Oligonucleotide-mediated knockdown of DUX4

Abstract

Provided herein are oligonucleotides for inhibiting the expression of Double Homeobox 4 (DUX4) and methods of using the oligonucleotides for reducing DUX4 expression in a subject.

Description

Docket No.: SOUF-003 / 01WOOLIGONUCLEOTIDE-MEDIATED KNOCKDOWN OF DUX4CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 728,473 filed on December 5, 2024, the entirety of which is incorporated herein by reference.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 360770-0003 SeqList ST26. xml, created December 04, 2025, which is 19,950,082 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUND

[0003] Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease affecting approximately 1 in 8,000 to 22,000 individuals worldwide, making it one of the most prevalent forms of muscular dystrophy. This autosomal dominant myopathy is characterized by progressive muscle weakness and atrophy, primarily impacting muscles in the face, shoulder girdle, and upper arms. As the condition progresses, additional muscle groups can be affected, such as the ankle dorsiflexors and proximal leg muscles, potentially leading to wheelchair dependence for around 20% of patients. Beyond muscular weakness, FSHD can also manifest with extramuscular symptoms, including hearing loss, retinal vasculopathy, and cardiac conduction defects. FSHD has two distinct types: FSHD1 and FSHD2. The root cause in both types is the de-repression of a specific genetic region known as the D4Z4 macrosatellite repeat array, located on chromosome 4: FSHD1 (95% of cases) - a contraction of the D4Z4 repeat array to less than 10 units; FSHD2 (5% of cases) - mutations in genes involved in regulating the D4Z4 array. Despite the different genetic mechanisms, both FSHD1 and FSHD2 result in a loss of methylation in the D4Z4 region, leading to the same clinical presentation. The de-repression of the D4Z4 array leads to the aberrant expression of the DUX4 gene in skeletal muscle. This gene encodes a transcription factor normally active during early embryonic development but silenced in adult tissues, except for specific isoforms in the testis and thymus. The increased expression of DUX4 in adult muscle is highly toxic, causing a cascade of cellular problems that contribute to muscle degeneration: oxidative stress, dysregulated transcript quality control, protein aggregation, inflammation, impaired myogenesis, and muscle atrophy.

[0004] Due to the critical role of DUX4 in FSHD pathogenesis, it has become the primary target for therapeutic development. Various oligonucleotide therapies targeting DUX4 have shownDocket No.: SOUF-003 / 01WOpromising results in preclinical studies. While significant progress has been made in understanding FSHD, further research is necessary to fully comprehend its complex nature and address the remaining unanswered questions. Overall, there is an unmet medical need for patients with FSHD that can be addressed by siRNA therapeutics.SUMMARY

[0005] In some embodiments, the present disclosure provides an oligonucleotide for inhibiting expression of DUX4, wherein the oligonucleotide comprises an antisense strand comprising at least 14 contiguous nucleotides substantially complementary to a sequence of nucleotides encoding DUX4, with no more than 4 mismatched nucleotides.

[0006] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an oligonucleotide described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] In some embodiments, the present disclosure provides methods of using provided oligonucleotides. In some embodiments, the present disclosure provides a method for inhibiting DUX4 expression or treating a DUX4 related disorder in a subject, the method comprising administering an effective amount of an oligonucleotide described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an oligonucleotide described herein to the subject.DETAILED DESCRIPTION

[0008] Provided herein are oligonucleotides for inhibiting the expression of Double Homeobox 4 (" DUX4"). In some embodiments, the oligonucleotide comprises an antisense strand substantially complementary to a sequence encoding DUX4. In some embodiments, the antisense strand comprises at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous nucleotides) substantially complementary to the sequence of nucleotides encoding DUX4, with no more than 4 mismatched nucleotides.

[0009] The term "‘antisense strand” refers to an oligonucleotide having a nucleotide sequence substantially complementary to a target sequence in a transcript, e.g., an mRNA encoding DUX4. In embodiments wherein the oligonucleotide is an RNAi agent, the term antisense strand may be used interchangeably with the term “guide strand”. In some embodiments, an antisense strand disclosed herein is 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.Docket No.: SOUF-003 / 01WO

[0010] The term “sense strand” refers to an oligonucleotide having a nucleotide sequence substantially complementary to an antisense strand, e.g., the antisense strand of an RNAi agent herein. Hie term “sense strand” may be used interchangeably with the term “passenger strand.” In some embodiments, a sense strand disclosed herein is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length. For example, each of the sense strands in Tables 1A-1F is 19 nucleotides in length and substantially complementary to the corresponding antisense strand shown in the same row.

[0011] As used herein, and unless otherwise indicated, the term “complementary-,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. In some embodiments, a duplex structure disclosed herein is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length.

[0012] The terms “complementary',” “completely complementary” and “substantially complementary'” herein can be used with respect to the base matching between tire antisense strand of an oligonucleotide, e.g., an RNAi agent, and a target sequence, or between the sense strand and the antisense strand of an RNAi agent, as will be understood from the context of their use. Complementary' sequences, e.g., between an antisense strand and a target sequence in a target transcript, or between the sense and antisense strand of an siRNA, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “completely complementary'” with respect to each other when there are 0 mismatched base pairs upon hybridization of the two sequences. However, where a first sequence is referred to as “substantially complementary ” with respect to a second sequence herein, the two sequences can be completely complementary', or they can form one or more, but generally not more than 5, 4, 3, 2, or 1 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RNA-induced silencing complex (RISC) pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, an siRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 19 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 19 nucleotidesDocket No.: SOUF-003 / 01WOthat is fully complementary to the shorter oligonucleotide, can yet be referred to as “completely complementary” for the purposes described herein.

[0013] “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non- Watson-Crick base pairs include, but are not limited to, G: U Wobble or Hoogsteen base pairing.

[0014] If an RNA strand contains one or more thymidines (“T”s) in the sequence, the thymidines (“T”s) represent uridines (“U”s). For example, the nucleotide “T”, as used in the unmodified siRNAs sense and antisense strands in Table 1A, for example, SEQ ID Nos: 1-15, 22-36, 43-128, 130-143, 152-315, 322-467, 471-475, 481-487, 489-511, 513, 516-524, 527-856, 868-975, 977- 1113, 1115-1133, 1135-1161, and 1163-1212, represents RNA uridine, and the corresponding RNA sense and antisense strands are listed in Table IF.

[0015] In some embodiments, the present disclosure provides an oligonucleotide or RNAi agent, as described herein, or a pharmaceutically acceptable salt thereof As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in, J. PHARMACEUTICAL SCIENCES, 1977, (66); 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the nucleic acids and analogues thereof of this disclosure include those derived from suitable inorganic and organic acids and bases. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. In some embodiments, a pharmaceutically acceptable salt is tire sodium salt. In some embodiments, a pharmaceutically acceptable salt is the potassium salt.

[0016] In some embodiments, the oligonucleotide comprises an antisense strand comprising at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous nucleotides) substantially complementary to a sequence of nucleotides within a transcript encoding DUX4. In some embodiments, the antisense strand has no more than 5 mismatched nucleotides to the sequence of nucleotides within the transcript encoding DUX4. In some embodiments, the antisense strand has no more than 4 mismatched nucleotides to tire sequence of nucleotides within the transcript encoding DUX4. In some embodiments, the antisense strand has no more than 3 mismatched nucleotides to the sequence of nucleotides within the transcript encoding DUX4. In some embodiments, the antisense strand has no more than 2 mismatched nucleotides to the sequence ofDocket No.: SOUF-003 / 01WOnucleotides within the transcript encoding DUX4. In some embodiments, the antisense strand has no more than 1 mismatched nucleotides to the sequence of nucleotides within the transcript encoding DUX4. In some embodiments, the antisense strand is completely complementary to the sequence of nucleotides within the transcript encoding DUX4 (e.g., 0 mismatches).

[0017] Tire DUX4 gene encodes a transcription factor that is normally involved in zygotic genome activation during the four-cell stage of early embryonic development. Afterward, DUX4 is epigenetically silenced in all adult tissues apart from the limited expression of unrelated DUX4 isoforms in the testis and thymus. Following transcription of the DUX4 gene, stochastic, low-level DUX4 protein expression occurs in the myofiber nuclei of the skeletal muscle. Inappropriate DUX4 protein expression in adult skeletal muscle is highly toxic and causes Facioscapulohumeral muscular dystrophy (FSHD). DUX4 is a transcription factor comprising a single protein. Exemplary sequences of DUX4 may be found for example at NCBI RefSeq ID NM_001306068.3 (SEQ ID NO: 2425). In some embodiments, DUX4 is encoded by a nucleotide sequence corresponding to the transcript having the NCBI RefSeq ID NM 001306068.3 (SEQ ID NO: 2425).

[0018] In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 75% nucleotide sequence identity to SEQ ID NO: 2425. In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 80% nucleotide sequence identity to SEQ ID NO: 2425. In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 85% nucleotide sequence identity to SEQ ID NO: 2425. In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 90% nucleotide sequence identity to SEQ ID NO: 2425. In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 95% nucleotide sequence identity to SEQ ID NO: 2425. In some embodiments, the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 99% nucleotide sequence identity to SEQ ID NO: 2425.

[0019] In some embodiments, the antisense strand is substantially complementary to a sequence of nucleotides corresponding to an untranslated region of the DUX4 transcript. In some embodiments, the antisense strand is substantially complementary to the sequence of nucleotides corresponding to an untranslated region of the DUX4 transcript with no more than 5, 4, 3, 2, 1, or 0 mismatches. In some embodiments, the antisense strand is completely complementary to the sequence of nucleotides corresponding to an untranslated region of the DUX4 transcript.Docket No.: SOUF-003 / 01WORNAi Agents

[0020] In some embodiments, the oligonucleotide is an RNAi agent or RNAi trigger for inhibiting expression of DUX4. As used herein, an ‘-RNAi agent” or “RNAi trigger” refers to an oligonucleotide molecule capable of inducing RNA interference (RNAi), which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. The RNAi agents disclosed herein include but are not limited to: short (or small) interfering RNAs (siRNAs), double stranded RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates (e.g., DsiRNAs).

[0021] In some embodiments, the RNAi agent is a double stranded RNA molecule comprising an antisense strand and a sense strand that are complementary to one another and hybridize to form a duplex or double stranded region. One strand of the RNAi agent, the antisense strand or guide strand, includes a region of complementarity to a target sequence in DUX4. The other strand, the sense strand or passenger strand, includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. In some embodiments, the double stranded RNA molecule may be formed by base pairing between two separate molecules of RNA (e.g, an antisense strand and a sense strand). In some embodiments, the double stranded RN A molecule is a self-complementary molecule formed by intramolecular base pairing between two separate regions of a single RNA molecule e.g., an antisense region linked to a sense strand through an unpaired RNA linker forming a loop or hairpin loop).

[0022] Where the two strands are part of a self-complementary molecule, the connecting RNA chain is referred to as a “hairpin loop,” A hairpin loop can comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop can comprise at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides or nucleotides not directed to the target site of the dsRNA. In some embodiments, the hairpin loop can be 10 or fewer nucleotides. In some embodiments, the hairpin loop can be 8 or fewer unpaired nucleotides. In some embodiments, the hairpin loop can be 4-10 unpaired nucleotides. In some embodiments, the hairpin loop can be 4-8 nucleotides. In some embodiments, the hairpin loop can contain 1-4 oligoethyne glycols, including ethylene glycol, di ethylene glycol, triethylene glycol, tetraethylene glycol, hexaethylene glycol, or any combination thereof.

[0023] Where the two substantially complementary strands of a double stranded RNA molecule comprise separate RNA molecules, those molecules need not, but can be covalently connected. In certain embodiments, where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3 ’-end of one strand and the 5 ’-end of the respective other strand forming the duplex structure, the connecting structure is referred to as aDocket No.: SOUF-003 / 01WO“linker” (though it is noted that certain other structures defined elsewhere herein can also be referred to as a “linker”). The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the double stranded RNA molecule minus any overhangs that are present in the duplex.

[0024] In some embodiments, the RNAi agent is an siRNA.

[0025] In some embodiments, the RNAi agent is a shRNA.

[0026] In some embodiments, the RNAi agent is a dicer substrate (e.g., a Dicer-substrate siRNA).

[0027] In some embodiments, the sense and antisense strands of the dsRNA are each independently about 15 to about 30 nucleotides in length, or about 25 to about 30 nucleotides in length, e.g., each strand is independently between 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15- 23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19- 21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length.

[0028] In some embodiments, the duplex structure is between 15 and 30 base pairs in length, e.g., between, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15- 17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21- 24, 21-23, or 21-22 base pairs in length.

[0029] An RNAi agent as described herein can further include one or more single-stranded nucleotide overhangs, e.g., an overhang of 1, 2, 3, or 4 nucleotides, RNAi agent having at least one nucleotide overhang can have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide, an inverted deoxynucleotide or an inverted abasic nucleotide. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5 '-end, 3'-end or both ends of either an antisense or sense strand of the RNAi agent. In certain embodiments, longer, extended overhangs are possible.

[0030] In some embodiments, the antisense strand is 21 nucleotides in length, and the sense strand is 19 nucleotides in length. In some embodiments, the antisense strand is 19 nucleotides in length, and the sense strand is 19 nucleotides in length.

[0031] The oligonucleotides disclosed herein may be unmodified or modified (e.g., chemically modified or conjugated). A modified oligonucleotide as disclosed herein comprises an identicalDocket No.: SOUF-003 / 01WOnucleobase sequence as compared to a corresponding unmodified oligonucleotide, but further comprises one or more modifications as disclosed herein.

[0032] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides from any one of the antisense strand sequences of Tables 1A-1F. In some embodiments, the antisense strand differs by no more than 3 nucleotides from any one ofthe antisense strand sequences of Tables 1A-1F. In some embodiments, the antisense strand differs by no more than 2 nucleotides from any one of the antisense strand sequences of Tables 1A-1F. In some embodiments, the antisense strand differs by no more than 1 nucleotide from any one ofthe antisense strand sequences of Tables 1A-1F. In some embodiments, the antisense strand comprises any one ofthe antisense strand sequences of Tables 1 A-1F. In some embodiments, the antisense strand consists of any one of the antisense strand sequences of Tables 1A-1F.

[0033] In some embodiments, the present disclosure provides oligonucleotides for inhibiting expression of DUX4, wherein the oligonucleotide comprises an antisense strand substantially complementary to a sequence encoding DUX4. In some embodiments, the oligonucleotide targets a sequence corresponding to positions selected from Table 4.

[0034] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand differs by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand differs by no more than 2 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand differs by no more than 1 nucleotide from the nucleotide sequence of any one of SEQ ID NOs: 607- 1212 or 1819-2424. In some embodiments, the antisense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the antisense strand differs by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the antisense strand differs by no more than 2 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the antisense strand differs by no more than 1 nucleotide from the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, theDocket No.: SOUF-003 / 01WOantisense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the antisense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 2437-2447.

