drive a balance between recycling and degradation of synaptic vesicles or neurotransmitter receptors, for example. id="p-87" id="p-87" id="p-87"

[0087] The neurological disease may be associated with aberrant lysosome degradation.

Alterations in the lysosome degradation may be present in the neurological disease, such as a neurodegenerative disease. Cathepsin imbalance during aging and age-related diseases may provoke deleterious effects on central nervous system (CNS) neurons and lysosomes may be sites for the unfolding and partial degradation of membrane proteins or their precursors that subsequently become expelled from a cell, or are released from dead cells and accumulate as pathological entities. id="p-88" id="p-88" id="p-88"

[0088] A health care professional may diagnose a subject as having a disease associated with motor neuron degeneration by the assessment of one or more symptoms of motor neuron degeneration. To diagnose a neurological disease, a physical exam may be followed by a thorough neurological exam. The neurological exam may assess motor and sensory skills, nerve function, hearing and speech, vision, coordination and balance, mental status, and changes in 151421.02101/134342068v. mood or behavior. Non-limiting symptoms of a disease associated with a neurological disease may be weakness in the arms, legs, feet, or ankles; slurring of speech; difficulty lifting the front part of the foot and toes; hand weakness or clumsiness; muscle paralysis; rigid muscles; involuntary jerking or writing movements (chorea); involuntary, sustained contracture of muscles (dystonia); bradykinesia; loss of automatic movements; impaired posture and balance; lack of flexibility; tingling parts in the body; electric shock sensations that occur with movement of the head; twitching in arm, shoulders, and tongue; difficulty swallowing; difficulty breathing; difficulty chewing; partial or complete loss of vision; double vision; slow or abnormal eye movements; tremor; unsteady gait; fatigue; loss of memory; dizziness; difficulty thinking or concentrating; difficulty reading or writing; misinterpretation of spatial relationships; disorientation; depression; anxiety; difficulty making decisions and judgments; loss of impulse control; difficulty in planning and performing familiar tasks; aggressiveness; irritability; social withdrawal; mood swings; dementia; change in sleeping habits; wandering; and change in appetite. id="p-89" id="p-89" id="p-89"

[0089] Tests may be performed to rule diseases and disorders that may have symptoms similar to those of neurological diseases, measure muscle involvement, assess neuron degeneration.

Non-limiting examples of tests are electromyography (EMG); nerve conduction velocity study; laboratory tests of blood, urine, or other substances; magnetic resonance imaging (MRI); magnetic resonance spectroscopy; muscle or nerve biopsy; transcranial magnetic stimulation; genetic screening; x-rays; fluoroscopy; angiography; computed tomography (CT); positron emission tomography; cerebrospinal fluid analysis; intrathecal contrast-enhanced CT scan; electroencephalography; electronystagmography; evoked response; polysomnogram; thermography; and ultrasound. A health care professional may also assess the patient’s family 151421.02101/134342068v. history of diseases associated with motor neuron degeneration and make a diagnosis in part based on a familial history of neurological diseases. A healthcare professional may diagnose a disease associated with neurological disease in a subject after the presentation of one or more symptoms. id="p-90" id="p-90" id="p-90"

[0090] Neurodegenerative diseases result in the progressive destruction of neurons that affects neuronal signaling. For example, a neurodegeneration may be amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease, Friedreich’s ataxia, Lewy body disease, Parkinson’s disease, spinal muscle atrophy, primary lateral sclerosis, progressive muscle atrophy, progressive bulbar palsy, and pseudobulbar palsy. id="p-91" id="p-91" id="p-91"

[0091] Diseases associated with motor neuron degeneration may be a condition that results in the progressive destruction of motor neurons that interferes with neuronal signaling to the muscles, leading to muscle weakness and wasting. In healthy individuals, upper motor neurons transmit signals from the brain to lower motor neurons in the brain stem and spinal cord, which then transmit the signal to the muscles to result in voluntary muscle activity. The destruction of upper and lower motor neurons affects activity such as breathing, talking, swallowing, and walking, and overtime these functions can be lost. Examples of motor neuron diseases include, but are not limited to, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscle atrophy, progressive bulbar palsy, and pseudobulbar palsy. id="p-92" id="p-92" id="p-92"

[0092] Neuronal hyperexcitability may occur when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are over-activated by excess glutamate or by other compounds or neurotransmitters acting on the glutamate receptors. Excitotoxicity may result from neuronal hyperexcitability.

