RNAI agents targeting cideb and related methods

Abstract

Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting CIDEB (e.g., hCIDEB); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing CIDEB expression (e.g., mRNA expression), methods of treating CIDEB associated diseases, and methods of treating liver diseases (e.g., MASH).

Description

Attorney Docket No. 62801.91W001RNAI AGENTS TARGETING CIDEB AND RELATED METHODS RELATED APPLICATIONS

[0001] This application claims priority to U. S. Serial No.: 63 / 743.703, filed January 10, 2025, and U. S. Serial No.: 63 / 759,635, filed February 18, 2025, the entire contents of each of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 6, 2026, is named 62801_91WO01_SL.xml and is 3,689,411 bytes in size.1. FIELD

[0003] This disclosure relates to RNAi agents (e.g., double stranded RNA (dsRNA) agents comprising a sense strand and an antisense strand) targeting cell death inducing DNA fragmentation factor alpha like effector B (CIDEB) and methods of utilizing the same. This disclosure further relates to various methods of treating diseases (e.g., liver diseases (e.g., liver diseases characterized by the presence of one or more somatic mutation in CIDEB)), and methods of selecting subjects with a disease for a specific therapy (e.g., a therapy comprising a CIDEB inhibitor).2. BACKGROUND

[0004] The CIDE (cell death inducing DNA fragmentation factor alpha like effector) protein family is a family of lipid droplet-associated proteins. There are three members of the CIDE protein family, CIDE A, CIDEB, and CIDEC. Each of the CIDE proteins comprises a common CIDE-N domain and a CIDE-C domain, which varies between each of the members. The tissue expression pattern of each CIDE protein differs but is correlative with their association with lipid droplets — CIDEA and CIDEC are primarily expressed in adipose tissue, while CIDEB is highly expressed in the liver. The association of CIDE proteins with lipid droplets can be a direct physical interaction with the surface of the lipid droplet, as well as an association with other lipid droplet proteins, such as perilipin.Attorney Docket No. 62801.91W0013. SUMMARY

[0005] Provided herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents) comprising a sense strand and an antisense strand targeting CIDEB (e.g., hCIDEB); and methods of manufacturing and pharmaceutical compositions comprising the same. Further provided herein are methods of utilizing the agents (e.g., RNAi agents, dsRNA agents) including, e.g., methods of inhibiting or decreasing CIDEB expression (e.g., mRNA expression), methods of treating CIDEB associated diseases, and methods of treating liver diseases (e.g., metabolic dysfunction-associated steatohepatitis (MASH)).

[0006] Accordingly, in one aspect provided herein are double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of cell death inducing DNA fragmentation factor alpha like effector (CIDEB) (e.g., human CIDEB (hCIDEB)), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1,2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318. 97-141, 143-192, or 324.

[0007] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0008] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0009] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.Attorney Docket No. 62801.91W001

[0010] In one aspect, provided herein are dsRNA agents for inhibiting expression of CIDEB (e.g., hCIDEB), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3; and the nucleotide sequence of the sense strand differs by no more than 5 e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2 or 3.

[0011] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2 or 3.

[0012] In one aspect, provided herein are dsRNA agent for inhibiting expression of CIDEB (e.g., hCIDEB), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and wherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5 (e.g., 3 (e.g., 0, 1, 2, or 3))) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245- 1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251- 1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373- 1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932- 1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0. 1, 2, 3. 4, or 5 (e.g., 2 or 3)) nucleotides from the nucleotide sequence of the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0013] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0014] In some embodiments, the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3)Attorney Docket No. 62801.91W001nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0015] In one aspect, provided herein are dsRNA agents for inhibiting expression of CIDEB {e.g., hCIDEB), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0016] In some embodiments, the nucleotide sequence of the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0017] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and wherein the nucleotide sequence of the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0018] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 21 {e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and wherein the nucleotide sequence of the sense strand comprises at least 18 {e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0019] In one aspect, provided herein are dsRNA agents for inhibiting expression of CIDEBAttorney Docket No. 62801.91W001(e.g., hCIDEB), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-202.

[0020] In some embodiments, the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0021] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16. 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-202; and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17. 18. 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0022] In some embodiments, the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

[0023] For the sake of clarity, it is noted that the following embodiments are applicable to any of the foregoing aspects as if individually recited directly following each aspect.

[0024] In some embodiments, the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide. In some embodiments, at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified. In some embodiments, all of the nucleotides in the sense strand and / or antisense strand are modified. In some embodiments, all of the nucleotides in the sense strand and the antisense strand are modified.

[0025] In some embodiments, at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).Attorney Docket No. 62801.91W001

[0026] In some embodiments, (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strand comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro.

[0027] In some embodiments, (a) the sense strand comprises at least one 2’-O-methyl and at least one 2’-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

[0028] In some embodiments, at least one of the modified nucleotides comprises a modified nucleobase.

[0029] In some embodiments, the sense strand comprises at least one vinyl-phosphonate and / or the antisense strand comprises at least one vinyl-phosphonate. In some embodiments, the antisense strand comprises a 5' vinyl-phosphonate. In some embodiments, the sense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine) and / or the antisense strand comprises at least one vinyl-phosphonate-2'-0-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) (e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine). In some embodiments, the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine).

[0030] In some embodiments, the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

[0031] In some embodiments, the sense strand comprises at least one phosphorothioate and / or the antisense strand comprises at least one phosphorothioate.

[0032] In some embodiments, the sense strand comprises at least one phosphorothioate and the antisense strand comprises at least one phosphorothioate.

[0033] In some embodiments, each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20. 19. 18. 17. 16, or 15 nucleotides in length. In some embodiments, the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30 20-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides. In some embodiments, antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides. InAttorney Docket No. 62801.91W001some embodiments, antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

[0034] In some embodiments, the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides. In some embodiments, the antisense strand comprises a 3' overhang of 1, 2, or 3 nucleotides (e.g., 2 nucleotides). In some embodiments, the antisense strand comprises a 3' overhang of 2 nucleotides.

[0035] In some embodiments, the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotide pairs in length. In some embodiments, the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length. In some embodiments, the double stranded region is about 21 nucleotide pairs in length.

[0036] In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule.

[0037] In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules (z.e., connected only through the double stranded region).

[0038] In some embodiments, the nucleotide sequence of the antisense strand consists of 23 nucleotides; the nucleotide sequence of the sense strand consists of 21 nucleotides; the double stranded region is 21 nucleotide pairs in length; the antisense strand comprises a 3' overhang of 2 nucleotides; the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl e.g., vinyl-phosphonate-2'-O-methyluridine), at least one 2’-O-methyl, at least one 2'-deoxy-2’-fluoro and at least one phosphorothioate; and the sense strand comprises at least one 2'-O-methyl, at least one 2’-deoxy-2'-fluoro and at least one phosphorothioate.

[0039] In one aspect, provided herein are conjugates comprising a dsRNA agent described herein and a heterologous moiety.

[0040] In some embodiments, the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

[0041] In some embodiments, the heterologous moiety is carbohydrate. In some embodiments, the heterologous moiety comprises one or more GalNac. In some embodiments, the GalNac is triantennary GalNac.

[0042] In some embodiments, the heterologous moiety is a targeting moiety. In someAttorney Docket No. 62801.91W001embodiments, the targeting moiety specifically binds to a moiety expressed by hepatocytes (e.g., on the surface of the hepatocytes). In some embodiments, the targeting moiety comprises GalNac. In some embodiments, the GalNac is triantennary GalNac. In some embodiments, the targeting moiety directs the agent to hepatocytes through specific binding to the asialoglycoprotein receptor (e.g., expressed on the surface of hepatocytes).

[0043] In some embodiments, the heterologous moiety is attached to the dsRNA agent via a linker.

[0044] In some embodiments, the linker comprises triethylene glycol (TEG). In some embodiments, the heterologous moiety comprises GalNac and the linker is TEG. In some embodiments, the heterologous moiety comprises triantennary GalNac and the linker is TEG.

[0045] In some embodiments, the heterologous moiety and linker comprises Formula XXXIX below: / ‘wHQ

[0046] In some embodiments, the heterologous moiety attached to the 3' end of the sense and / or antisense strand and / or the 5' end of the sense and / or antisense strand, and / or at an internal site of the sense and / or antisense strand. In some embodiments, the heterologous moiety attached to the 3' end of the sense strand.

[0047] In some embodiments, the conjugate is set forth in Table 5.

[0048] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 203-298; and the nucleotide antisense strand comprises the nucleotide sequence set forth in the corresponding antisense strand (any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324).

[0049] In one aspect, provided herein are vectors (e.g., a viral vector, a non-viral vector) encoding an antisense strand described herein, a sense strand described herein, or both an antisenseAttorney Docket No. 62801.91W001described herein and a sense strand described herein.

[0050] In one aspect, provided herein are carriers comprising a dsRNA agent described herein, a conjugate described herein, or a vector described herein.

[0051] In some embodiments, the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, a dendrimer, a cationic delivery system, or a hydrogel. In some embodiments the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

[0052] In one aspect, provided herein are cells (or population of cells) comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, or a carrier described herein.

[0053] In one aspect, provided herein are pharmaceutical compositions comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, or a cell (or population of cells) described herein, and a pharmaceutically acceptable excipient.

[0054] In one aspect, provided herein are kits comprising a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0055] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, earner, or pharmaceutical composition into the cell. In some embodiments, the cell is in vitro, ex vivo, or in vivo. In some embodiments the cell is a subject (e.g., a human subject).

[0056] In one aspect, provided herein are methods of delivering a dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby deliver the dsRNA, conjugate, vector, earner, cell, or pharmaceutical composition to the subject.

[0057] In one aspect, provided herein are methods of reducing or inhibiting expression ofAttorney Docket No. 62801.91W001CIDEB (e.g., hCIDEB) in a cell, the method comprising delivering into the cell a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of CIDEB (e.g., hCIDEB) in the cell.

[0058] In one aspect, provided herein are methods of reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in a cell in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby reduce or inhibit expression of CIDEB (e.g., hCIDEB) in the cell in the subject.

[0059] In one aspect, provided herein are methods of treating, ameliorating, or preventing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the CIDEB (e.g., hCIDEB) associated disease in the subject.

[0060] In some embodiments, the treating, ameliorating, or preventing of the CIDEB (e.g., hCIDEB) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

[0061] In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

[0062] In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is liver fibrosis, cirrhosis, liver failure jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0063] In one aspect, provided herein are methods of treating, ameliorate, or preventing a liver disease in a subject, the method comprising administering to the subject a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the liver disease in the subject.

[0064] In some embodiments, the treating, ameliorating, or preventing of the liver disease isAttorney Docket No. 62801.91W001mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

[0065] In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD. In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0066] In one aspect, provided herein are methods of diagnosing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation indicates that the subject has a CIDEB (e.g., hCIDEB) associated disease.

[0067] In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is a liver disease. In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD. In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0068] In one aspect, provided herein are methods of diagnosing a liver disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, wherein the presence of the one or more somatic mutation indicates that the subject has a liver disease.

[0069] In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD. In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0070] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.Attorney Docket No. 62801.91W001

[0071] In some embodiments, the method further comprises administering to the subject an inhibitory nucleic acid molecule that inhibits expression of CIDEB if a CIDEB somatic mutation is detected in the DNA, RNA, or protein. In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0072] In one aspect, provided herein are methods of selecting a subject for administration of an inhibitory nucleic acid molecule that inhibits expression of CIDEB, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, wherein the subject is selected for administration of the inhibitory nucleic acid molecule if the one or more somatic mutation is present.

[0073] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.

[0074] In some embodiments, the method further comprises administering to the subject the inhibitory nucleic acid molecule if the subject is selected.

[0075] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0076] In one aspect, provided herein are methods of treating, ameliorating, or preventing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, and (c) administering to the subject an inhibitory nucleic acid that inhibits expression of CIDEB if the one or more CIDEB somatic mutation is detected in the DNA, RNA, or protein.

[0077] In some embodiments, the CIDEB (e.g., hCIDEB) associated disease is a liver disease. In some embodiments, the liver disease is fatty liver disease, steatotic liver disease, liverAttorney Docket No. 62801.91W001inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD. In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0078] In some embodiments, the treating, ameliorating, or preventing of the CIDEB (e.g., hCIDEB) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

[0079] In one aspect, provided herein are methods of treating, ameliorating, or preventing a liver disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, and (c) administering to the subject an inhibitory nucleic acid that inhibits expression of CIDEB if the one or more CIDEB somatic mutation is detected in the DNA, RNA, or protein.

[0080] In some embodiments, the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD. In some embodiments, the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

[0081] In some embodiments, (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.

[0082] In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein.