[0035] In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 2437-2447.

[0036] In some embodiments, the antisense strand consists of a nucleotide sequence having the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand consists of a nucleotide sequence having the nucleotide sequence of any one of SEQ ID NOs: 2437-2447.

[0037] In some embodiments, the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides from any one of the sense strand sequences of Tables 1A-1F. In some embodiments, the sense strand differs by no more than 3 nucleotides from any one of the sense strand sequences of Tables 1A-1F. In some embodiments, the sense strand differs by no more than 2 nucleotides from any one of the sense strand sequences of Tables 1A-1F. In some embodiments, the sense strand differs by no more than 1 nucleotide from any one of the sense strand sequences of Tables IA-1F, In some embodiments, the sense strand comprises a sequence of any one of the sense strands of Tables 1A-1F. In some embodiments, the sense strand consists of a sequence of any one of the sense strands of Tables 1A-1F.

[0038] In some embodiments, the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand differs by no more than 3 nucleotidesDocket No.: SOUF-003 / 01WOfrom the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand differs by no more than 2 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand differs by no more than 1 nucleotide from the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, tire sense strand differs by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the sense strand differs by no more than 2 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the sense strand differs by no more than 1 nucleotide from the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the sense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the sense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 2426-2436.

[0039] In some embodiments, the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 2426-2436.

[0040] In some embodiments, the sense strand consists of a nucleotide sequence having the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand consists of a nucleotide sequence having the nucleotide sequence of any one of SEQ ID NOs: 2426-2436.Docket No.: SOUF-003 / 01WO

[0041] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2437-2447, and the sense strand comprises a nucleotide sequence at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 2426-2436.

[0042] In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity’) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424, and the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity’) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 2437-2447, and the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to a portion of the nucleotide sequence of any one of SEQ ID NOs: 2426-2436.

[0043] In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424, and the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 1-606 or 1213-1818, In some embodiments, the antisense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotideDocket No.: SOUF-003 / 01WOsequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 2437-2447, and the sense strand comprises a nucleotide sequence having at least 90% nucleotide sequence identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity) to the nucleotide sequence of any one of SEQ ID NOs: 2426-2436

[0044] In some embodiments, the antisense strand consists of a nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424, and the sense strand consists of a nucleotide sequence of any one of SEQ ID Nos: 1-606 or 1213-1818. In some embodiments, the antisense strand consists of a nucleotide sequence of any one of SEQ ID NOs: 2437-2447, and the sense strand consists of a nucleotide sequence of any one of SEQ ID Nos: 2426-2436.

[0045] In some embodiments, the oligonucleotide of the present disclosure targets a sequence of nucleotides corresponding to any one of positions 11-29, 13-31, 61-79, 67-85, 109-127, 115-133, 124-142, 125-143, 131-149, 133-151, 163-181, 164-182, 165-183, 187-205, 188-206, 203-221, 204-222, 277-295, 292-310, 299-317, 300-318, 301-319, 307-325, 315-333, 316-334, 339-357, 347-365, 348-366, 349-367, 404-422, 412-430, 420-438, 532-550, 533-551, 619-637, 620-638, 621-639, 708-726, 747-765, 748-766, 749-767, 779-797, 781-799, 852-870, 1036-1054, 1100- 1118, 1101-1119, 1107-1125, 1109-1127, 1115-1133, 1131-1149, 1132-1150, 1140-1158, 1141- 1159, 1147-1165, 1148-1166, 1149-1167, 1163-1181, 1171-1189, 1428-1446, 1619-1637, 1628- 1646, 1629-1647, 1635-1653, 1636-1654, 1637-1655, 1638-1656, 1639-1657, 1651-1669, 1652-1670, 1653-1671, 1654-1672, 1655-1673, 1656-1674, 27-45, 28-46, 251-269, 252-270, 317-335, 355-373, 363-381, 437-455, 452-470, 453-471, 547-565, 548-566, 549-567, 565-583, 579-597, 581-599, 588-606, 627-645, 652-670, 659-677, 668-686, 692-710, 715-733, 717-735, 732-750, 733-751, 813-831, 827-845, 843-861, 845-863, 877-895, 892-910, 893-911, 939-957, 956-974, 989-1007, 1028-1046, 1067-1085, 1083-1101, 1084-1102, 1085-1103, 1212-1230, 1213-1231, 1235-1253, 1251-1269, 1260-1278, 1261-1279, 1267-1285, 1268-1286, 1269-1287, 1274-1292, 1279-1297, 1284-1302, 1288-1306, 1389-1407, 1390-1408, 1421-1439, 1427-1445, 1612-1630, or 1613-1631 of SEQ ID NO: 2425 (NM_001306068.3).

[0046] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1C, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from a sense strand selected from Table 1C. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1C, and the sense strand comprises a nucleotide sequenceDocket No.: SOUF-003 / 01WOdiffering by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from a sense strand selected from Table 1C. In some embodiments, the antisense strand comprises an antisense strand selected from Table 1C, and the sense strand comprises a sense strand selected from Table 1C. In some embodiments, the antisense strand consists of an antisense strand selected from Table 1C, and the sense strand consists of a sense strand selected from Table 1C.

[0047] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1821, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1215. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1821, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1215. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1821, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1215. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1821, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1215.

[0048] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1823, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1217. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1823, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1217. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1823, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1217. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1823, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1217.

[0049] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1846, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguousDocket No.: SOUF-003 / 01WOnucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1240. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1846, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1240. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1846, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1240. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1846, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1240.

[0050] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1852, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1246. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1852, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1246. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1852, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1246. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1852, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1246.

[0051] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1870, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1264. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1870, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1264. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1870, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1264. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1870, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1264.Docket No.: SOUF-003 / 01WO

[0052] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1876, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1270. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1876, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1270. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1876, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1270. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1876, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1270.

[0053] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1878, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1272. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1878, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1272. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1878, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1272, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1878, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1272.

[0054] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1879, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1273. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1879, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1273. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1879, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1273. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1879, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1273.

[0055] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1884, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1278. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1884, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1278. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1884, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1278. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1884, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1278.

[0056] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1886, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1280. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1886, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1280. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1886, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1280. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1886, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1280.

[0057] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1903, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1297. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1903, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1297. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1903, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1297. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1903, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1297.

[0058] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1904, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1298. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1904, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1298, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1904, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1298. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1904, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1298.

[0059] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO:1905, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1299. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1905, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1299. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1905, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1299, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1905, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1299.Docket No.: SOUF-003 / 01WO

[0060] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1919, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1313. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1919, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1313. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1919, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1313. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1919, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1313.

[0061] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1920, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1314. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1920, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1314. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1920, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1314, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1920, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1314.

[0062] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1933, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1327. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1933, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1327. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1933, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1327. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1933, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1327.

[0063] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1934, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1328. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1934, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1328. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1934, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1328. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1934, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1328.

[0064] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1968, and tire sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1362. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1968, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1362. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1968, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1362. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1968, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1362.

[0065] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1975, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1369. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1975, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1369. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1975, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1369. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1975, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1369.

[0066] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1982, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1376. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1982, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1376, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1982, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1376. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1982, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1376.

[0067] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1983, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1377. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1983, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1377. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1983, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1377, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1983, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1377.Docket No.: SOUF-003 / 01WO

[0068] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1984, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1378. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1984, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1378. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1984, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1378. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1984, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1378.

[0069] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1990, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1384. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1990, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1384. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1990, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1384, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1990, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1384.

[0070] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1998, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1392. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1998, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1392. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1998, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1392. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1998, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1392.

[0071] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1999, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1393. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1999, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1393. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1999, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1393. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1999, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1393.

[0072] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2005, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1399. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2005, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1399. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2005, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1399. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2005, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1399.

[0073] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2013, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1407. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2013, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1407. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2013, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1407. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2013, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1407.

[0074] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2014, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1408. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2014, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1408, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2014, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1408. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2014, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1408.

[0075] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO:2015, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1409. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2015, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1409. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2015, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1409, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2015, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1409.Docket No.: SOUF-003 / 01WO

[0076] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2044, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1438. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2044, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1438. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2044, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1438. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2044, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1438.

[0077] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2049, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1443. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2049, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1443. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2049, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1443, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2049, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1443.

[0078] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2050, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1444. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2050, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1444. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2050, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1444. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2050, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1444.

[0079] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2082, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1476. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2082, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1476. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2082, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1476. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2082, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1476.

[0080] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2083, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1477. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2083, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1477. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2083, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1477. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2083, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1477.

[0081] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2090, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1484. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2090, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1484. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2090, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1484. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2090, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1484.

[0082] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2091, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1485. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2091, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1485, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2091, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1485. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2091, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1485.

[0083] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO:2092, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1486. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2092, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1486. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2092, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1486, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2092, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1486.Docket No.: SOUF-003 / 01WO

[0084] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2105, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1499. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2105, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1499. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2105, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1499. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2105, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1499.

[0085] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2113, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1507. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2113, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1507. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2113, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1507. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2113, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1507.

[0086] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2114, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1508. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2114, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1508. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2114, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1508. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2114, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1508.

[0087] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2115, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1509. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2115, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1509. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2115, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1509. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2115, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1509.

[0088] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2132, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1526. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2132, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1526. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2132, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1526. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2132, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1526.

[0089] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2134, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1528. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2134, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1528. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2134, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1528. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2134, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1528.

[0090] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2143, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1537. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2143, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1537, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2143, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1537. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2143, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1537.

[0091] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2167, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1561. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2167, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1561. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2167, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1561, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2167, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1561.Docket No.: SOUF-003 / 01WO

[0092] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO:2186, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1580. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2186, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1580. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2186, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1580. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2186, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1580.

[0093] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2187, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1581. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2187, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1581. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2187, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1581. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2187, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1581.

[0094] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2190, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1584. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2190, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1584. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2190, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1584. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2190, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1584.

[0095] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2192, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1586. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2192, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1586. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2192, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1586. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2192, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1586.

[0096] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2198, and tire sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1592. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2198, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1592. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2198, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1592. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2198, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1592.

[0097] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2204, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more thanDocket No.: SOUF-003 / 01WO4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1598. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2204, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1598. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2204, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1598. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2204, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1598.

[0098] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2205, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1599. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2205, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1599, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2205, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1599. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2205, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1599.

[0099] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2209, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1603. in some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2209, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1603. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2209, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1603, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2209, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1603.Docket No.: SOUF-003 / 01WO

[0100] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2210, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1604. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2210, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1604. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2210, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1604. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2210, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1604.

[0101] In some embodiments, tire antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2216, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1610. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2216, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1610. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2216, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1610, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2216, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1610.

[0102] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2217, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1611. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2217, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1611. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2217, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1611. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2217, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1611.

[0103] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2218, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1612. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2218, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1612. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2218, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1612. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2218, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1612.

[0104] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2232, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1626. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2232, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1626. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2232, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1626. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2232, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1626.

[0105] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2235, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1629. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2235, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1629. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2235, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1629. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2235, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1629.

[0106] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2236, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1630. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2236, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1630, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2236, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1630. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2236, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1630.

[0107] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2251, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1645. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2251, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1645. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2251, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1645, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2251, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1645.Docket No.: SOUF-003 / 01WO

[0108] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2260, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1654. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2260, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1654. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2260, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1654. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2260, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1654.

[0109] In some embodiments, tire antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2261, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1655. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2261, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1655. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2261, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1655, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2261, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1655.

[0110] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2267, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1661. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2267, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1661. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2267, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1661. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2267, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1661.

[0111] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2268, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1662. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2268, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1662. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2268, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1662. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2268, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1662.

[0112] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2269, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1663. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2269, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1663. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2269, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1663. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2269, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1663.

[0113] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2270, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1664. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2270, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1664. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2270, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1664. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2270, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1664.

[0114] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2271, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1665. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2271, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1665, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2271, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1665. In some embodiments, the antisense strand consists ofthe nucleotide sequence SEQ ID NO: 2271, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1665.

[0115] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2276, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1670. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2276, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1670. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2276, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1670, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2276, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1670.Docket No.: SOUF-003 / 01WO

[0116] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2277, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1671. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2277, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1671. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2277, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1671. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2277, and the sense strand consists ofthe nucleotide sequence SEQ ID NO: 1671.

[0117] In some embodiments, tire antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2278, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1672. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2278, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1672. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2278, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1672, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2278, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1672.

[0118] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2279, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1673. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2279, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1673. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2279, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1673. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2279, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1673.

[0119] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2280, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1674. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2280, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1674. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2280, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1674. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2280, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1674.

[0120] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2281, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1675. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2281, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1675. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2281, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1675. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2281, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1675.

[0121] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2283, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1677. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2283, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1677. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2283, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1677. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2283, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1677.

[0122] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2284, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1678. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2284, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1678, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2284, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1678. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2284, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1678.

[0123] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2292, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1686. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2292, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1686. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2292, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1686, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2292, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1686.Docket No.: SOUF-003 / 01WO

[0124] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2293, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1687. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2293, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1687. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2293, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1687. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2293, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1687.

[0125] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2299, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1693. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2299, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1693. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2299, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1693, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2299, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1693.

[0126] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2300, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1694. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2300, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1694. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2300, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1694. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2300, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1694.

[0127] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2305, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1699. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2305, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1699. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2305, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1699. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2305, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1699.

[0128] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2306, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1700. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2306, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1700. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2306, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1700. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2306, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1700.

[0129] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2307, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1701. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2307, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1701. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2307, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1701. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2307, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1701.

[0130] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2308, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1702. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2308, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1702, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2308, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1702. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2308, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1702.

[0131] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2317, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1711. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2317, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1711. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2317, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1711, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2317, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1711.Docket No.: SOUF-003 / 01WO

[0132] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2318, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1712. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2318, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1712. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2318, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1712. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2318, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1712.

[0133] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2319, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1713. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2319, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1713. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2319, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1713, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2319, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1713.

[0134] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2321, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1715. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2321, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1715. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2321, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1715. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2321, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1715.

[0135] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2324, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1718. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2324, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1718. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2324, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1718. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2324, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1718.

[0136] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2325, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1719. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2325, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1719. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2325, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1719. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2325, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1719.

[0137] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2326, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1720. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2326, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1720. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2326, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1720. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2326, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1720.

[0138] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2330, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1724. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2330, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1724, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2330, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1724. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2330, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1724.

[0139] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2331, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1725. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2331, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1725. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2331, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1725, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2331, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1725.Docket No.: SOUF-003 / 01WO

[0140] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2333, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1727. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2333, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1727. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2333, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1727. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2333, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1727.

[0141] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2334, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1728. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2334, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1728. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2334, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1728, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2334, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1728.

[0142] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2336, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1730. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2336, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1730. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2336, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1730. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2336, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1730.

[0143] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2338, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1732. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2338, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1732. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2338, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1732. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2338, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1732.

[0144] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2339, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1733. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2339, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1733. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2339, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1733. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2339, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1733.

[0145] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2340, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1734. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2340, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1734. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2340, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1734. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2340, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1734.