Excitotoxicity is the pathological process by which nerve cells are damaged or killed by 151421.02101/134342068v. excessive stimulation. The excessive stimulation allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes can damage cell structures such as components of the cytoskeleton, membrane, and DNA. id="p-93" id="p-93" id="p-93"

[0093] Neuronal hyperexcitability may be involved in spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity), epilepsy, painful neuropathies, attention deficit hyperactivity disorder, autism, central pain syndromes, neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, frontotemporal dementia, schizophrenia, Rasmussen’s encephalitis, Huntington’s disease, alcoholism or alcohol withdrawal and especially over-rapid benzodiazepine withdrawal, and also Huntington's disease. Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia. Blood sugars are the primary glutamate removal method from inter-synaptic spaces at the NMDA and AMPA receptor site. id="p-94" id="p-94" id="p-94"

[0094] The herein described methods of treatment may comprise administering to a subject in need thereof a composition comprising an effective amount of one or more antisense oligonucleotides that treats neurological diseases by inhibiting SYF2 expression. The one or more antisense oligonucleotides may decrease or inhibit neurodegeneration. The one or more antisense oligonucleotides may decrease neuronal hyperexcitability. id="p-95" id="p-95" id="p-95"

[0095] The composition may inhibit SYF2 activity or expression. The one or more antisense oligonucleotides can be combined with additional therapeutic agents. id="p-96" id="p-96" id="p-96"

[0096] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include aqueous, lipid, oily or other solutions, 151421.02101/134342068v. solutions in simulated cerebrospinal fluid, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions and the like. Typically, an ASO of the disclosure will be administered directly to the CNS of the subject. Accordingly, the formulation or composition will be sterile and more preferably be suitable for injection. The following formulations and methods are merely exemplary and are in no way limiting. id="p-97" id="p-97" id="p-97"

[0097] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations may be presented in unit-dose or multi- dose sealed containers, such as ampules and vials, and may be stored as liquids or in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The formulation may be provided in a pre-filled syringe. id="p-98" id="p-98" id="p-98"

[0098] Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed one or more antisense or inhibitory nucleic acids and compositions. Sequential administration includes administration before or after the disclosed one or more antisense or inhibitory nucleic acids or compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed one or more antisense or inhibitory nucleic acids. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed one or more antisense or inhibitory nucleic acids. In some embodiments, administration of an additional therapeutic agent 151421.02101/134342068v. with a disclosed one or more antisense or inhibitory nucleic acids may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. When used in combination with one or more other active ingredients, the one or more antisense or inhibitory nucleic acids of the disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the disclosure include those that contain one or more other active ingredients, in addition to one or more antisense or inhibitory nucleic acids of the disclosure. The above combinations include combinations of one or more antisense or inhibitory nucleic acids of the disclosure not only with one other active compound, but also with two or more other active compounds. For example, the compound of the disclosure may be combined with a variety of drugs to treat neurological diseases. The antisense oligonucleotide may be covalently linked to another oligonucleotide, such as one with a target other than SYF2. The antisense oligonucleotide may be covalently linked to an antibody. id="p-99" id="p-99" id="p-99"

[0099] The disclosed one or more antisense or inhibitory nucleic acids can be combined with the following, but are not limited, anticholinergic drugs, anticonvulsants, antidepressants, benzodiazepines, decongestants, muscle relaxants, pain medications, and/or stimulants.

Additional types of therapy and treatment include, but are not limited to digital communication devices, feeding tubes, mechanical ventilation, nutritional support, deep brain stimulation, occupational therapy, physical therapy, and/or speech therapy. id="p-100" id="p-100" id="p-100"

[0100] The disclosed composition(s) may be incorporated into a pharmaceutical composition suitable for administration to a subject (such as a patient, which may be a human or non-human).

The pharmaceutical compositions may comprise a carrier (e.g., a pharmaceutically acceptable carrier). Any suitable carrier can be used within the context of the disclosure, and such carriers 151421.02101/134342068v. are well known in the art. The choice of carrier will be determined, in part, by the particular use of the composition (e.g., administration to an animal) and the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the composition of the present invention. id="p-101" id="p-101" id="p-101"

[0101] The pharmaceutical compositions may include a therapeutically effective amount or a prophylactically effective amount of the antisense oligonucleotide. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of one or more antisense or inhibitory nucleic acids of the disclosure are outweighed by the therapeutically beneficial effects.