[0083] In some embodiments, the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

[0084] In one aspect, provided herein are in vitro methods of screening a sample from a subject for one or more somatic CIDEB mutation, the method comprising (a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; and (b) detecting the presence or absenceAttorney Docket No. 62801.91W001of one or more somatic CIDEB mutation in the DNA, RNA, or protein.

[0085] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is biopsy. In some embodiments, the sample is a liver biopsy.

[0086] In some embodiments, at least one of the one or more somatic mutation is a loss of function mutation. In some embodiments, at least one of the one or more somatic mutation is a gain of function mutation.

[0087] In some embodiments, the subject is a human.

[0088] In one aspect, provided herein are dsRNA agents described herein, conjugates described herein, vectors described herein, carriers described herein, cells (or populations of cells) described herein, or pharmaceutical compositions described herein for use in a method of treating, ameliorating, or preventing a CIDEB associated disease (e.g., a CIDEB associated disease described herein) in a subject.

[0089] In one aspect, provided herein are dsRNA agents described herein, conjugates described herein, vectors described herein, carriers described herein, cells (or populations of cells) described herein, or pharmaceutical compositions described herein for use in a method of treating, ameliorating, or preventing a liver disease (e.g., a liver disease described herein) in a subject.

[0090] In one aspect, provided herein are uses of a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein for the manufacture of a medicament for the treatment, amelioration, or prevention of a CIDEB associated disease (e.g., a CIDEB associated disease described herein) in a subject.

[0091] In one aspect, provided herein are uses of a dsRNA agent described herein, a conjugate described herein, a vector described herein, a carrier described herein, a cell (or population of cells) described herein, or a pharmaceutical composition described herein for the manufacture of a medicament for the treatment, amelioration, or prevention of a liver disease (e.g., a liver disease described herein) in a subject.

[0092] Provided herein are, inter alia, various methods of treating diseases (e.g., liver diseases (e.g., liver diseases characterized by the presence of one or more somatic mutation in CIDEB)), methods of selecting subjects with a disease for a specific therapy (e.g., a CIDEB inhibitor), and methods of diagnosing a disease (e.g., a liver disease (e.g., a liver disease characterized by the presence of one or more somatic mutation in CIDEB)).Attorney Docket No. 62801.91W001

[0093] Accordingly, in one aspect, provided herein are methods of treating, ameliorating, or preventing a liver disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, and administering a therapy to the subject if the one or more TM6SF2 germline mutation is present.

[0094] In one aspect, provided herein are methods of treating, ameliorating, or preventing a CIDEB associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, and administering a therapy to the subject if the one or more TM6SF2 germline mutation is present.

[0095] In one aspect, provided herein are methods of treating, ameliorating, or preventing a liver disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, and administering a CIDEB inhibitor to the subject if the one or more TM6SF2 germline mutation is present.

[0096] In one aspect, provided herein are methods of selecting a subject for administration of a CIDEB inhibitor, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the subject is selected for administration of the CIDEB inhibitor if the one or more TM6SF2 germline mutation is present.

[0097] In some embodiments, the method further comprises administering the CIDEB inhibitor to the subject if the subject is selected.

[0098] In one aspect, provided herein are methods of predicting the presence of a disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or havingAttorney Docket No. 62801.91W001detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a disease (e.g., liver disease) characterized by the presence of one or more somatic CIDEB mutation.

[0099] In one aspect, provided herein are methods of predicting the presence of a disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates a higher likelihood that the subject has a disease (e.g., liver disease) characterized by the presence of one or more somatic CIDEB mutation (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).

[0100] In one aspect, provided herein are methods of predicting the likelihood that a subject will develop a disease characterized by the presence of one or more somatic mutations in CIDEB, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject is more likely to develop a disease characterized by the presence of one or more somatic mutations in CIDEB (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).

[0101] In one aspect, provided herein are methods of predicting the likelihood that a subject will develop a CIDEB associated disease, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject is more likely to develop a CIDEB associated disease (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).

[0102] In one aspect, provided herein are methods of diagnosing a disease characterized byAttorney Docket No. 62801.91W001the presence of one or more somatic CIDEB mutation in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a disease characterized by the presence of one or more somatic CIDEB mutation.

[0103] In one aspect, provided herein are methods of diagnosing a CIDEB associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a CIDEB associated disease.

[0104] In one aspect, provided herein are in vitro method of screening a sample from a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; (b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein; and (c) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein.

[0105] For the sake of clarity, it is to be understood that the following embodiments are applicable to any of the foregoing aspects as if recited in full after each individual aspect above.

[0106] In some embodiments, the germline TN6F2 mutation is a loss of function mutation. In some embodiments, the one or more germline TM6SF2 mutation comprises a single nucleotide polymorphism. In some embodiments, the one or more germline TM6F2 mutation comprises a non- synonymous mutation (e.g., a non-synonymous single nucleotide polymorphism). In some embodiments, the one or more germline TM6SF2 mutation comprises a missense mutation, a nonsense mutation, a truncation, an insertion, or a deletion. In some embodiments, the germline TM6F2 mutation comprises the rs58542926 single nucleotide polymorphism. In some embodiments, the germline TM6F2 mutation comprises the rs58542926 C> T single nucleotide polymorphism. In some embodiments, the germline TM6F2 mutation comprises the rs58542926 OT single nucleotide polymorphism in one or both TM6F2 alleles. In some embodiments, the germline TM6SF2 mutation results in expression of a TNF6F2 protein comprising an E167KAttorney Docket No. 62801.91W001amino acid substitution, amino acid numbering relative to the amino acid sequence set forth in SEQ ID NO: 1188. In some embodiments, the encoded TNF6F2 protein comprising the E167K amino acid substitution exhibits reduced function {e.g., relative to a reference TNF6F2 protein {e.g., the TNF6F2 protein comprising the amino acid sequence set forth in SEQ ID NO: 1188)).

[0107] In some embodiments, the presence of the one or more germline TM6SF2 mutation indicates that the subject has a disease {e.g., a liver disease) characterized by the presence of one or more somatic CIDEB mutation. In some embodiments, the presence of the one or more germline TM6SF2 mutation indicates that the subject is more likely to develop a disease {e.g., a liver disease) characterized by the presence of one or more somatic CIDEB mutation {e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present). In some embodiments, the method further comprises detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein.

[0108] In some embodiments, at least one of the one or more somatic CIDEB mutation is a loss of function mutation. In some embodiments, the one or more somatic CIDEB mutation comprises a single nucleotide polymorphism. In some embodiments, the one or more somatic CIDEB mutation comprises a non-synonymous mutation {e.g., a non- synonymous single nucleotide polymorphism). In some embodiments, the one or more somatic CIDEB mutation comprises a mis sense mutation, a nonsense mutation, a truncation, an insertion, or a deletion.

[0109] In some embodiments, the therapy comprises a CIDEB inhibitor. In some embodiments, the CIDEB inhibitor is an inhibitory nucleic acid molecule that inhibits expression of CIDEB. In some embodiments, the inhibitory nucleic acid molecule comprises an siRNA agent, antisense oligonucleotide, or miRNA agent. In some embodiments, the inhibitory nucleic acid molecule comprises an agent described herein. In some embodiments, the inhibitory nucleic acid molecule comprises a dsRNA agent described herein.

[0110] In some embodiments, the therapy is a standard of care therapy for the treatment, prevention, and / or amelioration of the disease. In some embodiments, the therapy is an antidiabetic therapy {e.g., described herein), an anti-obesity therapy {e.g., described herein), an antihypertension therapy, an anti-dyslipidemia therapy, a therapy to increase HDL {e.g., described herein), a therapy to decrease LDL and / or triglycerides {e.g., described herein), diet, and / or exercise, or any combination of the foregoing. In some embodiments, the therapy is a GLP1 agonist {e.g., described herein {e.g., semaglutide)). In some embodiments, the therapy is a thyroid hormoneAttorney Docket No. 62801.91W001receptor beta (NR1 A2) agonist (e.g., described herein (e.g., resmetirom)).

[0111] In some embodiments, the subject is at high risk for a disease, is suspected of having a disease, is predicted to have a disease, has one or more risk factors for a disease, or has been diagnosed with a disease. In some embodiments, the subject is overweight or obese (defined as described herein), is a type-2 diabetic, has hypertension, has a high body mass index (defined as described herein), has dyslipidemia, has low HDL (defined as described herein), has high LDL (defined as described herein), has high triglycerides (defined as described herein), or any combination of the foregoing.

[0112] In some embodiments, the disease is a liver disease. In some embodiments, the disease is a CIDEB associated disease. In some embodiments, the disease is characterized by the presence of one or more somatic CIDEB mutation. In some embodiments, the disease comprises fatty liver, liver inflammation, liver steatosis, and / or liver fibrosis. In some embodiments, the disease is nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, alcoholic fatty liver disease (AFLD), cirrhosis, metabolic dysfunction associated steatotic liver disease (MASLD), metabolic-associated steatohepatitis (MASH), metabolic dysfunction associated fatty liver disease (MAFLD), metabolic dysfunction and alcohol associated steatotic liver disease (MetALD), steatotic liver disease (SLD), or cryptogenic SLD. In some embodiments, the disease is fatty liver. In some embodiments, the disease is MASH. In some embodiments, the disease is MAFLD.

[0113] In some embodiments, the sample is a blood, tissue, or cell sample. In some embodiments, the sample is a biopsy. In some embodiments, the sample is a liver biopsy.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] FIG. 1 is a bar graph showing the relative expression of TM6SF2 in hepatic cells treated with a vector control, TM6SF2-WT expressing, TM6SF2-E167K variant expressing, or treated with siRNA targeting TM6SF2.

[0115] FIG. 2 is a bar graph showing the level of intracellular lipid accumulation in hepatic cells treated with BSA (control) or fatty acid and treated with a vector control, TM6SF2-WT expressing, TM6SF2-E167K variant expressing, or treated with siRNA targeting TM6SF2.

[0116] FIG. 3 is a bar graph showing the level of intracellular lipid accumulation (spot intensity object) in primary human hepatocytes treated with siRNA control, siRNA targetingAttorney Docket No. 62801.91W001CIDEB and siRNA control, siRNA targeting TM6SF2 and siRNA control, or siRNA targeting CIDEB and siRNA targeting TM6SF2.5. DETAILED DESCRIPTION

[0117] The inventors have discovered, inter alia, RNAi agents that inhibit expression of CIDEB (e.g., hCIDEB). As such, the RNAi agents described herein are useful for the treatment of CIDEB mediated diseases such as liver diseases (e.g., fatty liver disease, liver inflammation, MASH). As such, the current disclosure provides RNAi agents (e.g., dsRNAi agents comprising a sense strand and an antisense strand) capable of inhibiting CIDEB expression (e.g., in a cell, in a cell in a subject); and their use in, inter alia, pharmaceutical compositions, and methods of treating diseases e.g., liver diseases).

[0118] The inventors have further discovered an association between the presence of inherited germline TM6SF2 variations and acquired somatic mutations in CIDEB in subjects with liver disease (e.g., metabolic dysfunction-associated steatohepatitis (MASH)). As such, the determination of the presence of germline TM6SF2 variations is useful in, inter alia, methods of treating and diagnosing diseases characterized by the presence of one or more somatic CIDEB mutation. As such, further provided herein are, inter alia, methods of treating diseases (e.g., liver diseases (e.g., liver diseases characterized by the presence of one or more somatic mutation in CIDEB)), methods of selecting subjects with a disease for a specific therapy (e.g., a CIDEB inhibitor), and methods of diagnosing a disease (e.g., a liver disease (e.g., a liver disease characterized by the presence of one or more somatic mutation in CIDEB)).TABLE OF CONTENTS5.1 Definitions5.2 CIDEB Inhibitors5.3 CIDEB Targeting INAMs5.3.1 Antisense Strand5.3.1.1 Targeting Region5.3.1.2 Overall Length5.3.2 Sense Strand5.3.2.1 Antisense Strand Complementarity5.3.2.2 Overall LengthAttorney Docket No. 62801.91W001Antisense Strandsi Agents)de Linkagescleoside LinkagesAttorney Docket No. 62801.91W001Exemplary ConjugatesActivity of INAMs (e.g., RNAi Agents) & Conjugates ThereofMethods of Making INAMs (e.g., RNAi Agents) & Conjugates Thereof VectorsCarriersLipid Based Carriers / Lipid NanoformulationsCationic Lipids (Positively Charged) and Ionizable LipidsNon-Cationic Lipids (e.g., Phospholipids)Structural LipidsPolymers and Polyethylene Glycol (PEG) - LipidsPercentages of Lipid Nanoformulation ComponentsHost CellsPharmaceutical CompositionsMethods of UseMethods of Utilizing RNAi Agents Described HereinMethods of DeliveryMethods of Reducing or Inhibiting CIDEB ExpressionMethods of Treating, Ameliorating, or Preventing a CIDEB Associated DiseaseMethods of Treating, Ameliorating, or Preventing a Liver Disease Methods of Diagnosing and / or Prognosticating a Liver Disease Methods of Screening, Identifying, and Selecting a Subject for Treatment with a CIDEB Inhibitory AgentIn Vitro Methods of Screening Samples for Somatic CIDEB Mutations Methods Related to TM6SF2Methods of Treating a DiseaseMethods of Selecting a SubjectMethods of Predicting the Presence of a DiseaseMethods of Predicting the Likelihood of Developing a DiseaseMethods of Diagnosing a CIDEB Associated DiseaseMethods of Screening a SampleAttorney Docket No. 62801.91W0015.13.2.7 Germline TM6SF2 Variations5.13.2.8 Somatic CIDEB Variations5.13.2.9 Samples5.13.2.10 Standard of Care5.14 Kits5.1 Definitions

[0119] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0120] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0121] In this application, the use of the singular includes the plural unless specifically stated otherwise. For example, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0122] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and “consisting essentially of’ are also provided.