[0146] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2341, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1735. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2341, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1735, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2341, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1735. In some embodiments, the antisense strand consists ofthe nucleotide sequence SEQ ID NO: 2341, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1735.

[0147] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2345, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1739. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2345, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1739. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2345, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1739, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2345, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1739.Docket No.: SOUF-003 / 01WO

[0148] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2346, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1740. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2346, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1740. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2346, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1740. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2346, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1740.

[0149] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2349, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1743. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2349, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1743. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2349, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1743, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2349, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1743.

[0150] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2350, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1744. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2350, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1744. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2350, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1744. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2350, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1744.

[0151] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2353, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1747. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2353, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1747. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2353, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1747. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2353, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1747.

[0152] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2354, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1748. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2354, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1748. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2354, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1748. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2354, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1748.

[0153] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2355, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1749. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2355, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1749. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2355, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1749. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2355, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1749.

[0154] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2361, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1755. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2361, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1755, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2361, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1755. In some embodiments, the antisense strand consists ofthe nucleotide sequence SEQ ID NO: 2361, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1755.

[0155] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2362, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1756. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2362, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1756. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2362, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1756, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2362, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1756.Docket No.: SOUF-003 / 01WO

[0156] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2363, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1757. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2363, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1757. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2363, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1757. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2363, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1757.

[0157] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2367, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1761. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2367, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1761. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2367, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1761, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2367, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1761.

[0158] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2369, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1763. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2369, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1763. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2369, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1763. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2369, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1763.

[0159] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2371, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1765. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2371, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1765. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2371, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1765. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2371, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1765.

[0160] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2372, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1766. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2372, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1766. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2372, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1766. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2372, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1766.

[0161] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2373, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1767. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2373, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1767. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2373, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1767. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2373, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1767.

[0162] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2380, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1774. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2380, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1774, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2380, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1774. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2380, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1774.

[0163] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2381, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1775. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2381, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1775. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2381, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1775, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2381, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1775.Docket No.: SOUF-003 / 01WO

[0164] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2387, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1781. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2387, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1781. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2387, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1781. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2387, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1781.

[0165] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2389, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1783. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2389, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1783. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2389, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1783, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2389, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1783.

[0166] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2392, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1786. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2392, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1786. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2392, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1786. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2392, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1786.

[0167] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2393, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1787. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2393, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1787. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2393, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1787. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2393, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1787.

[0168] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2396, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1790. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2396, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1790. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2396, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1790. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2396, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1790.

[0169] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2397, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1791. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2397, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1791. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2397, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1791. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2397, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1791.

[0170] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2398, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1792. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2398, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1792, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2398, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1792. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2398, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1792.

[0171] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2402, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1796. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2402, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1796. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2402, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1796, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2402, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1796.Docket No.: SOUF-003 / 01WO

[0172] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2403, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1797. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2403, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1797. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2403, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1797. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2403, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1797.

[0173] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2404, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1798. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2404, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1798. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2404, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1798, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2404, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1798.

[0174] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2405, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1799. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2405, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, orDocket No.: SOUF-003 / 01WO4 nucleotides) from SEQ ID NO: 1799. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2405, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1799. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2405, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1799.

[0175] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2406, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1800. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2406, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1800. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2406, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1800. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2406, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1800.

[0176] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2407, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1801. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2407, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1801. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2407, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1801. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2407, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1801.

[0177] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2412, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by noDocket No.: SOUF-003 / 01WOmore than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1806. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2412, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1806. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2412, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1806. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2412, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1806.

[0178] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2416, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1810. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2416, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1810, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2416, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1810. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2416, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1810.

[0179] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2419, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1813. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2419, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1813. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2419, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1813, In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2419, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1813.Docket No.: SOUF-003 / 01WO

[0180] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2420, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1814. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2420, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1814. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2420, and the sense strand comprises the nucleotide sequence SEQ ID NO: 1814. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2420, and the sense strand consists of the nucleotide sequence SEQ ID NO: 1814.

[0181] In some embodiments, the oligonucleotide of the present disclosure targets a sequence of nucleotides corresponding to any one of positions 61-79, 404-422, 412-430, 420-438, 668-686, 1163-1181, 1619-1637, 1628-1646, 1629-1647, 1635-1653, 1636-1654, 1651-1669, 1652-1670, 1653-1671, 1654-1672, 1655-1673, 1656-1674, 1213-1231, and 1267-1285 of SEQ ID NO: 2425 (NM_001306068.3).

[0182] In some embodiments, the oligonucleotide of the present disclosure targets a sequence of nucleotides corresponding to any one of positions 668-686, 1628-1646, 1635-1653, 1652-1670, 1654-1672, 1655-1673, and 1656-1674 of SEQ ID NO: 2425 (NM_001306068.3).

[0183] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from the nucleotide sequence of any one of SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, 1184, 1846, 2044, 2049, 2232, 2251, 2260, 2261, 2267, 2268, 2276, 2277, 2278, 2279, 2280, 2281, 2381, 2396, 2050, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2334, 2444, 2445, 2446, and 2447, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from the nucleotide sequence of any one of SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, 578, 1240, 1438, 1443, 1626, 1645, 1654, 1655, 1661, 1662, 1670, 1671, 1672, 1673, 1674, 1675, 1775, 1790, 1444, 2426, 2427, 2428, 2429, 2430, 2431, 2432, 1728, 2433, 2434, 2435, and 2436. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (forDocket No.: SOUF-003 / 01WOexample, 1, 2, 3, or 4 nucleotides) from the nucleotide sequence of any one of SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, 1184, 1846, 2044, 2049, 2232, 2251, 2260, 2261, 2267, 2268, 2276, 2277, 2278, 2279, 2280, 2281, 2381, 2396, 2050, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2334, 2444, 2445, 2446, and 2447, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from the nucleotide sequence of any one of SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, 578, 1240, 1438, 1443, 1626, 1645, 1654, 1655, 1661, 1662, 1670, 1671, 1672, 1673, 1674, 1675, 1775, 1790, 1444, 2426, 2427, 2428, 2429, 2430, 2431, 2432, 1728, 2433, 2434, 2435, and 2436. In some embodiments, the antisense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, 1184, 1846, 2044, 2049, 2232, 2251, 2260, 2261, 2267, 2268, 2276, 2277, 2278, 2279, 2280, 2281, 2381, 2396, 2050, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2334, 2444, 2445, 2446, and 2447, and the sense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, 578, 1240, 1438, 1443, 1626, 1645, 1654, 1655, 1661, 1662, 1670, 1671, 1672, 1673, 1674, 1675, 1775, 1790, 1444, 2426, 2427, 2428, 2429, 2430, 2431, 2432, 1728, 2433, 2434, 2435, and 2436. In some embodiments, the antisense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, 1184, 1846, 2044, 2049, 2232, 2251, 2260, 2261, 2267, 2268, 2276, 2277, 2278, 2279, 2280, 2281, 2381, 2396, 2050, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2334, 2444, 2445, 2446, and 2447, and the sense strand consists of the nucleotide sequence of any one of SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, 578, 1240, 1438, 1443, 1626, 1645, 1654, 1655, 1661, 1662, 1670, 1671, 1672, 1673, 1674, 1675, 1775, 1790, 1444, 2426, 2427, 2428, 2429, 2430, 2431, 2432, 1728, 2433, 2434, 2435, and 2436.

[0184] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1D, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from a sense strand selected from Table 1D. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1D, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from aDocket No.: SOUF-003 / 01WOsense strand selected from Table 1D. In some embodiments, the antisense strand comprises an antisense strand selected from Table 1D, and the sense strand comprises a sense strand selected from Table 1D. In some embodiments, the antisense strand consists of an antisense strand selected from Table 1D, and the sense strand consists of a sense strand selected from Table 1D,

[0185] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1E, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from a sense strand selected from Table 1E. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from an antisense strand selected from Table 1E, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from a sense strand selected from Table 1E. In some embodiments, the antisense strand comprises an antisense strand selected from Table 1E, and the sense strand comprises a sense strand selected from Table 1E. In some embodiments, the antisense strand consists of an antisense strand selected from Table 1E, and the sense strand consists of a sense strand selected from Table 1E.

[0186] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, and 1184, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, and 578. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, and 1184, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, and 578. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, and 1184, and the sense strand comprises the nucleotide sequence SEQ ID NOs: 28, 226, 231, 232,Docket No.: SOUF-003 / 01WO414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, and 578. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, and 1184, and the sense strand consists of the nucleotide sequence SEQ ID NOs: 28, 226, 231, 232, 414, 433, 442, 443, 449, 450, 458, 459, 460, 461, 462, 463, 516, 563, and 578.

[0187] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 1, 2, 3, or 4 nucleotides from a sequence selected from SEQ ID NOs: 1048, 1055, 1065, 1067, 1068, 1069, and 1122. In some embodiments, the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 1, 2, 3, or 4 nucleotides from a nucleotide sequence selected from SEQ ID NOs: 442, 449, 459, 461, 462, 463, and 516.

[0188] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 1, 2, 3, or 4 nucleotides from a sequence selected from SEQ ID NOs: 3441, 3448, 3458, 3460, 3461, 3462, and 3514. In some embodiments, the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 1, 2, 3, or 4 nucleotides from a nucleotide sequence selected from SEQ ID NOs: 2861, 2868, 2878, 2880, 2881, 2882, and 2923.

[0189] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1048, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 442. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1048, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 442, In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1048, and the sense strand comprises the nucleotide sequence SEQ ID NO: 442. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1048, and the sense strand consists of the nucleotide sequence SEQ ID NO: 442.

[0190] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) fromDocket No.: SOUF-003 / 01WOSEQ ID NO: 1055, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 449. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1055, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 449. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1055, and the sense strand comprises the nucleotide sequence SEQ ID NO: 449. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1055, and the sense strand consists of the nucleotide sequence SEQ ID NO: 449.

[0191] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1065, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 459. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1065, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 459. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1065, and the sense strand comprises the nucleotide sequence SEQ ID NO: 459. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1065, and the sense strand consists of the nucleotide sequence SEQ ID NO: 459.

[0192] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1067, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 461. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1067, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 461. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1067, and the sense strand comprises the nucleotide sequenceDocket No.: SOUF-003 / 01WOSEQ ID NO: 461. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1067, and the sense strand consists of the nucleotide sequence SEQ ID NO: 461.

[0193] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1068, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 462. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1068, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 462. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1068, and the sense strand comprises the nucleotide sequence SEQ ID NO: 462. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1068, and the sense strand consists of the nucleotide sequence SEQ ID NO: 462.

[0194] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1069, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 463. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1069, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 463. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1069, and the sense strand comprises the nucleotide sequence SEQ ID NO: 463. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1069, and the sense strand consists of the nucleotide sequence SEQ ID NO: 463.

[0195] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1122, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 516. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4Docket No.: SOUF-003 / 01WOnucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 1122, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 516. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 1122, and the sense strand comprises the nucleotide sequence SEQ ID NO: 516. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 1122, and the sense strand consists of the nucleotide sequence SEQ ID NO: 516.

[0196] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2437, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2426. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2437, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2426. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2437, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2426. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2437, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2426.

[0197] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2438, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2427. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2438, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2427. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2438, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2427. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2438, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2427.Docket No.: SOUF-003 / 01WO

[0198] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2439, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2428. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2439, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2428. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2439, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2428. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2439, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2428.

[0199] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2440, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2429. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2440, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2429. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2440, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2429. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2440, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2429.

[0200] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2441, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2430. In some embodiments, the antisense strand comprises aDocket No.: SOUF-003 / 01WOnucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2441, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2430. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2441, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2430. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2441, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2430.

[0201] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2442, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2431. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2442, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2431. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2442, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2431. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2442, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2431.

[0202] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2443, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2432. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2443, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2432. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2443, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2432. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2443, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2432.Docket No.: SOUF-003 / 01WO

[0203] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2444, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2433. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2444, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2433. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2444, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2433. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2444, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2433.

[0204] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2445, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2434. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2445, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2434. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2445, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2434. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2445, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2434.

[0205] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2446, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2435. In some embodiments, the antisense strand comprises a nucleotide sequenceDocket No.: SOUF-003 / 01WOdiffering by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2446, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2435. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2446, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2435. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2446, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2435.

[0206] In some embodiments, the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2447, and the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, or 19 contiguous nucleotides) differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2436. In some embodiments, the antisense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2447, and the sense strand comprises a nucleotide sequence differing by no more than 4 nucleotides (for example, 1, 2, 3, or 4 nucleotides) from SEQ ID NO: 2436. In some embodiments, the antisense strand comprises the nucleotide sequence SEQ ID NO: 2447, and the sense strand comprises the nucleotide sequence SEQ ID NO: 2436. In some embodiments, the antisense strand consists of the nucleotide sequence SEQ ID NO: 2447, and the sense strand consists of the nucleotide sequence SEQ ID NO: 2436.

[0207] A DUX4 RNAi agent described herein can contain one or more mismatches to the target sequence. In some embodiments, a DUX4 RNAi agent as described herein contains no more than 4 mismatches (e.g., no more than 4, 3, 2, 1, or 0 mismatches to the target sequence). If the antisense strand of the RNAi agent contains mismatches to a target sequence, it may be preferable that the area of mismatch is not located in the center of the region of complementarity. If the antisense strand of the RNAi agent contains mismatches to the target sequence, it may be preferable that the mismatch be restricted to be within the last 5 nucleotides from either the 5' - or 3 ’-end of the region of complementarity. For example, for a 21 nucleotide RNAi agent, the strand which is complementary to a region of, e.g., DUX4, generally does not contain any mismatch within the central 11 nucleotides. The methods described herein or methods known in the art can be used to determine whether an RNAi agent containing a mismatch to a target sequence is effective in inhibiting the expression ofDUX4. Consideration of the efficacy of RNAi agents with mismatches in inhibiting expression of a target gene is important, especially if the particular regionDocket No.: SOUF-003 / 01WOof complementarity in a target gene is known to have polymorphic sequence variation within the population.

[0208] In some embodiments, any one of the RNAi agents described herein can reduce expression levels of DUX4. In some embodiments, reduction in expression levels is assayed using a DUX4 reporter construct, e.g., see Examples 1 and 2. In some embodiments, DUX4 RNA expression is measured using a reporter or tag (e.g., luciferase, or fluorescent tag). The skilled artisan will appreciate that various approaches to generating a reporter construct for assessing RNAi agent activity may be used in the art, including commercially available kits, e.g., the psiCHECK-2 vector (Promega). In some embodiments, any one of the RNAi agents described herein can reduce expression levels of a DUX4 reporter when assayed in cultured cells. Any suitable cells known in the art may be used to assess the RNAi agents. In some embodiments, the cultured cells are Hepal-6. In some embodiments, administration of any one of the RNAi agents disclosed herein to a cultured cell results in a reduction in expression level of a DUX4. In some embodiments, administration of the RNAi agent results in at least a 55% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 60% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 65% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 70% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 75% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of tire RNAi agent results in at least an 80% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 85% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 90% reduction in expression levels of the DUX4 reporter. In some embodiments, administration of the RNAi agent results in at least a 95% reduction in expression levels of the DUX4 reporter.