A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. id="p-102" id="p-102" id="p-102"

[0102] The pharmaceutical compositions may include one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such 151421.02101/134342068v. as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as releasing agents, coating agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator. id="p-103" id="p-103" id="p-103"

[0103] The route by which the disclosed one or more antisense or inhibitory nucleic acids are administered, and the form of the composition will dictate the type of carrier to be used. id="p-104" id="p-104" id="p-104"

[0104] The pharmaceutical compositions of the disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be parenteral including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal, intracerebroventricular, or intraventricular, administration. In one embodiment the antisense or inhibitory nucleic acid is administered by intravenous, intraperitoneal, or as a bolus injection or administered directly into the target organ. In another embodiment, the antisense or inhibitory nucleic acid is administered intrathecally or intra-cerebroventricular as a bolus injection. id="p-105" id="p-105" id="p-105"

[0105] Carriers for systemic administration typically include at least one of solvent, diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions. 151421.02101/134342068v. id="p-106" id="p-106" id="p-106"

[0106] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. id="p-107" id="p-107" id="p-107"

[0107] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%. id="p-108" id="p-108" id="p-108"

[0108] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%. id="p-109" id="p-109" id="p-109"

[0109] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic composition is typically about 0.1 to about 10%. id="p-110" id="p-110" id="p-110"

[0110] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%. id="p-111" id="p-111" id="p-111"

[0111] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. id="p-112" id="p-112" id="p-112"

[0112] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%. 151421.02101/134342068v. id="p-113" id="p-113" id="p-113"

[0113] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%. id="p-114" id="p-114" id="p-114"

[0114] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%. id="p-115" id="p-115" id="p-115"

[0115] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%. id="p-116" id="p-116" id="p-116"

[0116] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%. id="p-117" id="p-117" id="p-117"

[0117] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%. id="p-118" id="p-118" id="p-118"

[0118] Compositions and formulations for parenteral, intrathecal, intra-cerebroventricular, or intraventricular administration can include sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. For example, an intrathecal cerebrospinal fluid (CSF) catheter can be used to deliver antisense formulations of the disclosure. The catheter can be inserted at the L3 or L4 vertebrae. The distal tip of the catheter 151421.02101/134342068v. extends within the intrathecal space to approximately the Ll vertebrae. Antisense oligonucleotides are dissolved in saline, are sterilized by filtration, and are administered at 0. ml/min in a 1.0 ml volume followed by a 0.5 ml sterile water flush. Total infusion time is 4. min. id="p-119" id="p-119" id="p-119"

[0119] Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent. id="p-120" id="p-120" id="p-120"

[0120] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and , Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976). id="p-121" id="p-121" id="p-121"

[0121] In vivo testing of candidate antisense or inhibitory nucleic acids may be conducted by means known to one of ordinary skill in the art. For example, the candidate one or more antisense or inhibitory nucleic acids may be administered to a mammal, such as a mouse or a rabbit. The mammal may be administered, by any route deemed appropriate, a dose of a candidate antisense or inhibitory nucleic acids. Conventional methods and criteria can then be used to monitor animals for signs of reduction or improvement of motor neuron activity and/or expression or activity of SYF2 gene or protein, respectively. If needed, the results obtained in the presence of the candidate antisense or inhibitory nucleic acids can be compared with results in control animals that are not treated with the candidate antisense or inhibitory nucleic acids.

Dosing studies may be performed in, or in conjunction with, the herein described methods for identifying one or more antisense or inhibitory nucleic acids capable of treating a neurological 151421.02101/134342068v. disease and/or any follow-on testing of candidate antisense or inhibitory nucleic acids in vivo.