[0123] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0124] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwiseAttorney Docket No. 62801.91W001indicated.

[0125] The terms “about” or “comprising essentially of’ refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of “about” or “comprising essentially of’ should be assumed to be within an acceptable error range for that particular value or composition.

[0126] As used herein, the term “administering” refers to the physical introduction of an agent, e.g., a therapeutic agent (or a precursor of the therapeutic agent that is metabolized or altered within the body of the subject to produce the therapeutic agent in vivo) to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Administration includes administration to a subject by a third party; as well as self-administration by the subject.

[0127] As used herein, the term “agent” is used generically to describe any macro or micro molecule. Exemplary moieties include, but are not limited polypeptides, proteins, peptides, polynucleotides (e.g., DNA, RNA), small molecules, carbohydrates, lipids, synthetic polymers e.g., polymers of PEG).

[0128] As used herein, the term “antisense strand” refers to an RNA molecule (e.g., part of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region of complementarity comprising a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to a target nucleic acid sequence (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)).

[0129] As used herein, the term “bicyclic sugar” refers to a modified sugar (e.g., ribose) moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In some embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In some embodiments, the furanosyl sugar moiety is a ribosyl moiety.

[0130] As used herein, the term “bicyclic nucleoside” (“BNA”) is a nucleoside comprising a bicyclic sugar.Attorney Docket No. 62801.91W001

[0131] As used herein, the term “blunt end” refers to a dsRNA molecule that does not contain any unpaired nucleotides at the end (e.g., 3' terminus, 5' terminus) of the dsRNA molecule (i.e., no nucleotide overhang(s)). The dsRNA molecule can have, for example, a blunt end at the 3' end, 5' end, or both the 3' and 5' end of the molecule.

[0132] As used herein, the term “CIDEB” or “cell death inducing DNA fragmentation factor alpha like effector” refers to the lipid droplet-associated protein primarily expressed in the liver and functions, e.g., to promote unilocular lipid droplet formation by mediating lipid droplet fusion. The mRNA sequence of a reference hCIDEB gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_014430.4). The amino acid sequence of a reference hCIDEB protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_055245). The term CIDEB includes naturally occurring variants of CIDEB. CIDEB gene and mRNA sequences of e.g., human, mouse, rat. non-human primate (e.g., rhesus macaque, Macaca fascicularis (cynomolgus monkey)), are readily available through publicly available databases, including, e.g., GenBank, UniProt, OMIM, and the Macaca genome project web site.

[0133] As used herein, a “CIDEB inhibitor” refers to an agent that reduces and / or inhibits expression and / or function of CIDEB. The CIDEB inhibitor can function to reduce and / or inhibit expression and / or function of CIDEB at the DNA level, RNA (e.g., mRNA level), or protein level. In specific embodiments, the CIDEB inhibitor is an inhibitory nucleic acid molecule (IN AM) (e.g., described herein).

[0134] As used herein, the term “CIDEB associated disease” refers to a disease that is mediated and / or influenced in part by an alteration in CIDEB (e.g., any one or more of an alteration in expression, function, variations, etc.). For example, any one of more of the onset, severity, progression, treatment susceptibility, etc. of the disease can be mediated and / or influenced in part by an alteration in CIDEB (e.g., any one or more of an alteration in expression, function, variations, etc.). In some embodiments, the CIDEB associated disease is characterized by the presence of one or more somatic CIDEB mutation. In some embodiments, the CIDEB associated disease is characterized by the presence of one or more somatic CIDEB mutation, wherein any one of more of the onset, severity, progression, treatment susceptibility, etc. of the disease is mediated and / or influenced in part by the presence of the one or more somatic CIDEB mutation.

[0135] As used herein, the term “complementary” in reference to a first nucleotide sequence (e.g., a sense strand or a target mRNA) in relation to a second nucleotide sequence (e.g., anAttorney Docket No. 62801.91W001antisense strand), refers to the ability of a nucleic acid molecule comprising the first nucleotide sequence to hybridize to a nucleic acid molecule comprising the second nucleotide sequence and form a double stranded region (through base pair hydrogen bonds) under suitable in vivo or vitro conditions {e.g., under certain standard conditions, under mammalian {e.g., human) physiological conditions). A person of ordinary skill in the art would be able to select the set of conditions most appropriate for a hybridization test. Complementary sequences include, e.g., Watson-Crick base pairs. For example, complementary nucleobase pairs include adenine (A) and thymine (T); adenine (A) and uracil (U); and cytosine (C) and guanine (G). Complementary nucleobase pairs include natural and modified nucleotides, and nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. As such, determinations of complementarity (as described herein) are independent of nucleotide chemical modifications {e.g., as described herein). For example, (C) and 5-methyl cytosine (mC) are both complementary to (G).

[0136] As used herein, the term “conjugation” refers to chemical conjugation of an agent {e.g., a nucleic acid molecule) with a moiety {e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer {e.g., polymers of polyethylene glycol (PEG)), etc.). The moiety can be directly connected to the agent {e.g., nucleic acid molecule) or indirectly connected through a linker, e.g., as described herein. Chemical conjugation methods are well known in the art, as are commercially available conjugation reagents and kits, with detailed instructions for their use readily available from the commercial suppliers.

[0137] As used herein, the term “differing by no more than X nucleotides” in reference to a nucleotide sequence means that the nucleotide sequence comprises no more than X (wherein X is a specified number {e.g., 3, 2, 1, 0)) nucleotide variations (as defined herein) relative to a reference sequence. For example, the phrase “wherein the nucleotide sequence of the antisense strand differs by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: X” means that the nucleotide sequence comprises no more than 3 nucleotide variations relative to the nucleotide sequence set forth in the cited SEQ ID NO: X.

[0138] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology. The term disease includes infection {e.g., a viral, bacterial, fungal, protozoal infection). The term disease includes other conditions caused by anAttorney Docket No. 62801.91W001infection.

[0139] As used herein, the term “double stranded RNA agent” or “dsRNA agent” refers to a complex of two RNA molecules comprising a double stranded region comprising two anti-parallel and at least partially (e.g., substantially, fully) complementary nucleic acid sequences that form the double stranded region. For example, in some embodiments, the dsRNA agent comprises a sense strand and an antisense strand.

[0140] The terms “DNA” and “polydeoxyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.

[0141] As used herein, the term “fully complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, 100% (all), of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of the first and / or second nucleic acid molecule.

[0142] As used herein, the term “germline mutation” refers to one or more nucleotide alteration (e.g., variation, modification (e.g., variation)) in the germline genomic DNA sequence (e.g., of a gene) of an individual and are therefore inherited from a parent.

[0143] As used herein, the term “heterologous,” when used to describe a first element in reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a nucleic acid molecule comprising a “heterologous moiety” means a nucleic acid molecule that is joined to a moiety (e.g., carbohydrate, small molecule, polypeptide, polynucleotide, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that is not joined to the nucleic acid molecule in nature.

[0144] Whether a subject has a “high body mass index” or “high BMI” can be determined by a medical professional according to medical diagnostic standards. In some embodiments, a subject has a “high BMI” if the subject has a BMI of 25 kg / m2or greater.

[0145] Whether a subject has “high LDL” or “high low-density lipoprotein” can be determined by a medical professional according to medical diagnostic standards. In some embodiments, a subject has “high LDL” if the subject has an LDL level of equal to or greater than 100 milligrams per deciliter (mg / dl) in the absence of coronary artery disease and equal to or greater than 70 mg / dl the presence of coronary artery disease.Attorney Docket No. 62801.91W001

[0146] Whether a subject has “high triglycerides” can be determined by a medical professional according to medical diagnostic standards. In some embodiments, a subject has “high triglycerides” if the subject has a triglyceride level of equal to or greater than 150 mg / dl.

[0147] As used herein, the term “isolated” with reference to a polypeptide, protein, or polynucleotide refers to a polypeptide, protein, or polynucleotide that is substantially free of other cellular components with which it is associated in the natural state.

[0148] Whether a subject has “low HDL” or “low high-density lipoprotein” can be determined by a medical professional according to medical diagnostic standards. In some embodiments, a subject has “low HDL” if the subject has an HDL level of equal to or less than 50 mg / dl for a female subject and equal to or less than 40 mg / dl for a male subject.

[0149] As used herein, the term “nucleotide variation,” “variant nucleotide,” or use of the term “variation” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleic acid molecule that comprises at least one substitution, addition, deletion, or inversion of one or more nucleotide compared to a reference nucleic acid molecule. As used herein, the term “variant” or “variation” with reference to a peptide or protein refers to a peptide or protein that comprises at least one substitution, addition, deletion, or inversion of an amino acid residue compared to a reference peptide or protein.

[0150] As used herein, the term “modified agent” refers to any agent (or any component thereof e.g., any nucleic acid molecule thereof)) {e.g., described herein, e.g., an antisense strand, a sense strand, a dsRNA agent, RNAi agent, etc.) that comprises one or more modified nucleotide (as defined herein).

[0151] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., §§ 5.5, 5.5.1. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNAi agent or component thereof {e.g., described herein, e.g., a sense strand, an antisense strand, a dsRNA agent) is considered to constitute a modified nucleotide.

[0152] As used herein, the term “moiety” is used generically to describe any macro or microAttorney Docket No. 62801.91W001molecule that can be operably connected to a protein described herein. Exemplary moieties include, but are not limited small molecules, polypeptides, polynucleotides (e.g., DNA, RNA), carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0153] As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that extends from the double stranded region of a nucleic acid molecule (e.g., a dsRNA molecule (e.g., a dsRNA molecule described herein)). For example, when a 3'-end of one strand of a dsRNA extends beyond the 5'-end of the other strand, or vice versa, there is a nucleotide overhang.

[0154] As used herein, the term, “non-complementary nucleotide mismatch” refers to a nucleotide within a region of complementarity (as described herein) that is not complementary to the corresponding nucleotide in the target nucleic acid molecule.

[0155] As used herein, the term “obtaining a sample” refers to the acquisition of a sample. The term includes the direct acquisition from a subject and the indirect acquisition through one or more third parties wherein one of the third parties directly acquired the sample from the subject.

[0156] Whether a subject is “obese” can be determined by a medical professional according to medical diagnostic standard. In some embodiments, a subject is “obese” if the subject has a body mass index value of 30 kg / m2or greater. See, e.g., Muller, M., Geisler, C. Defining obesity as a disease. Eur J Clin Nutrli, 1256-1258 (2017). https: / / doi.org / 10.1038 / ejcn.2017.155; the entire contents of which are incorporated herein by reference for all purposes.

[0157] Whether a subject is “overweight” can be determined by a medical professional according to medical diagnostic standards. In some embodiments, a subject is “overweight” if the subject has a body mass index value of equal to or greater than 25 kg / m2and less than 30 kg / m2. See, e.g., Muller, M., Geisler, C. Defining obesity as a disease. Eur J Clin NutrTC 1256-1258 (2017). https: / / doi.org / 10.1038 / ejcn.2017.155; the entire contents of which are incorporated herein by reference for all purposes.

[0158] As used herein, the term “operably connected” refers to the linkage of two moieties in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory polynucleotide e.g., a promoter, enhancer, or other expression control element is operably linked to a polynucleotide that encodes a protein if it affects the transcription of theAttorney Docket No. 62801.91W001polynucleotide that encodes the protein. The term “operably connected” can also refer to the conjugation of a moiety to e.g., a polynucleotide or polypeptide {e.g., the conjugation of a PEG polymer to a protein).