[0209] In some embodiments, reduction in expression levels is assayed using an RT-qPCR assay, e.g., see Example 3, to perform relative quantification of mRNA expression of a DUX4 panel, e.g., a panel of DUX4’s targets, in cardiomyocytes (e.g., FSHD MB200 cells, which is human myoblast cell line used to study facioscapulohumeral muscular dystrophy (FSHD)). In some embodiments, reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4 targets, e.g., a DUX4 panel comprising one or more gene of CCNA1, SLC34A2, ZSCAN4, PRAMEF2, PRAMEF17, PRAMEFI2, LEUTX, HNRNPCL1, RFPL4B, PRAMEF1, PRAMEF19, TRIM43B, TRIM43, PRAMEF14, PRAMEF11, KDM4E, RFPL2, PRAMEF15, PRAMEF6, ZNF280A, PRAMEF9, TRIM49, KHDC1P1, PRAMEF4,Docket No.: SOUF-003 / 01WOTPRX1, TRIM49B, TRIM51CP, KLF17, TRIM51BP, TRIM53CP, C1DP2, TRIM53AP, TRIM51, PRAMEF8, MBD3L2B, KHDC1L, ALPG, TRIM49C, MBD3L2, ZNF705G, MBD3L3, PRAMEF7, TRIM43CP, PRAMEF10, HNRNPCL4, TRIM53BP, TRIM51EP, or MBD3L5. In some embodiments, the reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4 targets, e.g., a DUX4 panel comprising one or more of LEUTX, TRIM43, KHDC1L, MBD3L2, CCNA1, ZSCAN4, SLC34A2, or PRAMEF6. In some embodiments, the reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4 targets, e.g., a DUX4 panel comprising one or more of KHDC1L, LEUTX, MBD3L2, and ZSCAN4. The skilled artisan will appreciate that various approaches to quantify knockdown of DUX4 expression (e.g., via quantify’ of expression of the DUX4 panel) for assessing RNAi agent activity may be used in the art, including commercially available kits, e.g., from Thermo. In some embodiments, any one of the RNAi agents described herein can reduce mRNA expression level of the DUX4 panel when assayed in cultured cells. Any suitable cells known in the art may be used to assess the RNAi agents. In some embodiments, the cultured cells are FSHD MB200 cells. In some embodiments, administration of any one of the RNAi agents disclosed herein to a cultured cell results in a reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 30% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 35% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 40% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 45% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 50% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 55% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 60% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 65% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 70% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 75% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least an 80% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least an 85% reduction in mRNA expression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 90% reduction in mRNADocket No.: SOUF-003 / 01WOexpression level of the DUX4 panel. In some embodiments, administration of the RNAi agent results in at least a 95% reduction in mRNA expression level of the DUX4 panel.Single-stranded antisense oligonucleotides

[0210] In some embodiments, the oligonucleotide is a single -stranded antisense oligonucleotide, or “ASO.” ASOs comprise an antisense strand with at least partial complementary to a target sequence in an RNA. Upon binding to a target sequence, downregulation of the RNA may be achieved through various mechanisms, including, but not limited to, sterically blocking translation or recruitment of RNase H.

[0211] In some embodiments, the ASO comprises a nucleic acid sequence of at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) that differ by no more than 1, 2, 3, or 4 nucleotides from any one of SEQ ID NOs: 607-1212 or 1819- 2424. In some embodiments, the ASO comprises a nucleotide sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the ASO comprises a nucleic acid sequence of at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) that differ by no more than 1, 2, 3, or 4 nucleotides from any one of SEQ ID NOs: 2437-2447. In some embodiments, the ASO comprises a nucleotide sequence of any one of SEQ ID NOs: 2437-2447.

[0212] In some embodiments, the single-stranded ASO comprises a nucleic acid sequence comprising at least 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by no more than 1, 2, 3, or 4 nucleotides from any one of SEQ ID NOs: 634, 832, 837, 838, 1020, 1039, 1048, 1049, 1055, 1056, 1064, 1065, 1066, 1067, 1068, 1069, 1122, 1169, 1184, 1846, 2044, 2049, 2232, 2251, 2260, 2261, 2267, 2268, 2276, 2277, 2278, 2279, 2280, 2281, 2381, 2396, 2050, 2437, 2438, 2439, 2440, 2441, 2442, 2443, 2334, 2444, 2445, 2446, and 2447.

[0213] In some embodiments, the ASO comprises 2'-deoxy ribonucleotides and phosphorothioate internucleoside linkages.

[0214] In some embodiments, the ASO is a “gapmer” ASO comprising a 2'-deoxy "gap" region flanked by "wings" having nucleotides with 2'-modified ribonucleotides. In some embodiments, the ASO is an " MOE gapmer" in which the 2'-modified ribonucleotide is a 2'-O-methoxyethyl (2'-M0E or simply MOE) modification, and each of the intemucleoside linkages is a phosphorothioate.Modified Nucleotides

[0215] The oligonucleotides disclosed herein may be modified or unmodified. In some embodiments, any one of the oligonucleotides contain one or more modifications. As used herein,Docket No.: SOUF-003 / 01WOa modification to a nucleotide or “modified nucleotide” refers to any nucleotide other than the canonical ribonucleotides adenine, guanine, cytosine, and uracil.

[0216] In some embodiments, the oligonucleotide comprises one or more modified nucleotides. In some embodiments, no more than 1, 2, 3, 4, or 5 of the nucleotides of the oligonucleotide are unmodified nucleotides. In some embodiments, all nucleotides of the oligonucleotide are modified nucleotides.

[0217] In some embodiments, wherein the oligonucleotide is an RNAi agent, the antisense strand comprises one or more modified nucleotides. In some embodiments, no more than 1, 2, 3, 4, or 5 of the nucleotides of the antisense strand are unmodified nucleotides. In some embodiments, all nucleotides of the antisense strand are modified nucleotides.

[0218] In some embodiments, wherein the oligonucleotide is an RNAi agent, the sense strand comprises one or more modified nucleotides. In some embodiments, no more than 1, 2, 3, 4, or 5 of the nucleotides of the sense strand are unmodified nucleotides. In some embodiments, all nucleotides of the sense strand are modified nucleotides.

[0219] Modified nucleotides include, but are not limited to 2'-modified nucleotides, 3' to 3' linkages (inverted) nucleotides, bridged nucleotides, 2',3'-seco nucleotide mimics (e.g., unlocked nucleobase analogues (UNAs), locked nucleotides (LNAs), 5'-(S)-metliyl-2’-deoxy-2’-fluoronucleotide (5’Me-Nf), vinyl phosphonate deoxyribonucleotides, vinyl phosphonate nucleotides, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic and N-(methane sulfonyl) phosphoramidate group. In some embodiments, 2'-modified nucleotides (e.g., a nucleotide with agroup other than a hydroxyl group at the 2' position ofthe five-membered sugar ring) include, but are not limited to, 2'-O-methyl nucleotides (represented herein as a lower case letter n in a nucleotide sequence), 2'-deoxy-2'-fluoro nucleotides (represented herein as Nf, also represented herein as 2'-fluoro nucleotide). In some embodiments, a modified nucleotide is a nucleotide comprising a 5'-methylphosphate group. In some embodiments, a modified nucleotide is a nucleotide comprising a 5'-C-methylphosphate group.

[0220] In some embodiments, modified nucleotides include, but are not limited to, deoxyribonucleotides, nucleotide mimics, abasic nucleotides, 5' to 5' linkages (inverted) nucleotides, non-natural base-comprising nucleotides, peptide nucleic acids (PNAs), 3'-O-methoxy (2' intemucleoside linked) nucleotides, 2’-deoxy-2’-fluoro-arabino nucleotides, cyclopropyl phosphonate nucleotides (cPipN), vinyl phosphonate 2 ’-(methoxyethyl) unlocked nucleotides, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, 2'-deoxy nucleotides (represented herein as dN), 2'-methoxy ethyloxy (2'-O-(2-methoxylethyl)) nucleotides, 2'-amino nucleotides, and 2'-alkyl nucleotides. It is not necessary for all positions in a givenDocket No.: SOUF-003 / 01WOcompound to be uniformly modified. Conversely, more than one modification may be incorporated in a single oligonucleotide. Modification at one nucleotide is independent of modification at another nucleotide.

[0221] In some embodiments, the nucleotide modification comprises a deoxyribonucleotide, a 3 ’-terminal deoxythymidine (dT) nucleotide, an abasic nucleotide, a 2'- modified nucleotide, a 3' to 3' linkages (inverted) nucleotide, a 5' to 5' linkages (inverted) nucleotide, a non-natural base-comprising nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5’ phosphate or 5’ phosphate mimic, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, or a nucleotide comprising a A-(methane sulfonyl) phosphoramidate group. In some embodiments, the nucleotide modification comprises a nucleotide comprising a 5'-methylphosphate group. In some embodiments, a modified nucleotide is a nucleotide comprising a 5'-C-methylphosphate group. In some embodiments, the oligonucleotide comprises a modified nucleotide selected from the group consisting of a deoxy nucleotide, a 3 ’-terminal deoxythymidine (dT) nucleotide, a 3'-3' inverted nucleotide linkage, a 5’-5’ inverted nucleotide linkage, a 5'-(E)-vinylphosphonate-2’-O-methyl-uridine-3’-phosphate, a 5'- (E)-vinylphosphonate-2'-O-methyl-uridine-3’-phosphorothioate, and a combination thereof.

[0222] In some embodiments, the one or more modifications is selected from a ribose modification, a backbone modification, a nucleobase modification, or a combination thereof. In some embodiments, the one or more modifications is a combination of a ribose modification, a backbone modification, and / or a nucleobase modification.

[0223] In some embodiments, the ribose modification comprises a locked nucleic acid (LNA), a tricyclo-DNA (tcDNA), 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-methoxyethyl (2'-M0E), 2'- deoxy-2'-arabino-fluoro, 2'-O-benzyl, 2'-O-methyl-4-pyridine, 2' cyclic ethyl (cET), phosphorodiamidate morpholino (PMO), glycol nucleic acid (GNA), unlocked nucleic acid (ETNA), a threose nucleic acid (TNA), or a combination thereof. In some embodiments, the ribose modification comprises a 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-methoxyethyl (2'-M0E), glycol nucleic acid (GNA), unlocked nucleic acid (UNA), a threose nucleic acid (TNA), or a combination thereof. In some embodiments, the ribose modification comprises a 2'-deoxy-2' -fluoro, 2'-O-methyl, glycol nucleic acid (GNA), unlocked nucleic acid (UNA), a threose nucleic acid (TNA), or a combination thereof, in some embodiments, the ribose modification is 2'-deoxy-2'-fluoro modification, a 2'-O-methyl modification, or a combination thereof.

[0224] In some embodiments, the oligonucleotide comprises one or more nucleobase modifications. Nucleobase modifications include, for example, synthetic and natural nucleobases, such as 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines,Docket No.: SOUF-003 / 01WO(e.g., 2 -aminopropyladenine, 5-propynyluracil, or 5-propynylcytosine), 5-methylcytosine (5-me- C), 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2 -aminoadenine, 6-alkyl (e.g., 6-methyl, 6-ethyl, 6-isopropyl, or 6-n-butyl) derivatives of adenine and guanine, 2 -alkyl (e.g., 2 -methyl, 2- ethyl, 2-isopropyl, or 2-n-butyl) and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine, 2-thiocytosine, 5-halouracil, cytosine, 5-propynyI uracil, 5-propynyl cytosine, 6- azo uracil, 6-azo cytosine, 6-azo thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo e.g., 5-bromo), 5 -trifluoromethyl, and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine, 7 -deazaadenine, 3-deazaguanine, and 3-deazaadenine, or combinations thereof.

[0225] In some embodiments, the oligonucleotide comprises one or more backbone modification or non-standard linkages (e.g., modified intemucleoside linkages). In some embodiments, a backbone modification is a non-phosphate-containing covalent internucleoside linkage. Modified intemucleoside linkages or backbones include, but are not limited to, 5’-phosphorothioate groups (represented herein as a lower case “s”), chiral phosphorothioates, thiophosphates, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, alkyl phosphonates (e.g., methyl phosphonates or 3'-alkylene phosphonates), chiral phosphonates, phosphinates, phosphoramidates (e.g., 3'-amino phosphoramidate, aminoalkylphosphoramidates, or thionophosphoramidates), thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, boranophosphates having normal 3 '-5' linkages, 2'-5' linked analogs of boranophosphates, or boranophosphates having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. In some embodiments, a modified backbone or modified intemucleoside linkage lacks a phosphorus atom. Modified intemucleoside linkages lacking a phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl intersugar linkages, mixed heteroatom and alkyl or cycloalkyl inter-sugar linkages, or one or more short chain heteroatomic or heterocyclic inter-sugar linkages. In some embodiments, modified intemucleoside backbones include, but are not limited to, siloxane backbones, sulfide backbones, sulfoxide backbones, sulfone backbones, formacetyl and thioformacetyl backbones, methylene formacetyl and thioform acetyl backbones, alkene-containing backbones, sulfamate backbones, methyleneimino and methylenehydrazino backbones, sulfonate and sulfonamide backbones, amide backbones, and other backbones having mixed N, O, S, and CH?, components.

[0226] In some embodiments, the backbone modification comprises phosphorothioate.

[0227] In some embodiments, any one of the oligonucleotides disclosed herein further comprise a sequence of 3 ’-terminal deoxythymidine (dT) nucleotides. In some embodiments, any one of the antisense strands described herein further comprises at least one terminal dT nucleotide.Docket No.: SOUF-003 / 01WOIn some embodiments, any one of the antisense strands described herein further comprises 2 or more terminal dT nucleotides, e.g., 2, 3, 4, or more terminal dT nucleotides. In some embodiments, wherein the oligonucleotide is an RNAi agent, any one of the sense strands described herein further comprises at least one terminal dT nucleotide. In some embodiments, any one of the sense strands described herein further comprises 2 or more terminal dT nucleotides, e.g., 2, 3, 4, or more terminal dT nucleotides. In some embodiments, the antisense and sense strand of an RNAi agent herein each contain one or more terminal dT nucleotides.