One of skill in the art of medicine may determine the appropriate dosage of one or more antisense or inhibitory nucleic acids. The dosage may be determined by monitoring the subject for signs of disease inhibition or amelioration. The dosage may be increased or decreased to obtain the desired frequency of treatment. The toxicity and efficacy of one or more antisense or inhibitory nucleic acids may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. determining the lethal dose to 50% of the population (LD50) and the dose therapeutically effective in 50% of the population (ED50). The dose ratio of LD50/ED50 is the therapeutic index and, indicating the ratio between the toxic and therapeutic effects. A delivery system may be designed to help prevent toxic side effects, by delivering the one or more antisense or inhibitory nucleic acids to specific targets, e.g., delivered specifically to motor or central nervous system neurons. The optimal dose of the one or more antisense or inhibitory nucleic acids may be determined based on results of clinical electrophysiology or electromyography to analyze excitability in peripheral nerves, for example. id="p-122" id="p-122" id="p-122"

[0122] The dosage for use in humans may be determined by evaluating data obtained from animal studies and cell culture assays. The preferred dosage will have little or no toxicity and include the ED50. The dosage may vary depending on the dosage form and route of administration. For any antisense or inhibitory nucleic acid used in the methods described herein, the dosage may be estimated initially in cell culture. A dose may be formulated in animal models that includes the concentration of the test compound which achieves a half maximal inhibition of symptoms (LD50) as determined in cell culture. Such information obtained from cell cultures and animal models may be used to more accurately determine useful doses in humans. 151421.02101/134342068v. id="p-123" id="p-123" id="p-123"

[0123] In another embodiment, an antisense oligonucleotide of the present invention is expressed from a transgene, e.g., as an antisense RNA transcript. A transgene may be administered to a subject in a DNA expression construct that is engineered to express an antisense RNA transcript in a subject. A DNA expression construct may be administered directly or using a viral vector (e.g., a recombinant AAV (rAAV) vector) or other suitable vector. Viral vectors that have been used for gene therapy protocols include, but are not limited to, retroviruses, other RNA viruses such as poliovirus or Sindbis virus, adenovirus, adeno-associated virus (AAV), herpes viruses, SV 40, vaccinia, lentivirus and other DNA viruses. id="p-124" id="p-124" id="p-124"

[0124] The present invention has multiple aspects, illustrated by the following non-limiting examples.

Examples id="p-125" id="p-125" id="p-125"

[0125] ASOs are an attractive therapeutic option for neurodegenerative diseases because of their ease of delivery to the central nervous system and their relatively low exposure to the periphery. These properties maximize target engagement in the central nervous system and minimize undesired target engagement or off-target effects in the periphery. id="p-126" id="p-126" id="p-126"

[0126] The disclosure provides novel antisense oligonucleotide (ASO) sequences targeting the SYF2 gene that can suppress SYF2 expression in human cells. SYF2 ASOs can also rescue the survival of motor neurons derived from sporadic ALS patients, while also rescuing TDP- mislocalization, neurodegeneration, and NMJ loss and resulting in improved motor function. id="p-127" id="p-127" id="p-127"

[0127] To identify ASO sequences that suppress SYF2 expression in human cells, ASOs are designed (see, Table 2) and synthesized as MOE gapmers, which contains sugar and linkage modifications that increase nuclease resistance and melting temperature while maintaining the 151421.02101/134342068v. ability to be used as a substrate of RNase H. As a control, NCASO was used, and the values were normalized to GapdH. id="p-128" id="p-128" id="p-128"

[0128] The disclosure provides ASOs that suppress SYF2 expression in human cells. These ASOs are capable of preventing neurodegeneration in ALS and FTD patients.

Example Human SYF2 ASO screen in HeLa cell (ASO 1-121) id="p-129" id="p-129" id="p-129"

[0129] Antisense oligonucleotides to human SYF2, which target sequences across genomic regions including untranslated regions (UTR) and intronic and exonic regions, were assessed in HeLa cells. Transfection was performed using 25 nM of antisense oligonucleotide with 2’-MOE gapmer chemistry (Figs. 1-3) or 2’-Ome gapmer chemistry (Fig. 4) delivered by LipofectamineTM 2000 (available from Thermo Fisher Scientific, Inc., of Waltham, MA, USA).

Cell harvesting occurred 72 hours post-transfection. A negative control (NC) ASO was tested as a control. id="p-130" id="p-130" id="p-130"

[0130] qRT-PCR analysis of human SYF2 levels in HeLa cells treated with ASO-1 to ASO- 121 was performed. The mRNA levels were determined using the ddCT method, with human GAPDH as the reference gene and the negative control ASO (NCASO) with a scrambled sequence as the reference group. SYF2 mRNA levels in all test conditions were compared to the NC ASO-treated cells using one-way ANOVA. The results for shown in Fig. 1 (ASO-1 to ASO- 50), Fig. 2 (ASO-51 to ASO-74), Fig. 3 (ASO-75-100), and Fig. 4 (ASO-101 to ASO-121). P- values are denoted as follows: **** p < 0.0001, *** p < 0.001, ** p < 0.01, and * p < 0.05.