[0159] As used herein, “partially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 70%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0160] The determination of “percent identity” between two sequences {e.g., protein (amino acid sequences) or polynucleotide (nucleic acid sequences)) can be accomplished using a mathematical algorithm. Determinations of identity (as described herein) are independent of nucleotide chemical modifications e.g., as described herein). For example, (mC) is identical to (C) for the purposes of determining identity. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporated by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SFet al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI-BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs {e.g., of XBLAST and NBLAST) can be used {see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, which is herein incorporated by reference in its entirety. Such anAttorney Docket No. 62801.91W001algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0161] As used herein, the term “pharmaceutical composition” means a composition that is suitable for administration to an animal, e.g., a human subject, and comprises a therapeutic agent and a pharmaceutically acceptable carrier or diluent. A “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0162] The terms “nucleic acid molecule” and “polynucleotide” are used interchangeably herein and refer to a polymer of DNA or RNA. The nucleic acid molecule can be single- stranded or double- stranded; contain natural, non-natural, or altered nucleotides; and contain a natural, nonnatural, or altered internucleoside linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of nucleic acid molecules from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application will recite thymidine (T) in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the thymidines (Ts) would be substituted for uracils (Us). Thus, any of the RNA polynucleotides encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, where each thymidine (T) of the DNA sequence is substituted with uracil (U).

[0163] As used herein, the term “plurality” means 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 9 or more, or 10 or more).

[0164] As used herein, the terms “protein” and “polypeptide” refers to a polymer of at least 2Attorney Docket No. 62801.91W001(e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorter polymers of amino acids (e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids (e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where proteins are contemplated herein, it should be understood that proteins folded into their three-dimensional structure are also provided herein.

[0165] As used herein, the term “region of complementarity” refers to a portion of a first nucleic acid molecule comprising a nucleotide sequence that is at least partially complementary to the nucleotide sequence of at least a portion of a second nucleic acid molecule.

[0166] The terms “RNA” and “polyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contain natural, non-natural, or altered intemucleoside linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule.

[0167] As used herein, the term “RNAi agent” refers to an agent that contains one or more RNA molecules which can mediate the targeted cleavage of an RNA molecule (e.g., an mRNA molecule) via an RNA-induced silencing complex (RISC) pathway. The RNAi agent, is thereby capable of e.g., modulating, e.g., inhibiting, the expression of a target gene (e.g., CIDEB) in a cell, e.g., a cell within a subject, such as a mammalian subject. In some embodiments, the RNAi agent is a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region, wherein optionally the sense strand and the antisense strand each independently comprise or consist of from about 19-23 nucleotides.

[0168] As used herein, the term “sample” encompasses a variety of biological specimens obtained from a subject. Exemplary sample types include, e.g., blood, red blood cells, and other liquid samples of biological origin (including, but not limited to, whole-blood, red blood cells (e.g., isolated from whole blood), peripheral blood mononuclear cells (PBMCs), serum, plasma, urine, saliva, amniotic fluid, stool, synovial fluid, etc.), nasopharyngeal swabs, solid tissue samples such as biopsies (or cells derived therefrom and the progeny thereof), tissue cultures (or cells derivedAttorney Docket No. 62801.91W001therefrom and the progeny thereof), and cell cultures (or cells derived therefrom and the progeny thereof). The term also includes samples that have been manipulated in any way after their procurement from a subject, such as by centrifugation, filtration, washing, precipitation, dialysis, chromatography, lysis, treatment with reagents, enriched for certain cell populations, refrigeration, freezing, staining, etc.

[0169] As used herein, the term “sense strand” refers to an RNA molecule (e.g., part of an RNAi agent (e.g., described herein), part of a dsRNA agent (e.g., described herein)) that comprises a region that is at least partially (e.g., substantially, fully) complementary to a region of the antisense strand (as defined herein). The sense strand is often referred to as such with reference to the orientation of the sequence of the sense strand being the same with respect to a target RNA (e.g., mRNA sequence).

[0170] As used herein, the term “single nucleotide polymorphism” refers to single base substitution in germline DNA.

[0171] As used herein, the term “somatic mutation” refers to one or more nucleotide alteration (e.g., variation, modification (e.g., variation)) in a genomic DNA sequence (e.g., of a gene) that is acquired during the lifetime of a subject. It is understood in the art that somatic mutations are not present in the germline DNA of an individual and are therefore not inherited from a parent like germline polymorphisms. Somatic mutations may occur spontaneously due to e.g., the infidelity of DNA replication occurring at each cell division creating substitutions, deletions, or additions of nucleotides into the DNA of a cell. A somatic mutation may also be caused by environmental factors such as e.g., ultraviolet radiation, chemical exposure, or virial infections.

[0172] As used herein, the term “subject” includes any animal, such as a human or other animal. In some embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the method subject is a non-human mammal. In some embodiments, the subject is a non-human mammal is such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In some embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus). Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots).Attorney Docket No. 62801.91W001

[0173] As used herein, “substantially complementary” means that in a hybridized pair of a first nucleic acid molecule and a second nucleic acid molecule, at least 85%, but not all, of the bases in a contiguous sequence of the first nucleic acid molecule will hybridize with the same number of bases in a contiguous sequence of the second nucleic acid molecule. The contiguous sequence may comprise all or a part of a first or second nucleic acid molecule.

[0174] In some embodiments, the term “substantially all” means at least 95%, 96%, 97%, 98% or 99%, e.g., of the subject of said sentence. The term “substantially all” preferably excludes 100%. For example, in some embodiments, the term “substantially all of the nucleotides in the sense strand and / or antisense strand are modified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are modified” means that at least 95%, 96%. 97%, 98% or 99% of said nucleotides are modified. For example, in some embodiments, the term “substantially all of the nucleotides of the agent are unmodified” means that at least 95%, 96%, 97%, 98% or 99% of said nucleotides are unmodified. For example, in some embodiments the term “wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the composition comprising the dsRNA agent as counterions for substantially all of the phosphodiester or phosphorothioate groups present in the dsRNA agent” means that wherein the dsRNA agent is in the sodium salt form, sodium ions are present in the composition comprising the dsRNA agent as counterions for at least 95%, 96%, 97%, 98% or 99% of the phosphodiester or phosphorothioate groups present in the dsRNA agent.

[0175] As used herein, the term “target nucleic acid sequence” refers to a contiguous portion of the nucleotide sequence of a nucleic acid sequence (e.g., an mRNA molecule formed during the transcription of a target gene e.g., CIDEB)). In some embodiments, the target nucleic acid sequence is an mRNA molecule formed during the transcription of a target gene (e.g., CIDEB)). In some embodiments, the target nucleic acid molecule comprises an mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence (e.g., mRNA) will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a CIDEB gene. In one embodiment, the target sequence is within the protein coding region of CIDEB.

[0176] As used herein, the term “therapeutically effective amount” of a therapeutic agent refers to any amount of the therapeutic agent that, when used alone or in combination with anotherAttorney Docket No. 62801.91W001therapeutic agent, improves a disease condition, e.g., protects a subject against the onset of a disease (or infection); improves a symptom of disease or infection, e.g., decreases severity of disease or infection symptoms, decreases frequency or duration of disease or infection symptoms, increases disease or infection symptom-free periods; prevents or reduces impairment or disability due to the disease or infection; or promotes disease (or infection) regression. The ability of a therapeutic agent to improve a disease condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0177] As used herein, the term “TM6SF2” or “transmembrane 6 superfamily member 2” refers to the transmembrane 6 superfamily member that functions, e.g., to in the regulation of liver fat metabolism and influences triglyceride secretion and hepatic lipid droplet content. The amino acid sequence of a reference hTM6SF2 protein is set forth in SEQ ID NO: 319 (NCBI Ref.: NP_001001524.2). The term TM6SF2 includes naturally occurring variants of TM6SF2. TM6SF2 gene and mRNA sequences of e.g., human, mouse, rat, non-human primate (e.g., rhesus macaque, Macaca fascicularis (cynomolgus monkey)), are readily available through publicly available databases, including, e.g., GenBank, UniProt, OMIM, and the Macaca genome project web site.

[0178] As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease and / or symptom(s) associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disease does not require that the disease, or symptom(s) associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease. To this end. the presently disclosed methods comprise administering a therapeutically effective amount of a composition as described herein.5.2 CIDEB Inhibitors

[0179] Provided and utilized herein are, inter alia, agents (e.g., RNAi agents, dsRNA agents), useful in, inter alia, inhibiting expression of cell death inducing DFFA like effector B (CIDEB) (e.g., human CIDEB (hCIDEB)) (e.g., within a cell, e.g., within a cell in a subject, e.g., aAttorney Docket No. 62801.91W001mammalian subject, e.g., a human subject) (e.g., through the degradation of CIDEB (e.g., hCIDEB) mRNA).