[0228] In some embodiments, any one of the oligonucleotides disclosed herein further comprises at least one phosphorothioate intemucleoside or phosphorodithioate internucleoside linkage. In some embodiments, any one of the oligonucleotides disclosed herein further comprises at least one phosphorothioate internucleoside linkage. In some embodiments, at least one phosphorothioate intemucleoside linkage is at the 5’ end of the antisense strand. In some embodiments, the oligonucleotide comprises at least 2 phosphorothioate intemucleoside linkages at the 5’ end of the antisense strand. In some embodiments, at least one phosphorothioate intemucleoside linkage is at the 3’ end of the antisense strand. In some embodiments, the oligonucleotide comprises at least 2 phosphorothioate intemucleoside linkages at the 3’ end of the antisense strand. In some embodiments, wherein the oligonucleotide is an RN Ai agent, the at least one phosphorothioate intemucleoside linkage is at the 5’ end of the sense strand. In some embodiments, the oligonucleotide comprises at least 2 phosphorothioate intemucleoside linkages at the 5’ end of the sense strand. In some embodiments, the at least one phosphorothioate intemucleoside linkage is at the 3’ end of the sense strand. In some embodiments, the oligonucleotide comprises at least 2 phosphorothioate intemucleoside linkages at the 3 ’ end of the sense strand.

[0229] In some embodiments, any one of the oligonucleotides disclosed herein further comprises a terminal, chiral modification. In some embodiments, the terminal chiral modification is at the first intemucleoside linkage at the 3’ end of the sense and / or antisense strand. In some embodiments, the terminal chiral modification is at tlie first and second intemucleoside linkage at the 3’ end of the sense and / or antisense strand. In some embodiments, the chiral modification comprises a phosphorus atom of the intemucleoside linkage being in either Rp or Sp configuration. In some embodiments, the siRNA agent further comprises a terminal, chiral modification occurring at the first intemucleoside linkage at the 3 ’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at tire first intemucleoside linkage at the 5’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5’ end of the sense strand, having the linkage phosphorus atom in either RpDocket No.: SOUF-003 / 01WOconfiguration or Sp configuration. In some embodiments, the siRNA agent further comprises a terminal, chiral modification occurring at the first and second intemucleoside linkages at the 3’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’ end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration. In some embodiments, the siRNA agent further comprises a terminal, chiral modification occurring at the first, second, and third intemucleoside linkages at the 3’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’ end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration. In some embodiments, the siRN A agent further comprises a terminal, chiral modification occurring at the first and second intemucleoside linkages at the 3’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the third intemucleoside linkages at the 3 ’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’ end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration. In some embodiments, the siRNA agent further comprises a terminal, chiral modification occurring at the first and second intemucleoside linkages at the 3’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first and second intemucleoside linkages at the 5 ’ end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’ end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

[0230] In some embodiments, any one of the oligonucleotides disclosed herein further comprises a phosphate or phosphate mimic at the 5 ’-end of the antisense strand. In some embodiments, a phosphate or phosphate mimic at the 5 ’-end of the antisense strand is a 5 ’-vinyl phosphonate (VP). In some embodiments, a phosphate or phosphate mimic at the 5 ’-end of the antisense strand is a 5’-(E)-vinyl phosphonate (VP).Docket No.: SOUF-003 / 01WORNAi Agent Modification Motifs

[0231] In some embodiments, any one of the antisense or sense strands disclosed herein are modified according to a modification motif or pattern.

[0232] In some embodiments, an antisense strand disclosed herein comprises a modification pattern nsNfsnnnNfnNfNfhnnnNfhNfnnnsnsn, wherein ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3’ -phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

[0233] In some embodiments, an antisense strand disclosed herein comprises a modification pattern vpUsNfsnmiNfiiNfNfimnnNfiiNfimnsnsn, wherein vpUs is a 5'-vinylphosphonate-2'-O-methyl-uridine-3‘-phosphorothioate; ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

[0234] In some embodiments, a sense strand disclosed herein comprises a modification pattern nsnsnnNfnNfNfNfnnnnnnnnnn, wherein ns is a 2'-O-methyl-nucleoside-3'- phosphorothioate; n is a 2'-O-methyl-nucieoside-3’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3 '-phosphate.

[0235] In some embodiments, a sense strand disclosed herein comprises a modification pattern NfsnsNfnNfhNfhNfhNfhNfhNfnNfnNf, wherein ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucIeoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

[0236] In some embodiments, an RNAi agent disclosed herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern nsnsnnNfnNfNfNfnnnnnnnnnn, and the antisense strand comprises a modification pattern nsNfsnnnNfnNfNfnnnnNfhNfnnnsnsn, wherein ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.[00237| In some embodiments, an RNAi agent disclosed herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern nsnsnnNfiiNfNfNfiinnnnnnnnn, and the antisense strand comprises a modification patern vpUsNfsnnnNfhNfNfnnnnNfhNfnnnsnsn, wherein vpUs is a 5'-vinylphosphonate-2'-O-methyl- uridine-3’-phosphorothioate; ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

[0238] In some embodiments, a strand of an RNAi agent comprises a modification pattern according to Nfsa(nNf)bnscn, wherein n is a 2'-O-methyl-nucleoside-3’-phosphate; Nfs is a 2'-Docket No.: SOUF-003 / 01WOdeoxy-2'-fluoro-nucleoside-3'-phosphorothioate; Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'- phosphate; and ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; and wherein a is at least 1. b is 5-10, and c is at least 1. In some embodiments, a is at least 2, b is at least 8, and c is at least 2. In some embodiments, a is 2, b is 8, and c is 2, In some embodiments, the strand of the RNAi agent comprises the modification pattern NfsNfsnNfhNfnNfhNfhNfnNfhNfhNfnsnsn. In some embodiments, the strand is the antisense strand. In some embodiments, the antisense strand comprises the sequence of any one of SEQ ID Nos: 607-1212 or 1819-2424. In some embodiments, the antisense strand comprises the sequence of any one of SEQ ID NOs: 2437-2447. In some embodiments, the strand is the sense strand. In some embodiments, the sense strand comprises tire sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises the sequence of any one of SEQ ID NOs: 2426-2436.

[0239] In some embodimen ts, a strand of an RNAi agent comprises a modification pattern according nsd(Nfn)eNf, wherein n is a 2'-O-methyl-nucleoside-3 ’ -phosphate; Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate; and ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; and wherein d is at least 1, and e is 5-10, In some embodiments, d is at least 2 and e is at least 8. In some embodiments, the RNAi agent comprises the modification pattern nsnsNfhNfhNfiiNfhNfiiNfnNfnNfnNf. In some embodiments, the strand is the sense strand. In some embodiments, the sense strand comprises the sequence of any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the sense strand comprises the sequence of any one of SEQ ID NOs: 2426-2436. In some embodiments, the RNAi agent comprises the modification pattern nsnsNfiiNfnNfnNfiiNfnNfhNfhNfnNfhsn. In some embodiments, the strand is the antisense strand. In some embodiments, the antisense strand comprises the sequence of any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the antisense strand comprises tire sequence of any one of SEQ ID NOs: 2437-2447.

[0240] In some embodiments, the antisense strand comprises a modification pattern according to Nfsa(nNf)bnscn, wherein n is a 2'-O-methyl-nucleoside-3’-phosphate; Nfs is a 2'- deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'- phosphate; and ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; and wherein a is at least 1, b is 5-10, and c is at least 1, and the sense strand comprises a modification pattern according to nsd(Nfn)eNf, wherein n is a 2'-O-methyl-nucleoside-3 ’-phosphate; Nf is a 2'-deoxy-2'-fluoro- nucleoside-3'-phosphate; and ns is a 2'-O-methyl-nucleoside-3'-phosphorothioate; and wherein d is at least 1, and e is 5-10. In some embodiments, the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOs: 607-1212 or 1819-2424. In some embodiments, the sense strand comprises a nucleotide sequence according to any one of SEQ ID NOs: 1-606 or 1213-1818. In some embodiments, the antisense strand comprises a nucleotide sequence accordingDocket No.: SOUF-003 / 01WOto any one of SEQ ID NOs: 2437-2447. In some embodiments, the sense strand comprises a nucleotide sequence according to any one of SEQ ID NOs: 2426-2436.

[0241] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand comprises the motif F(SF)nSnn, wherein n is from 2 to about 20, nn is 0 or 1, one of F and S is a 2'-deoxy-2’-fluoro modified nucleoside and the other of F and S is a 2'-O-methyl modified nucleoside. In some embodiments, each of the antisense and the sense strand is 17-23 nucleotides in length. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand sequence in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand sequence in Table IF.

[0242] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand comprises the chemical modification pattern of nNfnnnNfnNfNfhnnnNfnNfhnnnn and the sense strand comprises the chemical modification nnnnnnNfhNfNfNfiinnnnnnn, wherein n is a 2’-O-methyI-nucleoside and Nf is a 2’-deoxy-2’- fluoro-nucleoside. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212, In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence of any one according to SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.

[0243] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand comprises a region having the formula Xl-Y-X2, wherein Y is a subregion of from about 5 to about 12 linked nucleosides and each of XI subregion and X2 subregion is, independently, a plurality of linked nucleosides having the formula FSFS, where one of F and S is a 2'-deoxy-2’ -fluoro modified nucleoside and the other of F and S is a 2'-O-methyl modified nucleoside; and each internucleoside linkage of said XI subregion and X2 subregion is, independently, a phosphodiester or a phosphorothioate internucleoside linkage. In some embodiments, each of the antisense and the sense strand is 20-23 nucleotides in length. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in TableDocket No.: SOUF-003 / 01WOIF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.

[0244] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand comprises a contiguous sequence of linked nucleosides that define an alternating motif of the formula: 5'-Q(-L-Z-L-Q)n(-L-Z)nn-3', wherein: each L is an internucleoside linking group; either each Q is a 2'-deoxy-2’-fluoro nucleoside and each Z is a 2'-O-methyl nucleoside; or each Q is a 2'-O-methyl nucleoside and each Z is a 2'-deoxy-2’ -fluoro nucleoside; and n is from 8 to 14 and nn is 0 or 1. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-12.12.

[0245] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand is represented by the formula:wherein, Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-O-alkyl, 2'-substituted alkoxy, 2'-substituted alkyl, 2'-halo, EMA, and BNA / LNA; IT, T2', and T3' each independently represent a nucleotide comprising a chemical modification selected from the group consisting of DNA, RNA, LNA, 2’-deoxy-2’ -fluoronucleotide, and 5'-(S)-methyl2’-deoxy-2’-fluoronucIeotide; ql is 4 to 15 nucleotides in length; q3 or q7 is independently 1-6 nucleotide(s) in length; q2 or q6 is independently 1-3 nucleotide(s) in length; q4 is 0-3 nucleotide(s) in length; and q5 is 0-10 nucleotide(s) in length; and wherein: the antisense strand has 2 ’-deoxy-2 ’-fluoro modifications, and wherein the 2 ’-deoxy-2 ’-fluoro modifications on the antisense strand consist of four, and only four, 2 ’-deoxy-2 ’-fluoro modifications or six, and only six, 2 ’-deoxy-2 ’-fluoro modifications. In some embodiments, the antisense strand is 19-25 nucleotides in length. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.

[0246] In some embodiments, any one of the RN Ai agents disclosed herein comprises a modification pattern wherein the antisense strand and the sense strand are represented by the formula:Docket No.: SOUF-003 / 01WOwherein Bl, Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-0-alkyl, 2'-substituted alkoxy, 2 '-substituted alkyl, 2'-halo, ENA, and BNA / LNA; Cl is a thermally destabilizing nucleotide, selected from the group consisting of i) a nucleotide that forms a mismatch pair with the opposing nucleotide in the antisense strand, ii) a nucleotide having an abasic modification, and iii) a nucleotide having a sugar modification, and placed at a site opposite to the seed region (positions 2-8) of the antisense strand; T1', T2', and T3' each independently represent a nucleotide comprising a modification providing the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2'-0Me modification, wherein the modification is at the 2'-position of a ribose sugar of the nucleotide or at a position of anon-ribose nucleotide similar to the 2'-position of a ribose sugar; each n1, and q1 is independently 4 to 15 nucleotides in length; each q3, and q7 is independently 1-6 nucleotide(s) in length; each q2 and q6 is independently 1-3 nucleotide(s) in length; q5 is 0-10 nucleotide(s) in length; each n4, and q4 is independently 0-3 nucleotide(s) in length; n2 is 3 nucleotides in length, and T1 each are 2’-deoxy-2’-fluoronucleotides; n3 is 7 nucleotides in length, and B2 each are 2'-0Me nucleotides; and n5 is 3 nucleotides in length, and B3 each are 2'-0Me nucleotides. In some embodiments, wherein the antisense strand and sense strand are each 14 to 40 nucleotides. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.|00247| In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand is represented by the formula:Docket No.: SOUF-003 / 01WO(Is)wherein: Bl, B2, and B3 each independently represent a nucleotide containing a modification selected from the group consisting of 2'-O-alkyl, 2 '-substituted alkoxy, 2'-substituted alkyl, 2'-halo, ENA, and BNA / LNA; Cl is a thermally destabilizing nucleotide, selected from the group consisting of i) a nucleotide that forms a mismatch pair with the opposing nucleotide in the antisense strand, ii) a nucleotide having an abasic modification, and iii) a nucleotide having a sugar modification, and placed at a site opposite to the seed region (positions 2-8) of the antisense strand; T1 represents a nucleotide comprising a 2 ’-deoxy-2 ’-fluoro modification; nl or n3 is independently 4 to 15 nucleotides in length; n5 is 1-6 nucleotide(s) in length; n2 is 3; n4 is 0-3 nucleotide(s) in length; and wherein the sense strand has 2 ’-deoxy-2 "-fluoro modifications, and wherein the 2 ’-deoxy-2 ’-fluoro modifications on the sense strand consist of four, and only four, 2 ’-deoxy-2 ’-fluoro modifications, wherein the four 2 ’-deoxy-2 ’-fluoro modifications are at positions 7 and 9-11 from the 5 '-end of the sense strand. In some embodiments, wherein the antisense strand and sense strand are each 19-25 nucleotides. In some embodiments, the antisense strand corresponds to tire unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF,

[0248] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand is complementary to at least one portion of a mRNA of the target gene (e.g., DUX4), wherein the oligonucleotide is represented by the formula:wherein: Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-0 -methyl and 2’-deoxy-2’-fluoro; each Bl,Docket No.: SOUF-003 / 01WOB2, and B3 is 2'-0Me; Cl is glycerol nucleic acid (GNA) placed at a site opposite to the seed region (positions 2-8) of the antisense strand; IT, T2', and T3' are each 2’-deoxy-2’-fluoronucleotides, wherein: IT is at position 14 from the 5' end of the antisense strand, and q2 is 1; and T3' is at position 2 from the 5' end of the antisense strand, and q6 and q7 are 1; each nl, n3, and ql is independently 4 to 15 nucleotides in length; each n5 and q3 is independently 1-6 nucleotide(s) in length; q5 is 0-10 nucleotide(s) in length; each n4 and q4 is independently 0-3 nucleotide(s) in length; n2 is 3 nucleotides in length, and Tl each are 2’-deoxy-2’-fluoro nucleotides, and wherein (a) the oligonucleotide is covalently conjugated to at least one ligand; and (b) one of the Tl nucleotides is at position 11 from the 5' end of the sense strand. In some embodiments, the sense strand comprises 19-22 nucleotides and the antisense strand comprises 19-25 nucleotides. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.