Example 2 151421.02101/134342068v.

Select SYF2 ASOs in Ngn2-iNs id="p-131" id="p-131" id="p-131"

[0131] Selected sequences (ASO-19, ASO-24, ASO-25, ASO-32, ASO-35, ASO-42, ASO-43, ASO-63, ASO-69, ASO-70, ASO-80, ASO-86, and ASO-120 corresponding to SEQ ID NOs: 633, 638, 639, 646, 649, 656, 657, 677, 683, 684, 694, 700, and 734), which were identified based on their potency in lowering SYF2 mRNA levels and their conservation in non-human primates (NHP), were validated in human iPSC-derived cortical neurons (Ngn2-induced neurons, Ngn2-iNs). Gymnotic delivery was performed using 10 uM of antisense oligonucleotide. Cell harvesting occurred after 7 days of gymnosis. id="p-132" id="p-132" id="p-132"

[0132] qRT-PCR analysis of human SYF2 levels was performed in the Ngn2-iNs treated with the ASOs. The mRNA levels were determined using the ddCT method, with human HPRT as the reference gene and the negative control ASO (NC ASO) with a scrambled sequence as the reference group. SYF2 mRNA levels in all test conditions were compared to the NC ASO- treated cells using one-way ANOVA. The results are shown in Fig. 5. P-values are denoted as follows: **** p < 0.0001, *** p < 0.001, ** p < 0.01, and * p < 0.05.

Example Human SYF2 ASO screen in Ngn2-iNs (ASO 122-219) id="p-133" id="p-133" id="p-133"

[0133] A script was developed that systematically examined the entire target gene sequence, identifying 20 nucleotide sequences that met certain design criteria, including off-target prediction and evaluating sequence conservation in non-human primates. id="p-134" id="p-134" id="p-134"

[0134] 98 sequences, selected for having the lowest number of predicted off-targets and conserving in non-human primates, were synthesized and assessed in Ngn2-iNs. Gymnotic 151421.02101/134342068v. delivery was performed using 10 uM of antisense oligonucleotide. Cell harvesting occurred after 7 days of gymnosis. id="p-135" id="p-135" id="p-135"

[0135] qRT-PCR analysis of human SYF2 levels was performed in Ngn2-iNs treated with the ASOs. The mRNA levels were determined using the ddCT method, with human HPRT as the reference gene and the negative control ASO (NC ASO) with a scrambled sequence as the reference group. SYF2 mRNA levels in all test conditions were compared to the NC ASO- treated cells using one-way ANOVA. The results are shown in Fig. 6. P-values are denoted as follows: **** p < 0.0001, *** p < 0.001, ** p < 0.01, and * p < 0.05. ASO-122, ASO-123, ASO-125, ASO-135, ASO-136, ASO-150, ASO-159, ASO-160, ASO-165, ASO-171, ASO-185, ASO-189, ASO-191, ASO-196, ASO-197, ASO-198, ASO-199, ASO-201, and ASO-2 (corresponding to SEQ ID NOs: 736, 737, 739, 749, 750, 764, 773, 774, 779, 785, 799, 803, 805, 810, 811, 812, 813, 815, and 825) significantly reduced SYF2 expression levels. id="p-136" id="p-136" id="p-136"

[0136] The foregoing description and drawings should be considered as illustrative only of the principles of the invention. The invention is not intended to be limited by the preferred embodiment and may be implemented in a variety of ways that will be clear to one of ordinary skill in the art. Numerous applications of the invention will readily occur to those skilled in the art. Therefore, it is not desired to limit the invention to the specific examples disclosed or the exact construction and operation shown and described. Rather, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. All references cited herein are incorporated by reference. 151421.02101/134342068v.

ABSTRACT The present invention relates to SYF2 antisense oligonucleotides (ASOs), pharmaceutical compositions containing them, and methods for treating, inhibiting, suppressing, and preventing neurological diseases with them.