[0180] CIDEB is a lipid droplet-associated protein primarily expressed in the liver and functions, e.g., to promote unilocular lipid droplet formation by mediating lipid droplet fusion. The mRNA sequence of a reference hCIDEB gene is set forth in SEQ ID NO: 1 (NCBI Ref.: NM_014430.4). The reverse complement sequence of the hCIDEB mRNA is set forth in SEQ ID NO: 2. The amino acid sequence of a reference hCIDEB protein is set forth in SEQ ID NO: 3 (NCBI Ref.: NP_055245). See Table 1, herein.Table 1. The mRNA and Amino Acid Sequence of a Reference hCIDEB Protein.SEQ IDDescription Amino Acid SequenceNO CCCUUCCGGUGGAGCCAGCGCUGCGACCGCCUGCAGAAGGUUGACUGC GUGGUAGGGGGCCCAGAGCAAGCCGAAGGCAAGCACGAUGGCGCUCAC CAGCCGGCCCACCCGCGCCCCGUGCCGCCCGGAGCCCCAGCGGGCGCC CCGCAGCCGUGCCAGCGUCACGCUGUAGCAGCCGAGCAUCAGCCCGAA AGGAAGCACGAAAGCGGUCAGAGUCUCCAGGCUCAGGUGGGCGGCGGC GUGGACCGGCGACGGGUGGCACAGCUGGCAUACGCGGUCCCUCCACAG GUGGCGGUAGACGGCGGCCGGGACGGCGAGCAACAGGGCGGCCAGCCA GACCGCCAGCAGCAGGCGGCGGGCCAGGGCCGGGCUGCGCAGCCGAGG CGCCAGGAAGGGGCGGGUGACUGCGAGGCAGCGCUGCAGGCUGAGCAG GCCGGUGAGCAGCACGCUGGCGUACAUGCUGAGCGCGCACACGUAGUA CACCGCCUUGCAGCCCGCCUGGCCCAGCGGCCAGGCCUGCCGGGUCAG GAAGGCCACAAAGAGCGGCGUGAGCAGCAGCACCGCGCCGUCGGCCAG CGCCAGGUGCAGCACAAGCGUGGCCGCCAGCGGUCGCCCCCGUGCAGG CCGCCAGCCCGCCAAGCUCCACACCACGAAGCCGUUGCCAGGCAGCCChCIDEB mRNA CAGCAGCGCCGCCAGCAGCAGGAAGGCUGUGCCUGUGGCCCGCGAAGU CUUCCAGCUCAGCAGUGUCUCGUUCCCUGGGGGACGGUAGCAGACCGA CAUCCUUCUGGGCCUACAGGACACAGAAAAAAAGUGGGGAAGCUGGGG 1 NCBI Ref.: GACCCUACAAGGAUCCUUGGCAGGAAAGCAGGGAUUGUGUUCAUUUGA NM_014430.4 GGGUUUCACUGUCAGUGAGAGUCUCAGCUUCCAUGCAACUGUCCAUCA CGGCUGCAACUGAAAUCAGAGCUGGGACACAGCGCACCAGAAGCUAAA GUCUUGAUGCCAUCAAAGGACAUCCCUGCCCCAUUCACAUCUCUGUCA CGUCCACUAAUCGGCAAAAGGAGAAAAGUGAGAGAAGAUGACCUAAGU GUGACUGCAGCAGGCAGCUCUGGAAAAUGAAGCCAGAGCAGUGAGCCA GCCCCUCCUCCGACCAAGGAGGAAGGAAAGAGCAGCCCCAGCACAGGA GAGAACCACCCAGCCCAGAAGUUCCAGGGAAGGAACUCUCCGGUCCAC CAUGGAGUACCUCUCAGCUCUGAACCCCAGUGACUUACUCAGGUCAGU AUCUAAUAUAAGCUCGGAGUUUGGACGGAGGGUCUGGACCUCAGCUCC ACCACCCCAGCGACCUUUCCGUGUCUGUGAUCACAAGCGGACCAUCCG GAAAGGCCUGACAGCUGCCACCCGCCAGGAGCUGCUAGCCAAAGCAUU GGAGACCCUACUGCUGAAUGGAGUGCUAACCCUGGUGCUAGAGGAGGA UGGAACUGCAGUGGACAGUGAGGACUUCUUCCAGCUGCUGGAGGAUGA CACGUGCCUGAUGGUGUUGCAGUCUGGUCAGAGCUGGAGCCCUACAAGGAGUGGAGUGCUGUCAUAUGGCCUGGGACGGGAGAGGCCCAAGCACAGAttorney Docket No. 62801.91W001CAAGGACAUCGCCCGAUUCACCUUUGACGUGUACAAGCAAAACCCUCG AGACCUCUUUGGCAGCCUGAAUGUCAAAGCCACAUUCUACGGGCUCUA CUCUAUGAGUUGUGACUUUCAAGGACUUGGCCCAAAGAAAGUACUCAG GGAGCUCCUUCGUUGGACCUCCACACUGCUGCAAGGCCUGGGCCAUAU GUUGCUGGGAAUUUCCUCCACCCUUCGUCAUGCAGUGGAGGGGGCUGA GCAGUGGCAGCAGAAGGGCCGCCUCCAUUCCUACUAAGGGGCUCUGAG CUUCUGCCCCCAGAAUCAUUCCAACCGACCCACUGCAAAGACUAUGAC AGCAUCAAAUUUCAGGACCUGCAGACAGUACAGGCUAGAUAACCCACC CAAUUUCCCCACUGUCCUCUGAUCCCCUCGUGACAGAACCUUUCAGCA UAACGCCUCACAUCCCAAGUCUAUACCCUUACCUGAAGAAUGCUGUUC UUUCCUAGCCACCUUUCUGGCCUCCCACUUGCCCUGAAAGGCCAAGAU CAAGAUGUCCCCCAGGCAUCUUGAUCCCAGCCUGACUGCUGCUACAUC UAAUCCCCUACCAAUGCCUCCUGUCCCUAAACUCCCCAGCAUACUGAU GACAGCCCUCUCUGACUUUACCUUGAGAUCUGUCUUCAUACCCUUCCC CUCAAACUAACAAAAACAUUUCCAAUAAAAAUAUCAAAUAUUUACCAC UAA UUAGUGGUAAAUAUUUGAUAUUUUUAUUGGAAAUGUUUUUGUUAGUUU GAGGGGAAGGGUAUGAAGACAGAUCUCAAGGUAAAGUCAGAGAGGGCU GUCAUCAGUAUGCUGGGGAGUUUAGGGACAGGAGGCAUUGGUAGGGGA UUAGAUGUAGCAGCAGUCAGGCUGGGAUCAAGAUGCCUGGGGGACAUC UUGAUCUUGGCCUUUCAGGGCAAGUGGGAGGCCAGAAAGGUGGCUAGG AAAGAACAGCAUUCUUCAGGUAAGGGUAUAGACUUGGGAUGUGAGGCG UUAUGCUGAAAGGUUCUGUCACGAGGGGAUCAGAGGACAGUGGGGAAA UUGGGUGGGUUAUCUAGCCUGUACUGUCUGCAGGUCCUGAAAUUUGAU GCUGUCAUAGUCUUUGCAGUGGGUCGGUUGGAAUGAUUCUGGGGGCAG AAGCUCAGAGCCCCUUAGUAGGAAUGGAGGCGGCCCUUCUGCUGCCAC UGCUCAGCCCCCUCCACUGCAUGACGAAGGGUGGAGGAAAUUCCCAGC AACAUAUGGCCCAGGCCUUGCAGCAGUGUGGAGGUCCAACGAAGGAGC UCCCUGAGUACUUUCUUUGGGCCAAGUCCUUGAAAGUCACAACUCAUA GAGUAGAGCCCGUAGAAUGUGGCUUUGACAUUCAGGCUGCCAAAGAGG UCUCGAGGGUUUUGCUUGUACACGUCAAAGGUGAAUCGGGCGAUGUCC UUGCUGUGCUUGGGCCUCUCCCGUCCCAGGCCAUAUGACAGCACUCCAReverse CUCCUUGUAGGGCUCCAGCUCUGACCAGACUGCAACACCAUCAGGCAC Complement of GUGUCAUCCUCCAGCAGCUGGAAGAAGUCCUCACUGUCCACUGCAGUU 2 hCIDEB mRNA CCAUCCUCCUCUAGCACCAGGGUUAGCACUCCAUUCAGCAGUAGGGUC UCCAAUGCUUUGGCUAGCAGCUCCUGGCGGGUGGCAGCUGUCAGGCCU UUCCGGAUGGUCCGCUUGUGAUCACAGACACGGAAAGGUCGCUGGGGU GGUGGAGCUGAGGUCCAGACCCUCCGUCCAAACUCCGAGCUUAUAUUA GAUACUGACCUGAGUAAGUCACUGGGGUUCAGAGCUGAGAGGUACUCC AUGGUGGACCGGAGAGUUCCUUCCCUGGAACUUCUGGGCUGGGUGGUU CUCUCCUGUGCUGGGGCUGCUCUUUCCUUCCUCCUUGGUCGGAGGAGG GGCUGGCUCACUGCUCUGGCUUCAUUUUCCAGAGCUGCCUGCUGCAGU CACACUUAGGUCAUCUUCUCUCACUUUUCUCCUUUUGCCGAUUAGUGG ACGUGACAGAGAUGUGAAUGGGGCAGGGAUGUCCUUUGAUGGCAUCAA GACUUUAGCUUCUGGUGCGCUGUGUCCCAGCUCUGAUUUCAGUUGCAG CCGUGAUGGACAGUUGCAUGGAAGCUGAGACUCUCACUGACAGUGAAA CCCUCAAAUGAACACAAUCCCUGCUUUCCUGCCAAGGAUCCUUGUAGG GUCCCCCAGCUUCCCCACUUUUUUUCUGUGUCCUGUAGGCCCAGAAGG AUGUCGGUCUGCUACCGUCCCCCAGGGAACGAGACACUGCUGAGCUGG AAGACUUCGCGGGCCACAGGCACAGCCUUCCUGCUGCUGGCGGCGCUGCUGGGGCUGCCUGGCAACGGCUUCGUGGUGUGGAGCUUGGCGGGCUGGAttorney Docket No. 62801.91W001CGGCCUGCACGGGGGCGACCGCUGGCGGCCACGCUUGUGCUGCACCUG GCGCUGGCCGACGGCGCGGUGCUGCUGCUCACGCCGCUCUUUGUGGCC UUCCUGACCCGGCAGGCCUGGCCGCUGGGCCAGGCGGGCUGCAAGGCG GUGUACUACGUGUGCGCGCUCAGCAUGUACGCCAGCGUGCUGCUCACC GGCCUGCUCAGCCUGCAGCGCUGCCUCGCAGUCACCCGCCCCUUCCUG GCGCCUCGGCUGCGCAGCCCGGCCCUGGCCCGCCGCCUGCUGCUGGCG GUCUGGCUGGCCGCCCUGUUGCUCGCCGUCCCGGCCGCCGUCUACCGC CACCUGUGGAGGGACCGCGUAUGCCAGCUGUGCCACCCGUCGCCGGUC CACGCCGCCGCCCACCUGAGCCUGGAGACUCUGACCGCUUUCGUGCUU CCUUUCGGGCUGAUGCUCGGCUGCUACAGCGUGACGCUGGCACGGCUG CGGGGCGCCCGCUGGGGCUCCGGGCGGCACGGGGCGCGGGUGGGCCGG CUGGUGAGCGCCAUCGUGCUUGCCUUCGGCUUGCUCUGGGCCCCCUAC CACGCAGUCAACCUUCUGCAGGCGGUCGCAGCGCUGGCUCCACCGGAA GGGhCIDEB Protein MEYLSALNPSDLLRSVSNISSEFGRRVWTSAPPPQRPFRVCDHKRTIR KGLTAATRQELLAKALETLLLNGVLTLVLEEDGTAVDSEDFFQLLEDD TCLMVLQSGQSWSPTRSGVLSYGLGRERPKHSKDIARFTFDVYKQNPR 3 NCBI Ref.: DLFGSLNVKATFYGLYSMSCDFQGLGPKKVLRELLRWTSTLLQGLGHMNP_055245LLGISSTLRHAVEGAEQWQQKGRLHSY

[0181] CIDEB inhibitors can be any agent, including e.g., nucleic acid molecules (e.g., described herein), small molecules, proteins, peptides, carbohydrates, etc. or any combination of the foregoing.

[0182] In specific embodiments, the CIDEB inhibitor is an inhibitory nucleic acid molecule (INAM). INAMs include, but are not limited to, siRNA agents, antisense oligonucleotides, and miRNA agents. INAMs can be single stranded or double stranded. In specific embodiments, the INAM comprises an agent described herein. In specific embodiments, the INAM comprises a dsRNA agent described herein.

[0183] In some embodiments, the INAM comprises one or more RNA molecule. In some embodiments, the INAM comprises one or more single stranded RNA (ssRNA) molecules. In some embodiments, the INAM comprises a dsRNA agent. In some embodiments, the INAM is an antisense oligonucleotide. In some embodiments, the INAM is a miRNA molecule.5.3 CIDEB Targeting INAMs

[0184] In some embodiments, the INAM is an siRNA molecule. In some embodiments, the INAM comprises an antisense strand. In some embodiments, the INAM comprises a sense strand. In some embodiments, the INAM comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the INAM comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, theAttorney Docket No. 62801.91W001INAM comprises a dsRNA INAM comprising a sense strand and an antisense strand that hybridize to form a double stranded region. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., a single nucleic acid molecule comprising a hairpin loop). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules.5.3.1 Antisense Strand5.3.1.1 Targeting Region

[0185] Antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)).

[0186] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). The nucleotide sequence of the region of complementarity may be at least 75% complementary to the nucleotide sequence of the target nucleic acid molecule e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). The nucleotide sequence of the region of complementarity may be at least 85% complementary to theAttorney Docket No. 62801.91W001nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% (e.g., in some embodiments, preferably at least 95%, more preferably at least 98%) complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity is 100% complementary to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)).

[0187] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)). In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1Attorney Docket No. 62801.91W001(e.g., 0) non-complementary nucleotide mismatch relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more) non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 non-complementary nucleotide mismatches relative to the nucleotide sequence of the target nucleic acid molecule, wherein the one or more non-complementary nucleotide mismatches are within the last 3 (e.g., 2 or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. Methods known in the art and described herein can be utilized to evaluate the effect of any non-complementary mismatches between an antisense strand and a target nucleic acid molecule on functional properties (e.g., inhibition of expression of the target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA))).

[0188] In some embodiments, the region of complementarity comprises or consists of from about 15-30 nucleotides, e.g., 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 some embodiments, the region of complementarityAttorney Docket No. 62801.91W001comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 22 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0189] In some embodiments, the target nucleic acid molecule is part (e.g., a contiguous portion) of a larger nucleic acid molecule. For example, in some embodiments, the target nucleic acid molecule is a portion (e.g., a contiguous portion) of a target mRNA (e.g., a CIDEB mRNA). In some embodiments, the target nucleic acid molecule is a contiguous nucleotide sequence of a target mRNA (e.g., a CIDEB mRNA) of sufficient length to allow it to be a substrate for cleavage directed by an RNAi agent (e.g., an RNAi agent described herein, e.g., a dsRNA agent (e.g., described herein)) (i.e., cleavage through a RISC pathway).

[0190] In some embodiments, the target nucleic acid molecule is a target mRNA (e.g., a CIDEB mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a target mRNA (e.g., a CIDEB mRNA). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA (e.g., a CIDEB mRNA) formed in the expression of a target gene (e.g., a mammalian, primate, human, non-human primate, mouse, and / or rat gene) (e.g., a CIDEB gene). In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of a CIDEB (e.g., hCIDEB) mRNA. In some embodiments, the target nucleic acid molecule is at least a portion (e.g., a portion) of an mRNA formed in the expression of a CIDEB (e.g., hCIDEB) gene. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of the nucleotide sequence set forth in SEQAttorney Docket No. 62801.91W001ID NO: 1 (or a variant or fragment thereof). In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA encoding a target protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA encoding a CIDEB (e.g., hCIDEB) protein. In some embodiments, the target nucleic acid molecule comprises at least a portion (e.g., a portion) of an mRNA sequence encoding a protein comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant or fragment thereof).

[0191] In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-30 nucleotides, e.g., 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, 21-22, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22-24, 22-23, 23-30, 23-29, 23-28. 23-27, 23-26, 23-27, 23-26, 23-25. or 23-24 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 19-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-25 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of from about 21-23 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 19, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 19 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 20 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 21 nucleotides. In some embodiments, the target nucleic acid molecule comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.3.1.2 Overall Length

[0192] In some embodiments, the antisense strand comprises or consists of from about 15-30 nucleotides (e.g., 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 some embodiments, the antisense strand comprises or consists of from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22. 19-Attorney Docket No. 62801.91W00121, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the antisense strand comprises or consists of from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25, 22-23, 22-24, 22-25, 23-24, 23-25, 24-25 nucleotides). In some embodiments, the antisense strand comprises or consists of from about 15-30, 16-30, 17-30, 18-30, 19-30 20-30. 21-30. 22-30. 23-30. 24-30. 25-30. 36-30. 27-30. 28-30-, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0193] In some embodiments, the antisense strand comprises or consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the antisense strand comprises or consists of about 21 nucleotides. In some embodiments, the antisense strand comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.3.2 Sense Strand5.3.2.1 Antisense Strand Complementarity

[0194] As described above, sense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand. As such, pairs of sense and antisense strands can hybridize to form a double stranded region (e.g., under conditions in which the pairs will be used).