[0249] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the oligonucleotide is represented by the formula:(Iwherein Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-O-methyl and 2’-deoxy-2’-fhioro; each Bl, B2, and B3 is 2'-OMe nucleotides; Cl is glycerol nucleic acid (GNA) placed at a site opposite to the seed region (positions 2-8) of the antisense strand; Tl', T2', and T3' are each 2 ’-deoxy -2 ’-fluoro nucleotides, wherein: Tl' is at position 14 from the 5' end of the antisense strand, and q2 is 1; and T3' is at position 2 from the 5' end of the antisense strand, and q6 and q7 are 1; each nl, n3, and ql is independently 4 to 15 nucleotides in length; each n5 and q3 is independently 1-6 nucleotide(s) in length; q5 is 0-10 nucleotide(s) in length; each n4 and q4 is independently 0-3 nucleotide(s) in length; n2 is 3 nucleotides in length, and Tl each are 2 ’-deoxy-2’ -fluoro nucleotides, and whereinDocket No.: SOUF-003 / 01WO(a) the oligonucleotide is covalently conjugated to at least one ligand; and (b) one of the T1 nucleotides is at a position in the sense strand that is opposite to position 11 from the 5' end of the antisense strand; and (c) the oligonucleotide comprises at least one phosphorothioate internucleoside linkage. In some embodiments, the sense strand comprises 19-22 nucleotides and the antisense strand comprises 19-25 nucleotides. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to tire unmodified sense strand in Table IF.

[0250] In some embodiments, any one of the RNAi agents disclosed herein comprises a modification pattern wherein the antisense strand has sufficient complementarity to a target sequence to mediate RNA interference, wherein said sense strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5' region of the antisense strand or a precursor thereof, wherein the antisense strand further comprises one or both of the following characteristics: (i) 2, 3, 4, 5 or 62'-deoxy-2'-fluoro modifications; and (ii) 1, 2, 3, 4 or 5 phosphorothioate intemucleoside linkages; and said sense strand comprises one or both of the following characteristics: (iii) 2, 3, 4, or 52'-deoxy-2'-fluoro modifications; and (iv) 1, 2, 3, 4 or 5 phosphorothioate internucleoside linkages. In some embodiments, tire antisense strand and sense strand are each 14 to 40 nucleotides. In some embodiments, the antisense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 607-1212. In some embodiments, the sense strand corresponds to the unmodified nucleobase sequence according to any one of SEQ ID NOs: 1-606. In some embodiments, the antisense strand corresponds to the unmodified antisense strand in Table IF. In some embodiments, the sense strand corresponds to the unmodified sense strand in Table IF.Synthesis, Purification, and Analysis of the Oligonucleotides Described Herein

[0251] Oligomer synthesis of modified and unmodified nucleosides and nucleotides can be routinely performed according to literature procedures for DNA (Protocols for Oligonucleotides and Analogs, Ed. Agrawal (1993), Humana Press) and / or RNA (Scaringe, Methods (2001), 23, 206-217. Gait el al., Applications of Chemically synthesized RNA in RNA: Protein Interactions, Ed. Smith (1998), 1-36. Gallo et al., Tetrahedron (2001), 57, 5707-5713). The oligonucleotides provided herein can be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, LGC (Alexandria, MN). Any other means for such synthesis known in the art mayDocket No.: SOUF-003 / 01WOadditionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives. Methods of purification and analysis of oligomeric compounds are known to those skilled in the art. Analysis methods include capillary electrophoresis (CE), reverse-phase high performance liquid chromatography (RP-IIPLC), and electrospray-mass spectroscopy (ESI-MS). Such synthesis and analysis methods can be performed in multi -well plates. The oligonucleotides of the invention can be prepared using solution-phase or solid- phase organic synthesis, or enzymatically by methods known in the art. Organic synthesis offers the advantage that the oligomeric strands comprising non-natural or modified nucleotides can be easily prepared. Any other means for such synthesis known in the art can additionally or alternatively be employed. It is also known to use similar techniques to prepare other oligonucleotides, such as those comprising phosphorothioates, phosphorodithioates and alkylated derivatives of internucleoside linkages. The double-stranded oligonucleotides of the invention can be prepared using a two- step procedure. First, the individual strands of the double¬ stranded oligonucleotides are prepared separately. Then, the component strands are annealed. Regardless of the method of synthesis, the oligonucleotides can be prepared in a solution (e.g., an aqueous and / or organic solution) that is appropriate for formulation. For example, the oligonucleotides preparation can be precipitated and redissolved in pure double-distilled water, and lyophilized. The dried oligonucleotides can then be resuspended in a solution appropriate for the intended formulation process. Teachings regarding the synthesis of particular modified oligonucleotides can be found in the following U. S. patents or pending patent applications: U. S. Pat. Nos. 5,138,045 and 5,218,105, drawn to polyamine conjugated oligonucleotides; U. S. Pat. No. 5,212,295, drawn to monomers for the preparation of oligonucleotides having chiral phosphorus linkages; U. S. Pat. Nos. 5,378,825 and 5,541,307, drawn to oligonucleotides having modified backbones; U. S. Pat. No. 5,386,023, drawn to backbone-modified oligonucleotides and the preparation thereof through reductive coupling; U. S, Pat. No. 5,457,191, drawn to modified nucleobases based on the 3-deazapurine ring system and methods of synthesis thereof; U. S. Pat. No. 5,459,255, drawn to modified nucleobases based on N-2 substituted purines; U. S. Pat. No.5,521,302, drawn to processes for preparing oligonucleotides having chiral phosphorus linkages; U. S. Pat. No. 5,539,082, drawn to peptide nucleic acids; U. S. Pat. No. 5,554,746, drawn to oligonucleotides having beta-lactam backbones; U. S. Pat. No. 5,571,902, drawn to methods and materials for the synthesis of oligonucleotides; U. S. Pat. No. 5,578,718, drawn to nucleosides having alkylthio groups, wherein such groups can be used as linkers to other moieties attached at any of a variety of positions of the nucleoside; U. S. Pat. Nos. 5,587,361 and 5,599,797, drawn to oligonucleotides having phosphorothioate linkages of high chiral purity; U. S. Pat. No. 5,506,351, drawn to processes for the preparation of 2'-O-alkyl guanosine and related compounds, includingDocket No.: SOUF-003 / 01WO2,6-diaminopurine compounds; U. S. Pat. No. 5.587,469, drawn to oligonucleotides having N-2 substituted purines; U. S. Pat. No. 5,587,470, drawn to oligonucleotides having 3-deazapurines; U. S. Pat. No. 5,223,168, and U. S. Pat. No. 5,608,046, both drawn to conjugated 4'-desmethyl nucleoside analogs; U. S. Pat. Nos. 5,602,240, and 5,610,289, drawn to backbone-modified oligonucleotide analogs; and U. S. Pat. Nos. 6,262,241, and 5,459,255, drawn to, inter alia, methods of synthesizing 2'-deoxy-2’-fluoro-oligonucleotides. In some embodiments, the oligonucleotides described herein are chemically synthesized using a phosphoramidite approach, e.g., the method by Roy et al. Molecules. 2013; 18(11): 14268-14284; Hayakawa et al. Journal of the American Chemical Society. 1998;120(48): 12395-401; Beaucage, S. L. (1993). Oligodeoxyribonucleotides synthesis: Phosphoramidite approach. In Protocols for Oligonucleotides and Analogs: Synthesis and Properties (pp. 33-61). Humana Press, each of which is hereby incorporated by reference.Pharmaceutical Compositions

[0252] The present disclosure also includes pharmaceutical compositions and formulations comprising the oligonucleotides (e.g., an RNAi agent or ASO) described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein are pharmaceutical compositions comprising an oligonucleotide (e.g., an RNAi agent or ASO), as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions comprising the oligonucleotides described herein are useful for treating or preventing a condition or symptoms associated with DUX4 expression. Such pharmaceutical compositions are formulated based on the mode of delivery’. One example is compositions that are formulated for systemic administration via parenteral delivery', e.g., by subcutaneous (SC), intramuscular (IM), or intravenous (IV) delivery. In some embodiments, an oligonucleotide is formulated in buffer solutions such as phosphate-buffered saline solutions, liposomes, micellar structures, and capsids. In some embodiments, naked oligonucleotides or conjugates thereof are formulated in water or in an aqueous solution (e.g., water with pH adjustments). In some embodiments, naked oligonucleotides or conjugates thereof are formulated in basic buffered aqueous solutions (e.g., PBS), The pharmaceutical compositions of the invention may be administered in dosages sufficient to inhibit expression of the target gene.

[0253] A “pharmaceutically acceptable carrier or excipient” is a pharmaceutically acceptable solvent, suspending agent, or any other pharmacologically inert vehicle for delivering one or more oligonucleotides to a subject. The excipient can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with the oligonucleotide and the other components of a given pharmaceuticalDocket No.: SOUF-003 / 01WOcomposition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc,); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, com starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g, sodium lauryl sulphate, etc.).

[0254] In some embodiments, the present disclosure also includes a pharmaceutical composition suitable for injectable use, which comprises sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.

[0255] Formulations for topical administration of oligonucleotides can include sterile and non- sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the oligonucleotides in liquid or solid oil bases. The solutions can also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of tire present disclosure. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.

[0256] In some embodiments, the oligonucleotides herein are conjugated to one or more non- nucleotide groups including, but not limited to, a targeting group / targeting moiety, linking group, delive ry polymer, or a delivery vehicle. The non-nucleotide group can enhance targeting, delivery’, or attachment of the oligonucleotide.

[0257] In some embodiments, at least one nucleotide of the oligonucleotide herein is conjugated to one or more targeting ligands, such as a carbohydrate, amino sugar, cholesterol,Docket No.: SOUF-003 / 01WOpolypeptide, or lipid. Exemplar}' targeting ligands include, but are not limited to, thyrotropin, melanotropin, lectin, a glycoprotein, surfactant protein A, mucin carbohydrate, a multivalent lactose moiety, a multivalent galactose moiety, a N-acetylgalactosamine (GalNAc) moiety, a N-acetyl-glucosamine moiety, a multivalent mannose moiety, a multivalent fucose moiety, a glycosylated polypeptide, transferrin or an antibody, antibody fragment, protein, peptide, or aptamer capable of binding the transferrin receptor, bisphosphonate, polyglutamate, polyaspartate, cholesterol, bile acid, folate, vitamin B 12, biotin, an RGD peptide, or an RGD peptide mimetic. In some embodiments, the targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety. In some embodiments, the GalNAc moiety comprises a monovalent GalNAc moiety, a bivalent GalNAc moiety, a tri valent GalNAc moiety, or a tetravalent GalNAc moiety.

[0258] The non-nucleotide group can be covalently linked to the 3' and / or 5' end of either the antisense strand and / or the sense strand, when present. In some embodiments, when the oligonucleotide is an RNAi agent, the RNAi agent contains a non-nucleotide group linked to the 3' and / or 5' end of the sense strand. In some embodiments, a non-nucleotide group is linked to the 5' end of a DUX4 RNAi agent sense strand, A non-nucleotide group may be linked directly or indirectly to the oligonucleotide via a linker / linking group. In some embodiments, a non- nucleotide group is linked to the oligonucleotide via a labile, cleavable, or reversible bond or linker.

[0259] In some embodiments, the targeting moiety is a targeting ligand. In some embodiments, the targeting ligand is small molecule-based, sugar-based (e.g., saccharide-based), fatty acid-based, protein-based, or nucleic acid-based targeting ligand. In some embodiments, the targeting moiety is a protein-based targeting ligand. In some embodiments, the protein-based targeting ligand is an antibody, nanobody, affibody, a peptibody, or a peptide. In some embodiments, the protein-based targeting ligand is an antibody, a functional fragment thereof, or an antigen-binding fragment thereof,

[0260] Various formulations have been developed to facilitate oligonucleotide use. For example, oligonucleotides can be delivered to a subject or a cellular environment using a formulation that minimizes degradation, facilitates delivery and / or uptake, or provides another beneficial property to the oligonucleotides in the formulation. In some embodiments, an oligonucleotide herein is formulated in buffer solutions such as phosphate buffered saline solutions, liposomes, micellar structures and capsids. Formulations of oligonucleotides with cationic lipids can be used to facilitate transfection of the oligonucleotides into cells. For example, cationic lipids, such as lipofectin, cationic glycerol derivatives, and polycationic molecules (e.g., polylysine), can be used. Suitable lipids include Oligofectamine, Lipofectamine (Life Technologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.), or FuGene 6 (Roche),Docket No.: SOUF-003 / 01WOall of which can be used according to the manufacturer's instructions. Accordingly, in some embodiments, a formulation herein comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (see, e.g., Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 22nd edition, Pharmaceutical Press, 2013). In some embodiments, the formulations herein comprise an excipient. In some embodiments, an excipient confers to a composition improved stability, improved absorption, improved solubility and / or therapeutic enhancement of the active ingredient. In some embodiments, an excipient is a buffering agent (e.g., sodium citrate, sodium phosphate, a tris base, or sodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum, dimethylsulfoxide or mineral oil). In some embodiments, an oligonucleotide is lyophilized for extending its shelf-life and then made into a solution before use (e.g., administration to a subject). Accordingly, an excipient in a composition comprising any one of the oligonucleotides described herein may be a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol or polyvinylpyrrolidone) or a collapse temperature modifier (e.g., dextran, Ficoll® or gelatin).Methods of Treatment

[0261] The present disclosure also provides methods of using any one of the oligonucleotides disclosed herein, or a pharmaceutically acceptable salt thereof, or any one of the pharmaceutical compositions as described herein, to reduce or inhibit DUX4 expression in a subject. The methods include contacting one or more cells in a subject with an oligonucleotide of the disclosure, or a pharmaceutically acceptable salt thereof, or any one of the pharmaceutical compositions as described herein, thereby inhibiting expression of DUX4 in the cells. The present disclosure also provides use of any one of the oligonucleotides disclosed herein, or a pharmaceutically acceptable salt thereof, or any one of the pharmaceutical compositions as described herein, in the manufacture of a medicament for reducing or inhibiting DUX4 expression in a subject, or for preventing or treating a DUX4 related disorder in a subject. In some embodiments, the terms "‘inhibiting DUX4 expression” and “reducing DUX4 expression” are interchangeable.

[0262] Reduction in DUX4 expression can be assessed by any methods known in the art. For example, a reduction in the expression of DUX4 may be determined by determining the mRNA expression level of DUX4 or a panel of its targets using methods routine to one of ordinary skill in the art, e.g., northern blotting, qRT-PCR; by determining the protein level of DUX4 usingDocket No.: SOUF-003 / 01WOmethods routine to one of ordinary skill in the art, such as western blotting, immunological techniques.