Claims (31)

02101/134342068v. C L A I M S

1. A single stranded antisense oligonucleotide that suppresses the expression of a SYF2, wherein the antisense oligonucleotide has a nucleobase sequence that comprises at least 12 or 15 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-1052.

2. The antisense oligonucleotide of claim 1, wherein the antisense oligonucleotide comprises a nucleobase sequence of any one of SEQ ID NOs: 1-266, 533-573, and 615-833.

3. The antisense oligonucleotide of claim 1 or 2, wherein the antisense oligonucleotide has 18 to 20 linked nucleosides.

4. The antisense oligonucleotide of any of the preceding claims, wherein at least one internucleoside linkage is a modified internucleoside linkage.

5. The antisense oligonucleotide of claim 4, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

6. The antisense oligonucleotide of claim 4, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

7. The antisense oligonucleotide of any of the preceding claims, wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.

8. The antisense oligonucleotide of claim 7, wherein at least one internucleoside linkage is a phosphorothioate linkage and at least one internucleoside linkage is a phosphodiester linkage.

9. The antisense oligonucleotide of any of the preceding claims, wherein at least one nucleoside comprises a modified nucleobase. 151421.02101/134342068v.

10. The antisense oligonucleotide of claim 9, wherein the modified nucleobase is a 5-methylcytosine.

11. The antisense oligonucleotide of any of the preceding claims, wherein at least one nucleoside of the antisense oligonucleotide comprises a modified sugar moiety.

12. The antisense oligonucleotide of claim 11, wherein the modified sugar moiety comprises a 2'-O-methoxyethyl group.

13. The antisense oligonucleotide of claim 11, wherein the modified sugar moiety comprises a 2'-F.

14. The antisense oligonucleotide of claim 11, wherein the modified sugar moiety comprises a 2'-O-hexadecyl.

15. The antisense oligonucleotide of any of the preceding claims, wherein the antisense oligonucleotide is a gapmer.

16. The antisense oligonucleotide of claim 15, wherein the antisense oligonucleotide comprises: a gap segment consisting of 8 to 12 linked deoxynucleosides; a 5' wing segment consisting of 3 to 5 linked nucleosides; and a 3' wing segment consisting of 3 to 5 linked nucleosides, wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment and wherein a nucleoside of each wing segment comprises a modified sugar moiety.

17. The antisense oligonucleotide of claim 16, wherein each nucleoside of each wing segment comprises a modified sugar moiety.

18. The antisense oligonucleotide of claim 16, wherein the nucleosides making up each wing segment comprises at least two different modified sugar moieties. 151421.02101/134342068v.

19. The antisense oligonucleotide of claim 16, wherein the nucleosides making up each wing segment comprises the same modified sugar moiety.

20. The antisense oligonucleotide of claim 17, wherein the modified sugar moiety comprises a 2'-O-methoxyethyl group.

21. The antisense oligonucleotide of any of the preceding claims, wherein the antisense oligonucleotide comprises 15 to 50 nucleosides.

22. The antisense oligonucleotide of any of the preceding claims, wherein the antisense oligonucleotide is one of SEQ ID NOs: 267-316, 574-614, and 834-1052.

23. A pharmaceutical composition comprising the antisense oligonucleotide of any one of the preceding claims, and a pharmaceutically acceptable carrier, diluent and/or excipient.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is formulated for parenteral delivery.

25. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is formulated for intracerebroventricular injection.

26. A method of treating a subject having a neurological or neurodegenerative disease in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 23.

27. The method of claim 26, wherein the neurological disease is associated with neuronal hyperexcitability.

28. The method of claim 26, wherein the neurological disease is associated with aberrant endosomal trafficking.

29. The method of claim 26, wherein the neurological disease is associated with aberrant lysosomal trafficking. 151421.02101/134342068v.

30. The method of claim 26, wherein the neurological disease is selected from the group consisting of familial and sporadic amyotrophic lateral sclerosis (ALS), familial and sporadic frontotemporal dementia (FTD), progressive supranuclear palsy, Alzheimer's disease, chronic traumatic encephalopathy, Parkinson's disease, Charcot Marie Tooth 2A and 4B, Huntington's disease, dementia, transmissible spongiform encephalopathy, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxias, and Creutzfeldt-Jakob disease.

31. An oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases of any of the nucleobase sequences of SEQ ID NOs: 1-1052.