[0195] In some embodiments, the nucleotide sequence of the region of complementarity is at least substantially complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is fully complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0196] In some embodiments, the nucleotide sequence of the region of complementarity is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. For example, the nucleotide sequence of the region of complementarity may be at least 70% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of theAttorney Docket No. 62801.91W001region of complementarity may be at least 75% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 80% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 85% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 90% complementary to the nucleotide sequence of at least a portion of an antisense strand. The nucleotide sequence of the region of complementarity may be at least 95% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity is at least 95%, 96%, 97%, 98%, 99%, or 100% complementary to the nucleotide sequence of at least a portion of an antisense strand.

[0197] In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of one or more non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 5 (e.g., 4, 3, 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 3 (e.g., 2, 1, or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 2 (e.g., 1 or 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises or consists of no more than 1 (e.g., 0) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the nucleotide sequence of the region of complementarity comprises 0 non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand. In some embodiments, the region of complementarity comprises one or more (e.g., 2, 3, or more)Attorney Docket No. 62801.91W001non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non-complementary nucleotide mismatch is within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3'-end of the region of complementarity. In some embodiments, the region of complementarity comprises at least one but not more than 3 (e.g., 1, 2, or 3) non-complementary nucleotide mismatches relative to the nucleotide sequence of the at least a portion of an antisense strand, wherein the one or more non-complementary nucleotide mismatch is within the last 5 (e.g., 4, 3, 2, or 1) nucleotides from either the 5'- and / or 3 '-end of the region of complementarity.

[0198] In some embodiments, the region of complementarity comprises from about 15-30 nucleotides (e.g., 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 some embodiments, the region of complementarity comprises from about 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22- 25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides. In some embodiments, the region of complementarity comprises from about 19-21 (e.g., 19-20) nucleotides. In some embodiments, the region of complementarity comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19, 20, or 21 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 19 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 20 nucleotides. In some embodiments, the region of complementarity comprises or consists of about 21 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.53.2.2 Overall Length

[0199] In some embodiments, the sense strand comprises or consists of from about 15-30 nucleotides (e.g., 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,Attorney Docket No. 62801.91W001or 21-22 nucleotides). In some embodiments, the sense strand comprises or consists of from about 18-25 nucleotides (e.g., 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 nucleotides). In some embodiments, the sense strand comprises or consists of from about 19-25 nucleotide (e.g., 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 20-21, 20-22, 20-23, 20-24, 20-25, 21-22, 21-23, 21-24, 21-25. 22-23. 22-24. 22-25. 23-24. 23-25, 24-25 nucleotides). In some embodiments, the sense strand comprises or consists of from about 15-30, 16-30, 17-30, 18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

[0200] In some embodiments, the sense strand comprises or consists of not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25. 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the sense strand comprises or consists of about 19, 20, 21, 22, 23 nucleotides. In some embodiments, the sense strand comprises or consists of about 19, 20, 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 20 nucleotides, hi some embodiments, the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 21 nucleotides. In some embodiments, the sense strand comprises or consists of about 23 nucleotides. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.3.3 dsRNA Agents

[0201] In some embodiments, the INAM (e.g., RNAi agent) comprises a dsRNA agent comprising an antisense strand (e.g., described herein) and a sense strand (e.g., described herein) that hybridize to form a double stranded region (e.g., under conditions in which the dsRNA will be used (e.g., under physiological (e.g., mammalian, e.g., human) conditions within a cell)).

[0202] As described above, antisense strands (e.g., described herein) comprise a region of complementarity that comprises a nucleotide sequence that is at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of a target nucleic acid molecule (e.g., a target mRNA (e.g., a CIDEB mRNA), a portion of a target mRNA (e.g., a CIDEB mRNA)); and the sense strands comprise a region of complementarity that comprises a nucleotide sequence that isAttorney Docket No. 62801.91W001at least partially (e.g., substantially, fully) complementary to the nucleotide sequence of at least a portion of an antisense strand.5.3.3.1 Single & Multiple Nucleic Acid Molecules

[0203] As described herein, and known in the art, the sense strand and the antisense strand can be part of a single larger nucleic acid molecule (connected as a single stranded nucleic acid molecule) or separate nucleic acid molecules (only connected through the double stranded region). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules. In some embodiments, sense strand and the antisense strand are part of a single larger nucleic acid molecule.

[0204] In embodiments wherein the sense and antisense strands are part of a single nucleic acid molecule, the nucleic acid molecule may comprise a hairpin loop between the antisense strand and the sense strand to allow for formation of the double stranded region. In some embodiments, the hairpin loop comprises at least 1 (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 23, 25 or more) unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises at least one but less than 25, 23. 20. 10, 9, 8, 7, 6. 5, 4, 3, or 2 unpaired nucleotides (non-complementary nucleotide mismatches). In some embodiments, the hairpin loop comprises about 25. 23, 20, 9, 8, 7, 6, 5, 4. 3, or 1 unpaired nucleotide (non-complementary nucleotide mismatch).

[0205] Without wishing to be bound by theory, in embodiments wherein the sense strand and the antisense strand are part of a single nucleic acid molecule, after introduction into a suitable cell (e.g., a mammalian cell, e.g., a human cell), the nucleic acid molecule may be cleaved into a dsRNA molecule wherein the two strands of the dsRNA molecule are no longer part of the same nucleic acid molecule e.g., by a Type III endonuclease (e.g., Dicer) (see, e.g., Sharp et al. (2001) Genes Dev. 15:485, the entire contents of which are incorporated by herein by reference for all purposes).5.3.3.2 Length of Double Stranded Region

[0206] In some embodiments, the double stranded region is about 15-30 base pairs in length (e.g., 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 baseAttorney Docket No. 62801.91W001pairs in length). In some embodiments, the double stranded region is about 18-25 base pairs in length (e.g., 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21-25, 21-24, 21-23. 21-22. 22- 25, 22-24. 22-23, 23-25, 23-24 or 24-25 base pairs in length (e.g., 19-21 base pairs in length)). In some embodiments, the double stranded region is about 15-30, 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, 15-16, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. In some embodiments, the double stranded region is about 19-21 (e.g., 19-20) base pairs in length.

[0207] In some embodiments, the double stranded region is not more than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. or 30 base pairs in length. In some embodiments, the double stranded region is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 base pairs in length. In some embodiments, the double stranded region is about 19, 20, or 21 base pairs in length. In some embodiments, the double stranded region is about 19 base pairs in length. In some embodiments, the double stranded region is about 20 base pairs in length. In some embodiments, the double stranded region is about 21 base pairs in length. In some embodiments, the double stranded region is about 23 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.5.3.3.3 Nucleotide Overhangs & Blunt Ends

[0208] In some embodiments, the dsRNA agent comprises one or more (e.g., 1 or 2) nucleotide overhang. As is clear from the disclosure, but for the sake of clarity, the nucleotides of a nucleotide overhang can include one or more a modified (e.g., chemically modified) nucleotide (e.g., described herein, e.g., described in §§ 5.5, 5.5.1).

[0209] In some embodiments, the nucleotide overhang comprises from about 1-5 nucleotides (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, 4-5 nucleotides). In some embodiments, the nucleotide overhang comprises or consists of about 1, 2, 3, 4, or 5 nucleotides. In some embodiments, the nucleotide overhang comprises or consists of about 1 nucleotide. In some embodiments, the nucleotide overhang comprises or consists of about 2 nucleotides.

[0210] The nucleotide overhang(s) can be on the sense strand, the antisense strand, or both the sense strand and the antisense strand. In some embodiments, the sense strand comprises a nucleotide overhang. In some embodiments, the antisense strand comprises a nucleotide overhang.Attorney Docket No. 62801.91W001In some embodiments, the sense strand and the antisense strand both comprise a nucleotide overhang.

[0211] Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'- end, or both the 5’-end, 3'- end of an antisense or sense strand. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the sense strand comprises a nucleotide overhang at the 5'-end and the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5’-end and the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 3'-end: and the sense strand comprises a nucleotide overhang at the 3'-end. In some embodiments, the antisense strand comprises a nucleotide overhang at the 5'-end; and the sense strand comprises a nucleotide overhang at the 5'-end.

[0212] In some embodiments, the dsRNA agent comprises one or more blunt end. In some embodiments, the dsRNA agent comprises a blunt end at the end of the agent comprising the 3'end of the sense strand and the 5' end of the antisense strand. In some embodiments, the dsRNA agent comprises a blunt end at the end of the agent comprising the 5 'end of the sense strand and the 3' end of the antisense strand. In some embodiments, both ends of the dsRNA agent are blunt ends.5.3.3.4 Exemplary Structural Combinations of Sense & Antisense Strands

[0213] In some embodiments, the antisense strand and the sense strand contain the same number of nucleotides. In some embodiments, the antisense strand and the sense strand contain different numbers of nucleotides. In some embodiments, the nucleotide sequence of the sense strand is from about 1-5, 1-3, or 1-2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the sense strand is about 2 nucleotides shorter than the nucleotide sequence of the antisense strand. In some embodiments, the nucleotide sequence of the antisense strand is from about 1-5, 1-3, or 1-2 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 1, 2, 3, 4, or 5 nucleotides shorter than the nucleotide sequence of the sense strand. In some embodiments, the nucleotide sequence of the antisense strand is about 2 nucleotides shorter thanAttorney Docket No. 62801.91W001the nucleotide sequence of the sense strand.

[0214] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the double stranded region comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0215] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0216] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 21 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the sense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 21 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'end; and the sense strand comprises a 2-nucleotide overhang at the 3'end.Attorney Docket No. 62801.91W001

[0217] In some embodiments, the sense strand comprises or consists of 20 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 20 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 20 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5' end. In some embodiments, the 5' end of the antisense strand and 3' end of the sense strand form a blunt end. In some embodiments, the sense strand comprises or consists of 20 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consists of 20 nucleotides; the sense strand comprises a 1-nucleotide overhang at the 5 'end; and the 5' end of the antisense strand and 3' end of the sense strand form a blunt end.

[0218] In some embodiments, the sense strand comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 21 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises a 1-nucleotide overhang at the 5 'end. In some embodiments, the sense strand comprises or consists of 21 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the sense strand comprises a 1-nucleotide overhang at the 3 'end; and the sense strand comprises a 1-nucleotide overhang at the 5' end.

[0219] In some embodiments, the sense strand comprises or consists of 24 nucleotides. In some embodiments, the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the sense strand comprises or consists of 24 nucleotides; and the antisense strand comprises or consists of 23 nucleotides. In some embodiments, the double stranded region comprises or consists of 21 nucleotides. In some embodiments, the antisense strand comprises a 2-nucleotide overhang at the 3'end. In some embodiments, the sense strand comprises a 3-nucleotide overhang at the 3 'end. In some embodiments, the sense strand comprises or consists of 24 nucleotides; the antisense strand comprises or consists of 23 nucleotides; the double stranded region comprises or consists of 21 nucleotides; the antisense strand comprises a 2-nucleotide overhang at the 3'end; and the sense strand comprises a 3-nucleotide overhang at the 3' end.

[0220] In some embodiments, the sense strand comprises or consists of 19 nucleotides. In someAttorney Docket No. 62801.91W001embodiments, the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the sense strand comprises or consists of 19 nucleotides; and the antisense strand comprises or consists of 19 nucleotides. In some embodiments, the double stranded region comprises or consists of 19 nucleotides. In some embodiments, the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end. In some embodiments, the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end. In some embodiments, the sense strand comprises or consists of 19 nucleotides; the antisense strand comprises or consists of 19 nucleotides; the double stranded region comprises or consists of 19 nucleotides; the 5' end of the antisense strand (and 3' end of the sense strand) form a blunt end; and the 3' end of the antisense strand (and 5' end of the sense strand) form a blunt end.