[0263] In some embodiments, the reduction of DUX4 expression is determined by measuring DUX4 expression or a panel of its targets in a population of muscle cells deri ved from the subject. In some embodiments, reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4’s targets, e.g., a panel comprising one or more of LEUTX, TRIM43, KHDC1L, MBD3L2, CCNA1, ZSCAN4, SLC34A2, or PRAMEF6. In some embodiments, reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4's targets, e.g., a panel comprising one or more of CCNA1, SLC34A2, ZSCAN4, PRAMEF2, PRAMEF17, PRAMEF12, LEUTX, HNRNPCL1, RFPL4B, PRAMEF1, PRAMEFI9, TRIM43B, TRIM43, PRAMEFI4, PRAMEF11, KDM4E, RFPL2, PRAMEF15, PRAMEF6, ZNF280A, PRAMEF9, TRIM49, KHDC1P1, PRAMEF4, TPRX1, TRIM49B, TRIM51CP, KLF17, TRIM51BP, TRIM53CP, C1DP2, TRIM53AP, TRIM51, PRAMEF8, MBD3L2B, KHDC1L, ALPG, TRIM49C, MBD3L2, ZNF705G, MBD3L3, PRAMEF7, TRIM43CP, PRAMEFIO, HNRNPCL4, TRIM53BP, TRIM51EP, or MBD3L5. In some embodiments, the reduction in DUX4 expression is assessed by determining the mRNA expression level of a panel of DUX4’s targets, e.g., a DUX4 panel comprising one or more of KHDC1L, LEUTX, MBD3L2, and ZSCAN4. In some embodiments, the reduction of DUX4 expression is assessed by de termining the mRNA or pro tein expression of one or more circulating DUX4 targets (e.g., KHDC1L).

[0264] In some embodiments, the reduction of DUX4 expression is determined by measuring mRNA expression of DUX4 or its targets in a population of cancer cells derived from the subject. In some embodiments, the cancer cells are primary cancer cells or metastatic cancer cells. In some embodiments, the cancer cells are selected from malignant B cells, melanoma cancer cells, breast cancer cells, kidney cancer cells, bladder cancer cells, and prostate cancer cells. In some embodiments, the subject has one or more DUX4 related conditions selected from Capicua transcriptional repressor (QC)-rearranged sarcoma, undifferentiated round cell sarcoma, embryonal rhabdomyosarcoma ...

Claims

Docket No.: SOUF-003 / 01WOCLAIMSWhat is claimed is:

1. An oligonucleotide for inhibiting expression of DUX4, wherein the oligonucleotide comprises an antisense strand comprising at least 14 contiguous nucleotides substantially complementary to a sequence of nucleotides encoding DUX4, with no more than 4 mismatched nucleotides.

2. The oligonucleotide of claim 1, wherein the sequence of nucleotides encoding DUX4 comprises a nucleotide sequence having at least 90% nucleotide sequence identity to SEQ ID NO: 2425.

3. The oligonucleotide of claim 1 or 2, wherein the oligonucleotide targets a sequence of nucleotides corresponding to positions of SEQ ID NO: 2425 selected from Table 4.

4. The oligonucleotide of any one of claims 1-3, wherein the antisense strand is substantially or completely complementary to a sequence of nucleotides corresponding to an un translated region of the DUX4 transcript.

5. The oligonucleotide of any one of claims 1-4, wherein the oligonucleotide is an RNAi agent.

6. The oligonucleotide of claim 5, wherein the oligonucleotide is a double stranded small interfering RNA, a short hairpin RNA, or a Dicer-substrate siRNA (DsiRNA).

7. The oligonucleotide of claim 6, wherein the RNAi agent is a double-stranded small interfering RNA (siRNA) further comprising a sense strand, wherein the sense strand and antisense strand form a double stranded region,8. The oligonucleotide of any one of claims 1-7, wherein the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides (for example, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) differing by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 607-1212, 1819-2424, 2437-2447, or 3012- 3602, or a nucleotide sequence having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of any one of SEQ ID NOs: 607-1212, 1819-2424, 2437-2447, or 3012-Docket No.: SOUF-003 / 01WO9. The oligonucleotide of any one of claims 1-8, wherein the antisense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 607-1212, 1819-2424, 2437-2447, or 3012- 3602.

10. The oligonucleotide of any one of claims 7-9, wherein the sense strand comprises a nucleotide sequence differing by no more than 4, 3, 2, or 1 nucleotides from the nucleotide sequence of any one of SEQ ID Nos: 1-606, 1213-1818, 2426-2436, or 2448-3011, or a nucleotide sequence having at least 90% nucleotide sequence identity to a portion of the nucleotide sequence of any one of SEQ ID NOs: 1-606, 1213-1818, or 2426-2436, or 2448-3011.

11. The oligonucleotide of any one of claims 7-10, wherein the sense strand comprises the nucleotide sequence of any one of SEQ ID NOs: 1-606, 1213-1818, 2426-2436, or 2448-3011.

12. The oligonucleotide of any one of claims 7-11, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 607-1212, 1819-2424, 2437-2447, or 3012- 3602, and the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 1-606, 1213-1818, 2426-2436, or 2448-3011.

13. The oligonucleotide of any one of claims 7-12, wherein each strand is no more than 30 nucleotides in length, or 19-30 nucleotides in length, or 19-23 nucleotides in length, or 19-21 nucleotides in length.

14. The oligonucleotide of any one of claims 7-13, wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide or at least 2 nucleotides.

15. The oligonucleotide of any one of claims 7-14, wherein at least one strand comprises a 5" overhang of at least 1 nucleotide or at least 2 nucleotides.

16. The oligonucleotide of any one of claims 7-15, wherein the double stranded region is 15-30 nucleotide pairs in length, or 15-23 nucleotide pairs in length, or 17-25 nucleotide pairs in length, or 19-23 nucleotide pairs in length, or 19-21 nucleotide pairs in length,17. The oligonucleotide of any one of claims 7-16, wherein the antisense strand is 21 nucleotides in length and the sense strand is 19 nucleotides in length, or the antisense strand is 19 nucleotides in length and the sense strand is 19 nucleotides in length.Docket No.: SOUF-003 / 01WO18. The oligonucleotide of any one of claims 1-4, wherein the oligonucleotide is a single-stranded antisense oligonucleotide (ASO).

19. The oligonucleotide of claim 18, wherein the ASO comprises a nucleic acid sequence comprising at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) that differ by no more than 1, 2, 3, or 4 nucleotides from any one of SEQ ID NOs: 607-1212 or 3012-3602.

20. The oligonucleotide of claim 18 or 19, wherein the ASO comprises a nucleic acid sequence comprising at least 14 contiguous nucleotides (for example, 14, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides) that differ by no more than 1, 2, 3 or 4 nucleotides from any one of SEQ ID NOs: 1819-2424 or 2437-2447.

21. The oligonucleotide of any one of claims 1-20, wherein the oligonucleotide comprises one or more modifications.

22. The oligonucleotide of claim 21, wherein the one or more modifications is selected from a ribose modification, a backbone modification, a nucleobase modification, or a combination thereof.

23. The oligonucleotide of claim 22, wherein the ribose modification comprises a locked nucleic acid (LNA), a tricyclo-DNA (tcDNA), 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-methoxyethyl (2'- MOE), 2'-deoxy-2'-arabino-fluoro, 2'-O-benzyl, 2'-O-methyl-4-pyridine, 2' cyclic ethyl (cET), phosphorodiamidate morpholino (PMO), glycol nucleic acid (GNA), unlocked nucleic acid (UNA), a threose nucleic acid (TNA), or a combination thereof,24. The oligonucleotide of claim 23, wherein the ribose modification comprises a 2'-deoxy-2'-fluoro, 2'-O-methyl, glycol nucleic acid (GNA), unlocked nucleic acid (UNA), a threose nucleic acid (TNA), or a combination thereof.

25. The oligonucleotide of claim 23 or 24, wherein the ribose modification is a 2'-deoxy-2'-fluoro modification, a 2'-O-methyl modification, or a combination thereof.

26. The oligonucleotide of any one of claims 22-25, wherein the backbone modification comprises phosphorothioate, phosphorodithioate, methylphosphonate, methyoxypropyl-phosphonate, 5'-Docket No.: SOUF-003 / 01WO(E)-vinylphosphonate, 5'-methyl phosphonate, 5'-methyi phosphate, 5'-phosphorothioate, peptide nucleic acid (PNA), or a combination thereof.

27. The oligonucleotide of claim 26, wherein the backbone modification comprises a phosphorothioate.

28. The oligonucleotide of any one of claims 22-27, wherein the backbone modification comprises a phosphorothioate modification.

29. The oligonucleotide of any one of claims 22-28, wherein the nucleobase modification comprises 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, 5- methylcytosine (5-Me-C), 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2 -aminoadenine, N6-alkyl derivatives, N2-alkyl, 2-thiouracil, 2 -thiothymine, 2 -thiocytosine, 5-halouracil, cytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5- uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxy, 5-halo, 5-trifluoromethyl, N7-methylguanine, N7-methyladenine, 8-azaguanine, 8-azaadenine, 7- deazaguanine, 7-deazaadenine, 3 -deazaguanine, 3 -deazaadenine, or any combination thereof.

30. The oligonucleotide of claim 29, wherein the oligonucleotide comprises at least one modified nucleotide selected from the group consisting of a deoxy nucleotide, a 3 ’-terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-deoxy-2'-fluoro modified nucleotide, a 2' -deoxy -modified nucleotide, a 2’-5’-linked ribonucleotide (3’-RNA), a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-O-allyl- modified nucleotide, 2’-C-alkyl-modified nucleotide, 2’-hydroxyl-modified nucleotide, a 2’-O- (methoxy ethyl) modified nucleotide, a 2’-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate morpholino, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5 '-methylphosphate group, a nucleotide comprising a 5 ’ phosphate or 5 ’ phosphate mimic, a nucleotide comprising vinyl phosphonate, a glycol nucleic acid (GN A), a glycol nucleic acid S-Isomer (S-GNA), a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2’- deoxythymidine-3 ’phosphate, a nucleotide comprising 2’-deoxyguanosine-3’-phosphate; a cytidine-2'-phosphate, a guanosine-2'-phosphate, a uridine-2'-phosphate, an adenosine-2'-Docket No.: SOUF-003 / 01WOphosphate, a 2'-O-hexadecyl-adenosine-3'-phosphate, a 2'-O-hexadecyl-cytidine-3'-phosphate, a 2'-O-hexadecyl-guanosine-3'-phosphate, and a 2'-O-hexadecyl-uridine-3'-phosphate, a 3’-3' inverted nucleotide linkage, a 5 ’-5’ inverted nucleotide linkage, TNA, and combinations thereof.

31. The oligonucleotide of claim 30, wherein the oligonucleotide comprises a modified nucleotide selected from the group consisting of a deoxy nucleotide, a 3 ’-terminal deoxythymidine (dT) nucleotide, a 3'-3' inverted nucleotide linkage, a 5"-5’ inverted nucleotide linkage, a 5'-(E)- vinyIphosphonate-2’-O-methyl-uridine-3 ’-phosphate, and a combination thereof.

32. The oligonucleotide of claim 30 or 31, wherein the oligonucleotide comprises 5'-(E)- vinylphosphonate-2’-O-methyl-uridine-3 ’-phosphate.

33. The oligonucleotide of claim 21, wherein at least one of the modifications is a thermally destabilizing nucleotide modification.

34. The oligonucleotide of claim 33, wherein the thermally destabilizing nucleotide modification is selected from the group consisting of an abasic modification; a mismatch with the opposing nucleotide in the duplex; destabilizing sugar modification; a 2’-deoxy modification, an acyclic nucleotide, an unlocked nucleic acids (UNA); a glycerol nucleic acid (GNA), and a combination thereof.

35. The oligonucleotide of claim 31, wherein the modification composes a short sequence of 3’- terminal deoxythymidine nucleotide (dT).

36. Tire oligonucleotide of any one of claims 21-35, wherein the modifications on the nucleotides are 2’-O-methyl and 2’deoxy-2’-fluoro modifications.

37. The oligonucleotide of any one of claims 21-36, wherein the oligonucleotide comprises at least one phosphorothioate intemucleoside or phosphorodithioate intemucleoside linkage,38. The oligonucleotide of claim 37, wherein the oligonucleotide comprises 6-8 phosphorothioate internucleoside linkages.

39. The oligonucleotide of claims 37 or 38, wherein the oligonucleotide comprises at least 1, or at least 2, phosphorothioate intemucleoside linkage at a 5’ end of the sense strand.Docket No.: SOUF-003 / 01WO40. The oligonucleotide of any one of claims 37-39, wherein the oligonucleotide comprises at least 1 phosphorothioate intemucleoside linkage at a 3" end of the sense strand.

41. Tire oligonucleotide of any one of claims 37-40, wherein the oligonucleotide comprises at least 1, or at least 2, phosphorothioate internucleoside linkage at a 5’ end of the antisense strand.

42. The oligonucleotide of any one of claims 37-41, wherein the oligonucleotide comprises at least 1 phosphorothioate intemucleoside linkage at a 3’ end of the antisense strand.

43. The oligonucleotide of any one of claims 37-42, wherein no more than five of the nucleotides of the antisense strand are unmodified nucleotides.

44. The oligonucleotide of any one of claims 37-43, wherein all the nucleotides of the antisense strand are modified oligonucleotides.

45. The oligonucleotide of any one of claims 37-44, wherein no more than five of the nucleotides of the sense strand are unmodified nucleotides,46. The oligonucleotide of any one of claims 37-45, wherein all the nucleotides of the sense strand are modified nucleotides.

47. The oligonucleotide of any one of claims 7-46, wherein the antisense strand comprises a chemical modification pattern according to (Nfs)a(nNf)b(ns)cn, wherein:n is a 2'-O-methyl-nucleoside-3’-phosphate;Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate;Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate;ns is a 2'-O-methyl-nucleoside-3 '-phosphorothioate,a is at least 1;b is 5-10; andc is at least 1.

48. The oligonucleotide of claim 47, wherein the antisense strand comprises the chemical modification pattern NfsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn.Docket No.: SOUF-003 / 01WO49. The oligonucleotide of any one of claims 7-48, wherein the sense strand comprises a chemical modification pattern according to (ns)d(Nfn)eNf. wherein:n is a 2"-O-methyl-nucleoside-3‘-phosphate;Nf is a 2’-deoxy-2'-fluoro-nucleoside-3’-phosphate;ns is a2’-O-methyl-nucleoside-3?-phosphorothioate;d is at least 1; ande is 5-10.

50. The oligonucleotide of claim 49, wherein the sense strand comprises the chemical modification pattern nsnsNfnNfnNfnNfhNfhNfiiNfhNfiiNf.

51. The oligonucleotide of any one of claims 7-50, wherein each of the antisense and the sense strand is independently 17-23 nucleotides in length, wherein the antisense strand comprises the motif F(SF)nSnn, wherein n is from 2 to about 20, nn is 0 or 1, one of F and S is a 2’-deoxy-2’- fluoro modified nucleoside and the other of F and S is a 2'-O-methyl modified nucleoside.