[0221] In some embodiments, the antisense strand and the sense strand are part of the same larger nucleic acid molecule, wherein the nucleic acid molecule comprises or consists of 44 nucleotides, the antisense portion comprises or consists of 21 nucleotides, the sense strand portion of the nucleic acid molecule comprises 19 nucleotides, the double stranded region comprises or consists of 19 nucleotides, the antisense strand comprises a 2-nucleotide overhang at the 3 'end, and the intervening nucleotide sequence between the antisense strand and the sense strand comprises or consists of 4 unpaired nucleotides that create a hairpin loop.5.3.3.5 Exemplary Antisense Strands & Sense Strands

[0222] In some embodiments, the antisense strand is an antisense strand described herein. In some embodiments, the sense strand is a sense strand described herein. In some embodiments, the antisense strand is an antisense strand described in § 5.3.1. In some embodiments, the sense strand is a sense strand described in § 5.3.2. In some embodiments, the antisense strand is an antisense strand described in § 5.3.1; and the sense strand is a sense strand described in § 5.3.2. It is to be understood that any sense strand described herein (e.g., in § 5.3.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 5.3.1). For the sake of clarity, the entire contents of in § 5.3.1 and § 5.3.2, are incorporated by reference into the instant section in § 5.3.3.5.5.4 Exemplary CIDEB Targeting INAMs (e.g., RNAi Agents)

[0223] Provided herein are, inter alia, novel agents (e.g., INAMs. RNAi agents, dsRNA agents), useful in, inter alia, inhibiting expression of cell death inducing DFFA like effector BAttorney Docket No. 62801.91W001(CIDEB) (e.g., human CTDEB (hCIDEB)) (e.g., within a cell, e.g., within a cell in a subject, e.g., a mammalian subject, e.g., a human subject) (e.g., through the degradation of CIDEB (e.g., hCIDEB) mRNA).

[0224] In some embodiments, the agent (e.g., INAM, RNAi agent, dsRNA agent) comprises one or more RNA molecule. In some embodiments, the agent (e.g., INAM, RNAi agent, dsRNA agent) comprises an antisense strand. In some embodiments, the agent (e.g., INAM, RNAi agent, dsRNA agent) comprises a sense strand. In some embodiments, the agent comprises one or more single stranded RNA (ssRNA) molecules. In some embodiments, the agent (e.g., INAM, RNAi agent, dsRNA agent) comprises a dsRNA agent.

[0225] In some embodiments, the agent (e.g., INAM, RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand. In some embodiments, the agent (e.g., INAM, RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand that form a double stranded region. In some embodiments, the agent (e.g., INAM, RNAi agent) comprises a dsRNA agent comprising a sense strand and an antisense strand that hybridize to form a double stranded region. In some embodiments, the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., a single nucleic acid molecule comprising a hairpin loop). In some embodiments, the sense strand and the antisense strand are separate nucleic acid molecules.

[0226] Exemplary attributes of the antisense strands are set forth above in § 5.3.1.

[0227] Exemplary attributes of the sense strands are set forth above in § 5.3.2.

[0228] Exemplary attributes of the RNAi agents are set forth above in § 5.3.3.5.4.1 Exemplary Antisense Strands

[0229] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand differs by noAttorney Docket No. 62801.91W001more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0230] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 5 (e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in Table 2 or Table 3.

[0231] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotideAttorney Docket No. 62801.91W001sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0232] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0233] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.

[0234] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27. 28. 29, 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22. 23. 24, 25. 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2. or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3.

[0235] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18. 18-23, 18-22, 18-21, 18-20, 18-19, 19-23. 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3)Attorney Docket No. 62801.91W001nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3.

[0236] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or 3. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3.

[0237] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.

[0238] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strandAttorney Docket No. 62801.91W001differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0239] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318. 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0240] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%. 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand isAttorney Docket No. 62801.91W001at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0241] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0242] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.

[0243] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26. 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.Attorney Docket No. 62801.91W001

[0244] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18. 18-23, 18-22, 18-21, 18-20, 18-19, 19-23. 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the antisense strand comprises from about 19-23 {e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the antisense strand comprises from about 21-23 {e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0245] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0246] As described above. Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 {e.g., 15, 16, 17, 18. 19. 20, 21, 22, 23, 24, 25. 26. 27, 28, 29, 30 {e.g., 19, 20, 21. 22. 23 {e.g., 23))) contiguous nucleotides differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 and further comprising additional nucleotide sequences {e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous {e.g., either at the 3' end, the 5' end, or both the 3’ and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.

[0247] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotideAttorney Docket No. 62801.91W001sequence of the antisense strand differs by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 {e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 {e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202.

[0248] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the antisense strand of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the antisense strand of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 2 {e.g., 0, 1, or 2) nucleotides from the antisense strand of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 1 {e.g., 0 or 1) nucleotide from the antisense strand of any one of dsRNA agents 1-202.

[0249] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%. 89%. 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%. 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand isAttorney Docket No. 62801.91W001at least 97%, identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202.

[0250] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202.

[0251] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. As such, the disclosure further provides antisense strands wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.

[0252] In some embodiments, the antisense strand comprises at least 15 (e.g., 15. 16. 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.91W001nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28. 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0253] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0254] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or 3. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0255] As described above. Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the antisense strands. The disclosure further provides antisense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3 and further comprising additional nucleotide sequences (e.g., comprising fromAttorney Docket No. 62801.91W001about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1 -3, or 1 -2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select antisense strand.5.4.2 Exemplary Sense Strands

[0256] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3.

[0257] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 5 (e.g., 0, 1.2, 3. 4, or 5) nucleotides from the sense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the sense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in Table 2 or Table 3.

[0258] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%. 94%,Attorney Docket No. 62801.91W00195%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%. 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3.

[0259] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3.

[0260] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1. 2, 3. 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6. 1-5, 1-4, 1-3. or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select sense strand.

[0261] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the sense strand comprisesAttorney Docket No. 62801.91W001at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0262] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0263] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0264] Table 2 and 3 further identifies the target nucleic acid molecule within the reference CIDEB mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3 and further comprising additional nucleotideAttorney Docket No. 62801.91W001sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript identical to the select sense strand.

[0265] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0266] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96. or 321-323.

[0267] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%,Attorney Docket No. 62801.91W00195%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%. 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96. or 321-323.

[0268] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0269] Table 2 and 3 further identifies the target nucleic acid molecule within the cited reference CIDEB mRNA transcript (SEQ ID NO: 1) targeted by each of the sense strands. As such, the disclosure further provides sense strands wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1. 2, 3. 4, or 5 (e.g., no more than 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6. 1-5, 1-4, 1-3. or 1-2 nucleotides) at least partially complementary to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript targeted by the select sense strand.

[0270] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the sense strandAttorney Docket No. 62801.91W001comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0271] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0272] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0273] As described above, Table 2 and 3 further identifies the target nucleic acid molecule within the reference CIDEB mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15. 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguousAttorney Docket No. 62801.91W001nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9. 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript identical to the select sense strand.

[0274] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27. 28, 29. 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25. 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202.

[0275] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18. 18-23, 18-22, 18-21, 18-20, 18-19, 19-23. 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202.Attorney Docket No. 62801.91W001

[0276] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202.

[0277] As described above. Table 2 or Table 2 and 3 further identifies the target nucleic acid molecule within the reference CIDEB mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3' and 5' end) of the CIDEB mRNA transcript identical to the select sense strand.

[0278] In some embodiments, the sense strand comprises at least 15 (e.g., 15, 16, 17, 18. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the sense strand comprises at least 21 (e.g., 22, 23, 24, 25. 26. 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the sense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0279] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-Attorney Docket No. 62801.91W00121, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22. 19-21. 19-20. 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0280] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3.

[0281] As described above. Table 2 and 3 further identifies the target nucleic acid molecule within the reference CIDEB mRNA transcript at least partially identical to each of the sense strands. As such, disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22. 23. 24, 25, 26, 27, 28. 29. 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous (e.g., either at the 3' end, the 5' end, or both the 3’ and 5' end) of the CIDEB mRNA transcript identical to the select sense strand.

[0282] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-Attorney Docket No. 62801.91W0011291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952. 1922-1982, 1932-1972, 1937-1967. 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270. 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922- 1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291. 1241-1261, 1246-1276, 1251-1271. 1235-1295, 1245-1265, 1250-1280. 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923- 1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1.

[0283] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805. 1782-1800, 1912-1972, 1922-1942. 1927-1957, 1932-1952, 1922-1982. 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23. 20- 22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277. 1242-1272, 1247-1267, 1231-1291, 1241-1261. 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820,Attorney Docket No. 62801.91W0011772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291. 1241-1261. 1246-1276, 1251-1271, 1235-1295. 1245-1265. 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972. 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1.

[0284] As described above, Table 2 and 3 further identifies the target nucleic acid molecule within the reference CIDEB mRNA transcript at least partially identical to each of the sense strands. As such, the disclosure further provides sense strands comprising at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923- 1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1 and further comprising additional nucleotide sequences (e.g., comprising from about 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 nucleotides) at least partially identical to the region contiguous e.g., either at the 3' end, the 5' end. or both the 3' and 5' end) of the CIDEB mRNA transcript identical to the select sense strand.5.4.3 Exemplary Antisense Strands & Sense Strands

[0285] In some embodiments, the antisense strand is an antisense strand described herein. In some embodiments, the sense strand is a sense strand described herein. In some embodiments, the antisense strand is an antisense strand described in § 5.4.1. In some embodiments, the sense strand is a sense strand described in § 5.4.2. In some embodiments, the antisense strand is an antisense strand described in § 5.4.1; and the sense strand is a sense strand described in § 5.4.2. It is to be understood that any sense strand described herein (e.g., in § 5.4.2); and be utilized in combination with any antisense strand in a dsRNA agent described herein (e.g., in § 5.4.1). For the sake ofAttorney Docket No. 62801.91W001clarity, the entire contents of in § 5.4. land § 5.4.2, are incorporated by reference into the instant section in § 5.4.3.

[0286] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0. 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0287] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 5 (e.g., 0. 1, 2, 3, 4, or 5) nucleotides from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotidesAttorney Docket No. 62801.91W001from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 2 (e.g., 0. 1, or 2) nucleotides from the sense strand set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3 differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand set forth in Table 2 or Table 3.

[0288] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%. 89%, 90%, 91%, 92%. 93%, 94%, 95%, 96%. 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In someAttorney Docket No. 62801.91W001embodiments, the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 97%. identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3: and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0289] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence of any one of the sense strands set forth in Table 2 or Table 3; and the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3.

[0290] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19. 20, 21, 22, 23, 24, 25, 26, 27, 28. 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23. 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more thanAttorney Docket No. 62801.91W0013 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26. 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0291] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20. 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18. 18-23. 18-22, 18-21, 18-20, 18-19, 19-23. 19-22. 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23. 20-22. 20-21. 21-23. 21-22. 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.91W001nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0292] In some embodiments, the antisense strand comprises or consists of about 15. 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the senseAttorney Docket No. 62801.91W001strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21. 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28. 29. 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26. 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3: and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0293] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3Attorney Docket No. 62801.91W001differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or 3; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in Table 2 or 3.

[0294] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in Table 2 or 3; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3.

[0295] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the senseAttorney Docket No. 62801.91W001strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises at least 21 e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3.

[0296] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19. 15-18, 15-17, 15-16, 16-22, 16-20, 16-19. 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 orAttorney Docket No. 62801.91W0013. Tn some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3.

[0297] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3)Attorney Docket No. 62801.91W001nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3.

[0298] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in Table 2 or 3; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding sense strand set forth in Table 2 or 3.

[0299] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in Table 2 or 3; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3.

[0300] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one ofAttorney Docket No. 62801.91W001SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 5 (e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0301] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1,Attorney Docket No. 62801.91W0012, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 2 {e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand differs by no more than 2 {e.g., 0, 1. or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 1 {e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand differs by no more than 1 {e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0302] In some embodiments, the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 95%, 96%, 97%. 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 96%,Attorney Docket No. 62801.91W00197%, 98%, 99% or 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 97%. identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308. 4-96, or 321-323; and the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0303] In some embodiments, the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324. In some embodiments, the nucleotide sequence of the sense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323; and the nucleotide sequence of the antisense strand consists of the nucleotide sequence set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

[0304] In some embodiments, the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. hi some embodiments, the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In someAttorney Docket No. 62801.91W001embodiments, the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0305] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of anyAttorney Docket No. 62801.91W001one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0306] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18. 18-23, 18-22, 18-21, 18-20, 18-19, 19-23. 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3Attorney Docket No. 62801.91W001(e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0307] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. 28. 29. or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1,2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists ofAttorney Docket No. 62801.91W001about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists of about 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318. 97-141, 143-192, or 324; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0308] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises or consists of the nucleotideAttorney Docket No. 62801.91W001sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0309] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of any one of the sense strands set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0310] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20. 21, 22, 23, 24, 25, 26, 27, 28. 29, 30 (e.g., 19, 20. 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26. 27. 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises atAttorney Docket No. 62801.91W001least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28. 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96. or 321-323).

[0311] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21. 17-20, 17-19, 17-18, 18-23, 18-22, 18-21. 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308. 4-96. or 321-323). In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22. 20-21. 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1,2, or 3) nucleotides from the nucleotide sequence of the correspondingAttorney Docket No. 62801.91W001sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 19-23 e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96. or 321-323).