52. The oligonucleotide of any one of claims 7-51, wherein the antisense strand comprises the chemical modification pattern of nNfnnnNfnNfNfnnnnNfnNfnnnnn and the sense strand comprises the chemical modification nnnnnNfnNfNfNfnnnnnnnn, wherein n is a 2’-O-methyl- nucleoside and Nf is a 2 ’-deoxy-2’ -fluoro-nucleoside.

53. Tire oligonucleotide of any one of claims 7-52, wherein each of the antisense and the sense strand is independently 20-23 nucleotides in length, wherein the antisense strand comprises a region having the formula X1-Y-X2, wherein Y is a subregion of from about 5 to about 12 linked nucleosides and each of XI subregion and X2 subregion is, independently, a plurality’ of linked nucleosides having tire formula FSFS, where one of F and S is a 2'-deoxy-2’-fluoro modified nucleoside and the other of F and S is a 2'-O-methyl modified nucleoside; and each intemucleoside linkage of said XI subregion and X2 subregion is, independently, a phosphodiester or a phosphorothioate internucleoside linkage.

54. The oligonucleotide of any one of claims 7-53, wherein each of the antisense and tire sense strand is independently 17-23 nucleotides in length, wherein the antisense strand comprises a contiguous sequence of linked nucleosides that define an alternating motif of the formula: 5 '-Q(-L-Z-L-Q)n(-L-Z)nn-3'wherein:Docket No.: SOUF-003 / 01WOeach L is an intemucleoside linking group;either each Q is a 2 '-deoxy-2’ -fluoro-nucleoside and each Z is a 2'-O-methyl nucleoside; or each Q is a 2'-O-methyl nucleoside and each Z is a 2'-deoxy-2’ -fluoro nucleoside; andn is from 8 to 14 and nn is 0 or 1.

55. The oligonucleotide of any one of claims 7-54, wherein the antisense strand is 19-25 nucleotides in length and is represented by the formula:wherein:Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-0-alkyl, 2'-substituted alkoxy, 2'- substituted alkyl, 2'-halo, ENA, and BNA / LNA;Tl', T2', and T3' each independently represent a nucleotide comprising a chemical modification selected from the group consisting of DNA, RNA, LNA, 2'-deoxy-2’-fluoro, and 5'-methyl-2'-deoxy-2’-fluoro nucleotides;ql is 4 to 15 nucleotides in length;q3 or q7 is independently 1-6 nucleotide(s) in length;q2 or q6 is independently 1-3 nucleotide(s) in length;q4 is 0-3 nucleotide(s) in length; andq5 is 0-10 nucleotide(s) in length; andwherein:the antisense strand has 2'-deoxy-2’-fluoro modifications, and wherein the 2'-deoxy-2’- fluoro modifications on the antisense strand consist of four, and only four, 2'-deoxy-2’-fluoro modifications or six, and only six, 2'-deoxy-2’-fluoro modifications.

56. The oligonucleotide of any one of claims 7-55, wherein the antisense strand and sense strand are each 14 to 40 nucleotides, and is represented by the formula:Docket No.: SOUF-003 / 01WOwherein:Bl, Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-0-alkyl, 2'-substituted alkoxy, 2'- substituted alkyl, 2'-halo, ENA, and BNA / LNA;Cl is a thermally destabilizing nucleotide, selected from the group consisting of i) a nucleotide that forms a mismatch pair with the opposing nucleotide in the antisense strand, ii) a nucleotide having an abasic modification, and iii) a nucleotide having a sugar modification, and placed at a site opposite to the seed region (positions 2-8) of the antisense strand;T1', T2', and T3' each independently represent a nucleotide comprising a modification providing the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2'-0Me modification, wherein the modification is at the 2'-position of a ribose sugar of the nucleotide or at a position of a non-ribose nucleotide similar to the 2'-position of a ribose sugar;each n1, and q1 is independently 4 to 15 nucleotides in length;each q3, and q7 is independently 1-6 nucleotide(s) in length;each q2 and q6 is independently 1-3 nucleotide(s) in length;q5 is 0-10 nucleotide(s) in length;each n4, and q4 is independently 0-3 nucleotide(s) in length;n2 is 3 nucleotides in length, and T1 each are 2'-deoxy-2’ -fluoro nucleotides;n3 is 7 nucleotides in length, and B2 each are 2'-0Me nucleotides; andn5 is 3 nucleotides in length, and B3 each are 2'-0Me nucleotides., The oligonucleotide of any one of claims 7-56, wherein the anti sense strand and sense strand are each 19-25 nucleotides in length, wherein the sense strand is represented by the formula:Docket No.: SOUF-003 / 01WO(Is)wherein:Bl, B2, and B3 each independently represent a nucleotide containing a modification selected from the group consisting of 2'-0-alkyl, 2'-substituted alkoxy, 2'-substituted alkyl, 2'- halo, ENA, and BNA / LNA;Cl is a thermally destabilizing nucleotide, selected from the group consisting of i) a nucleotide that forms a mismatch pair with the opposing nucleotide in the antisense strand, ii) a nucleotide having an abasic modification, and iii) a nucleotide having a sugar modification, and placed at a site opposite to the seed region (positions 2-8) of the antisense strand;T1 represents a nucleotide comprising a 2'-deoxy-2’-fluoro modification;nl or n3 is independently 4 to 15 nucleotides in length;n5 is 1-6 nucleotide(s) in length;n2 is 3;n4 is 0-3 nucleotide(s) in length; andwherein the sense strand has 2'-deoxy-2’-fluoro modifications, and wherein the 2'-deoxy- 2’-fluoro modifications on the sense strand consist of four, and only four, 2'-deoxy-2’-fluoro modifications, wherein the four 2'-deoxy-2’-fluoro modifications are at positions 7 and 9-11 from the 5'-end of the sense strand.

58. The oligonucleotide of any one of claims 7-57, wherein the antisense strand is complementary’ to at least one portion of a mRNA of the target gene (e.g., DUX4), wherein:the sense strand comprises 19-22 nucleotides,the antisense strand comprises 19-25 nucleotides; andthe oligonucleotide is represented by the formula:3' 5'wherein:Docket No.: SOUF-003 / 01WOBl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-O-methyl and 2'-deoxy-2’-fluoro;each Bl, B2, and B3 is 2'-O-methyl nucleotide;Cl is glycerol nucleic acid (GNA) placed at a site opposite to the seed region (positions 2-8) of the antisense strand;T1', T2', and T3' are each 2'-F, wherein:T1' is at position 14 from the 5' end of the antisense strand, and q2 is 1; and T3' is at position 2 from the 5' end of the antisense strand, and q6 and q7 are 1; each nl, n3, and ql is independently 4 to 15 nucleotides in length;each n5 and q3 is independently 1-6 nucleotide(s) in length;q5 is 0-10 nucleotide(s) in length;each n4 and q4 is independently 0-3 nucleotide(s) in length;n2 is 3 nucleotides in length, and T1 each are 2'-dcoxy-2‘ -fluoro nucleotides, and wherein(a) the oligonucleotide is covalently conjugated to at least one ligand; and(b) one of the T1 nucleotides is at position 11 from the 5' end of the sense strand.

59. Tire oligonucleotide of any one of claims 7-58, wherein the sense strand comprises 19-22 nucleotides, the antisense strand comprises 19-25 nucleotides; and the oligonucleotide is represented by the formula:(Dwherein:Bl', B2', B3', and B4' each independently represent a nucleotide containing a modification selected from the group consisting of 2'-O-methyl and 2'-deoxy-2’-fluoro;each Bl, B2, and B3 is 2'-0Me;Cl is glycerol nucleic acid (GNA) placed at a site opposite to the seed region (positions 2-8) of the antisense strand;IT, T2', and T3' are each 2'-deoxy-2’ -fluoro, wherein:T1' is at position 14 from the 5' end of the antisense strand, and q2 is 1; and T3' is at position 2 from the 5' end of the antisense strand, and q6 and q7 are 1; each nl, n3, and ql is independently 4 to 15 nucleotides in length;each n5 and q3 is independently 1-6 nucleotide(s) in length;q5 is 0-10 nucleotide(s) in length;each n4 and q4 is independently 0-3 nucleotide(s) in length;n2 is 3 nucleotides in length, and T1 each are 2'-dcoxy-2‘ -fluoro, andwherein(a) the oligonucleotide is covalently conjugated to at least one ligand; and(b) one of the T1 nucleotides is at a position in the sense strand that is opposite to position 11 from the 5' end of the antisense strand; and(c) the oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

60. The oligonucleotide of any one of claims 7-59, wherein the antisense strand and sense strand are each 14 to 40 nucleotides, wherein the antisense strand has sufficient complementarity to a target sequence to mediate RNA interference, wherein said sense strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5' region of the antisense strand or a precursor thereof, wherein the antisense strand further comprises one or both of the following characteristics:(i) 2, 3, 4, 5 or 62'-deoxy-2’-fluoro modifications; and(ii) 1, 2, 3, 4 or 5 phosphorothioate internucleoside linkages; andsaid sense strand comprises one or both of the following characteristics:(iii) 2, 3, 4, or 5 2'-deoxy-2’-fluoro modifications; and(iv) 1, 2, 3, 4 or 5 phosphorothioate internucleoside linkages.

61. The oligonucleotide of any one of claims 7-46, wherein the antisense strand comprises a modification pattern nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn, wherein ns is a 2’-O-methyl- nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3 '-phosphate.

62. The oligonucleotide of any one of claims 7-46, wherein the antisense strand disclosed herein comprises a modification pattern vpUsNfsnnnNfnNfNfnnnNfnNfnnnsnsn, wherein vpUs is a 5'- vinylphosphonate-2'-O-methyl-uridine-3’ -phosphorothioate; ns is a 2'-O-methyl-nucleoside-3'- phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O- methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.Docket No.: SOUF-003 / 01WO63. The oligonucleotide of any one of claims 7-46, wherein the sense strand disclosed herein comprises a modification pattern nsnsnnNfnNfNfNfnnnnnnnnnn, wherein ns is a 2'-O-methyl- nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ‘-phosphate; and Nf is a 2'- deoxy-2'-fluoro-nucleoside-3'-phosphate,64. The oligonucleotide of any one of claims 7-46, wherein the sense strand disclosed herein comprises a modification pattern NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNf, wherein ns is a 2'-O- methyl-nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'- phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro- nucleoside-3 '-phosphate.

65. Tire oligonucleotide of any one of claims 7-46, wherein the sense strand comprises a modification pattern nsnsnnNfnNfNfNfnnnnnnnnnn, and the antisense strand comprises a modification pattern nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn, wherein ns is a 2'-O-methyl- nucleoside-3'-phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O-methyl-nucleoside-3 ’-phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

66. Tire oligonucleotide of any one of claims 7-46, wherein the sense strand comprises a modification pattern nsnsnnNfnNfNfNfnnnnnnnnnn, and the antisense strand comprises a modification pattern vpUsNfsnnnNfnNfNfnnnNfnNfnnnsnsn, wherein vpUs is a 5'- vinylphosphonate-2'-O-methyl-uridine-3’-phosphorothioate; ns is a 2'-O-methyl-nucleoside-3'- phosphorothioate; Nfs is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphorothioate; n is a 2'-O- methyl-nucleoside-3 ’ -phosphate; and Nf is a 2'-deoxy-2'-fluoro-nucleoside-3'-phosphate.

67. Tire oligonucleotide of any one of claims 7-66, wherein the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOs: 1819-2424 or 2437-2447.

68. The oligonucleotide of claim 67, wherein the sense strand comprises a nucleotide sequence according to any one of SEQ ID NOs: 1213-1818 or 2426-2436.

69. The oligonucleotide of any one of claims 7-68, further comprising a terminal, chiral modification occurring at the first internucleoside linkage at the 3 ’-end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the firstDocket No.: SOUF-003 / 01WOintemucleoside linkage at the 5’-end of the sense strand, having the linkage phosphorus atom in either Rp configuration or Sp configuration.

70. Tire oligonucleotide of any one of claims 7-69, further comprising a terminal, chiral modification occurring at the first and second intemucleoside linkages at the 3 ’-end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

71. Tire oligonucleotide of any one of claims 7-70, further comprising a terminal, chiral modification occurring at the first, second and third intemucleoside linkages at the 3 ’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

72. Hie oligonucleotide of any one of claims 7-71, further comprising a terminal, chiral modification occurring at the first, and second intemucleoside linkages at the 3’ end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the third intemucleoside linkages at the 3 ’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, a terminal, chiral modification occurring at the first intemucleoside linkage at the 5’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modification occurring at the first intemucleoside linkage at the 5 ’-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

73. Tire oligonucleotide of any one of claims 7-72, further comprising a terminal, chiral modification occurring at the first, and second intemucleoside linkages at the 3 ’-end of the antisense strand, having the linkage phosphorus atom in Sp configuration, a terminal, chiral modification occurring at the first, and second intemucleoside linkages at the 5 ’-end of the antisense strand, having the linkage phosphorus atom in Rp configuration, and a terminal, chiral modificationDocket No.: SOUF-003 / 01WOoccurring at the first intemucleoside linkage at the 5 ’-end of the sense strand, having the linkage phosphorus atom in either Rp or Sp configuration.

74. The oligonucleotide of any one of claims 1-73, further comprising a phosphate or phosphate mimic at the 5 ’-end of the antisense strand.

75. The oligonucleotide of claim 74, wherein the phosphate mimic is a 5 ’-vinyl phosphonate (VP).

76. The oligonucleotide of any one of claims 1-75, further comprising a targeting ligand.

77. The oligonucleotide of claim 76, wherein the targeting ligand is a small molecule-based, sugar- based (e.g.. saccharide-based), fatty acid-based, protein-based, or nucleic acid-based targeting ligand.

78. The oligonucleotide of claim 77, wherein the protein-based targeting ligand is an antibody, nanobody, affibody, peptibody, or a peptide,79. An oligonucleotide selected from the sense strands, antisense strands, and RNAi agents as listed in Tables 1A, IB, or IF, or a pharmaceutically acceptable salt thereof.

80. A pharmaceutical composition comprising the oligonucleotide of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

81. A method for inhibiting DUX4 expression or treating a DUX4 related disorder in a subject, the method comprising administering an effective amount of the oligonucleotide of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 80 to the subject.

82. The method of claim 81, wherein the subject is a human.

83. Ihe method of claim 81 or 82, wherein the reduction of DUX4 mRNA or protein expression levels is measured in a population of myocytes or cardiomyocytes derived from the subject.

84. The method of any one of claims 81-83, wherein the reduction of DUX4 mRNA or protein expression levels is measured in tissues derived from the subject.Docket No.: SOUF-003 / 01WO85. The method of any one of claims 81-84, wherein the DUX4-related disorder is facioscapulohumeral muscular dystrophy, a DUX4-related cancer, or a DUX4-medicated viral disease.

86. The method of any one of claims 81-85, further comprising administering to the subject an additional agent or a therapy suitable for treatment or prevention of a DUX4 related disorder.