[0312] In some embodiments, the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25. 26, 27, 28, 29, or 30 (e.g., 19, 20. 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 15, 16, 17, 18. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96. or 321-323). In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguousAttorney Docket No. 62801.91W001nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308. 4-96, or 321-323). In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28. 29. 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises or consists of about 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323). In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the correspondingAttorney Docket No. 62801.91W001sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323).

[0313] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324 differing by no more than 3 e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323) differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

[0314] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of any one of any one of the antisense strands set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the corresponding sense strand (e.g., as set forth in one of SEQ ID NOS: 299-308. 4-96, or 321-323).

[0315] In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 2 (e.g., 0, 1, or 2) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand differs by no more than 2 (e.g., 0, 1. or 2) nucleotides from the nucleotide sequence the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand differs by no more than 1 (e.g., 0 or 1) nucleotide from the nucleotide sequenceAttorney Docket No. 62801.91W001of the sense strand of the corresponding (the same) dsRNA agent.

[0316] In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the antisense strand of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding (the same) dsRNA agent differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 2 (e.g., 0, 1, or 2) nucleotides from the antisense strand of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strands of the corresponding (the same) dsRNA agent differing by no more than 2 (e.g., 0. 1, or 2) nucleotides from the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 differing by no more than 1 (e.g., 0 or 1) nucleotide from the antisense strand of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of any one of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 1 (e.g., 0 or 1) nucleotide from the sense strand of the corresponding (the same) dsRNA agent.

[0317] In some embodiments, the nucleotide sequence of the antisense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of theAttorney Docket No. 62801.91W001sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 96%, 97%, 98%, 99% or 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 97%, identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 97%, identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 98% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 98% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is at least 99% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is at least 99% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand is 100% identical to the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand is 100% identical to the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0318] In some embodiments, the nucleotide sequence of the antisense strand comprises theAttorney Docket No. 62801.91W001nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the nucleotide sequence of the antisense strand consists of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0319] In some embodiments, the antisense strand comprises at least 15 (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises at least 15 e.g., 15, 16, 17, 18, 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. 30 (e.g., 19. 20. 21. 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 19 (e.g., 20, 21, 22. 23. 24. 25. 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises at least 19 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 21 (e.g., 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises at least 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.91W001nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises at least 23 (e.g., 24, 25, 26, 27, 28, 29, 30 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises at least 21 e.g., 22, 23, 24, 25. 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21))) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0320] In some embodiments, the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22. 16-20. 16-19, 16-18, 16-17, 17-23, 17-22. 17-21. 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23. 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides fromAttorney Docket No. 62801.91W001the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0321] In some embodiments, the antisense strand comprises or consists of about 15, 16. 17, 18, 19, 20, 21. 22. 23. 24. 25, 26, 27, 28, 29, or 30 (e.g., 19. 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28. 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21, 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23, 24,Attorney Docket No. 62801.91W00125, 26, 27, 28, 29, 30 (e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of about 21, 22, 23, 24, 25. 26. 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent. In some embodiments, the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202; and the sense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0322] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence of the antisense strand of any one of dsRNA agents 1-202 differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the antisense strand set forth in any one of the dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the sense strand set forth in the corresponding (the same) dsRNA agent.

[0323] In some embodiments, the nucleotide sequence of the antisense strand comprises or consists of the nucleotide sequence the antisense strand of any one of dsRNA agents 1-202; and the nucleotide sequence of the sense strand comprises or consists of the nucleotide sequence of the sense strand of the corresponding (the same) dsRNA agent.

[0324] In some embodiments, the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265. 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280,Attorney Docket No. 62801.91W0011255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962. 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 19 (e.g., 20, 21) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982. 1932-1972, 1937- 1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises at least 19 (e.g., 20, 21, 22, or 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411. 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises at least 21 (e.g., 22 or 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285. 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938- 1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises at least 21 (e.g., 22 or 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from theAttorney Docket No. 62801.91W001corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises at least 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270. 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810. 1757-1805. 1782-1800, 1912-1972, 1922-1942. 1927-1957. 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises at least 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0325] In some embodiments, the sense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises from about 15-23 (e.g., 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-22, 16-20, 16-19, 16-18, 16-17, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-23, 18-22, 18-21, 18-20, 18-19, 19-23, 19-22, 19-21, 19-20, 20-23, 20-22. 20-21. 21-23. 21-22. 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982. 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and theAttorney Docket No. 62801.91W001antisense strand comprises from about 19-23 (e.g., 19-22, 19-21, 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285. 1235-1275. 1240-1270, 1245-1265, 1227-1287. 1237-1277. 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411. 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises from about 19-23 (e.g., 19-22, 19-21. 19-20, 20-23, 20-22, 20-21, 21-23, 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises from about 21-23 (e.g., 21-22, 22-23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

[0326] In some embodiments, the sense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (e.g., 19, 20, 21, 22, 23Attorney Docket No. 62801.91W001(e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25. 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277. 1242-1272, 1247-1267, 1231-1291. 1241-1261, 1246-1276, 1251-1271. 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 19, 20, 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1.2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 23)) contiguous nucleotides differing by no more than 3 (e.g., 0. 1, 2, or 3) nucleotides from nucleotides 1225-1285. 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of at about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by noAttorney Docket No. 62801.91W001more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 23, 24, 25, 26, 27, 28. 29, 30 e.g., 23) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295. 1245-1265, 1250-1280, 1255-1275. 1353-1411, 1363-1381, 1368-1396. 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 (e.g., 21, 22, 23 (e.g., 21)) contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 23 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275. 1240-1270, 1245-1265, 1227-1287. 1237-1277, 1242-1272, 1247-1267. 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2. In some embodiments, the sense strand comprises or consists of about 21 contiguous nucleotides differing by no more than 3 (e.g., 0, 1. 2, or 3) nucleotides from nucleotides 1225-1285, 1235-1275. 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276, 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391. 1762-1820, 1772-1810, 1757-1805. 1782-1800, 1912-1972, 1922-1942. 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968, or 1943-1963 of SEQ ID NO: 1; and the antisense strand comprises or consists of about 19 contiguous nucleotides differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the corresponding complementary nucleotide sequence of SEQ ID NO: 2.5.4.4 Exemplary dsRNA AgentsAttorney Docket No. 62801.91W001

[0327] For reference, set forth in Table 2 are the nucleotide sequences of parental unmodified dsRNA agents of the exemplary modified dsRNA agents set forth in Table 2 or 3.Table 2. Unmodified Sense and Antisense Strand Sequences of CIDEB dsRNA Agents. dsRNA Sense Range in Antisense Range in SEQ SEQ mRNA Targ SEQ Age NM_014 NM_014 etnt Sequence SequenceID ID NO ID NO Sequence ID NO 5 to 3 430.4 5 to 3 430.4CAGUAUC UCGAGCUUA GUCAGUAUCU UAAUAUA 1245- UAUUAGAUA 1243- AAUAUAAGCU 193 299 309 1931265 1265 AGCUCGA CUGAC CGGGUAUCUA CAGUAUCUAA UUCCGAGCU1247- 1245- UAUAUUAGA AUAUAAG UAUAAGCUCG 194 194 300 3101267 1267 CUCGGAA UACUG GAGAUCUAAUAUA CUAAUAU UAAACUCCG1251- 1249- AAGCUCG AGCUUAUAU AGCUCGGAGU 195 301 311 195 1271 1271 GAGUUUA UAGAU UUGUAAUAUA UCUAAUAUAA UCAAACUCC1252- 1250- AGCUCGG GAGCUUAUA GCUCGGAGUU 302 312 196 196 1272 1272 AGUUUGA UUAGA UGGUAUAAGC UGUCCAAAC AAUAUAAGCU1255- 1253- UCGGAGU UCCGAGCUU CGGAGUUUGG 197 303 313 197 1275 1275 UUGGACA AUAUU ACGUCAGGAC UGUACUGUC UUUCAGGACC1932- 1930- CUGCAGA UGCAGGUCC UGCAGACAGU 198 304 314 198 1952 1952 CAGUACA UGAAA ACACAGACAG UUAUCUAGC UGCAGACAGU1942- 1940- ACAGGCUAGA UACAGGC CUGUACUGU 199 199 305 315 1962 1962 UAGAUAA CUGCA UAAGCAGACAGUA AGACAGU UUUAUCUAG1941- 1943- ACAGGCU CCUGUACUG CAGGC UAGAU 200 306 316 200 1963 1963 AGAUAAA UCUGC AACGCUGCUA UAAUGCUUU GAGCUGCUAG1373- 1373- GCCAAAG GGCUAGCAG CCAAAGCAUU 201 307 317 201 1391 1393 CAUUA cue GGGAAUUU UAAGGGUGG UGGGAAUUUC1782- 1782- CCUCCAC AGGAAAUUC CUCCACCCUU 202 202 308 318 1802 1800 CCUUA CUU C

[0328] The nucleotide sequence of exemplary modified versions of the dsRNA agents set forth in Table 2 are set forth in Table 2 or 3. More specifically, Table 3 sets forth the nucleotide sequence of exemplary sense strands, antisense strands, and dsRNA agent pairs of sense and antisense strands. It is to be understood that while the sense and antisense strands are set forth in pairs in Table 2 or 3, the disclosure encompasses dsRNA agents comprising any sense strand and any antisense set forth in Table 2 or 3 (e.g., that are at least partially complementary (e.g., as could be determined by a person of ordinary skill in the art)). It is to be understood that while the nucleotide sequence of the sense strands and antisense strands in Table 2 or 3 are set forth as modified (i.e., contain at least one modified nucleotide), the disclosure encompasses the sense and antisense senseAttorney Docket No. 62801.91W001strands set forth in Table 2 or 3 comprising other nucleotide modifications (e.g., as described herein) or that are unmodified.Table 3. Modified Sense and Antisense Strand Sequences of CIDEB dsRNA Agents.dsRNA Range RangeSense SEQ SEQ mRNA SEQ in Antisense Sequence inAgent Sequence ID ID Target ID ID NM_01 5 to 3 NM_015 to 3 NO NO Sequence NO 4430.4 4430.4csasgua usCf sgagCf uUf Af uau GUCAGUAU uCf uAf A 1245- uAf gAf uacugsasc 1243- CUAAUAUA 1 f Uf auaa 321 9712 AGCUCGG 193 65 1265gcucgagsusauc usUf sccgAf gCf Uf uau CAGUAUCU uAf aUf A aUf uAf gauacsusg AAUAUAAG 1247- 1245- 322 2 194 98 f Uf aagc CUCGGAG 1267 1267ucggaaAUCUAAUA csusaau usAf saacUf cCf Gf ageaUf aAf G uUf aUf auuagsasu UAAGCUCG 1249- 1251- 3 323 99 195 f Cf ucgg GAGUUUG 1271 1271aguuuausasaua usCf saaaCf uCf Cf gag UCUAAUAU uAf aGf C cUf uAf uauuasgsa AAGCUCGG 1252- 1250- 4 4 142 100 f Uf cgga AGUUUGG 1272 1272guuugausasuaa usGf succAf aAf Cf ucc AAUAUAAG gCfuCfG gAf gCf uuauasusu CUCGGAGU 1255- 1253- 5 5 101 197 f Gf aguu UUGGACG 1275 1275uggacaUUUCAGGA uscsagg usGf suacUf gUf Cf ugcCCUGCAGA aCf cUf G aGf gUf ccugasasa 1932- 1930- 102 6 6 198 CAGUACA f Cf agac 1952 1952aguacaUGCAGACA csasgac usUf saucUf aGf Cf cugaGf uAf C uAf cUf gucugscsa GUACAGGC 1942- 1940- 7 7 103 199 UAGAUAA f Af ggcu 1962 1962agauaaasgsaca usUf suauCf uAf Gf ecu GCAGACAG gUf aCf A gUf aCf ugucusgsc UACAGGCU 1943- 1941- 104 8 8 200 f Gf gcua AGAUAAC 1963 1963gauaaacsasgua (vinu) sCfsgagCfuua GUCAGUAU uCf uAf A CUAAUAUA uauuAf gAf uacugsasc1245- 1243- f Uf auaa AGCUCGG 9 9 105 193 1265 1265 Gf Cf ucgagsusauc (vinu) sUfsccgAfgcu CAGUAUCU uAf aUf A uauaUfuAf gauacsusg AAUAUAAG 1247- 1245- f Uf aagc CUCGGAG 194 10 10 1061267 1267 Uf Cf ggaaAUCUAAUA csusaau (vinu) sAfsaacUfccgaUf aAf G agcuUfaUf auuagsasu UAAGCUCG 1251- 1249- f Cf ucgg GAGUUUG 11 11 107 195 1271 1271 Af Gf uuuaAttorney Docket No. 62801.91W001usasaua (vinu) sCfsaaaCfucc UCUAAUAU uAf aGf C gagcUf uAf uauuasgsa AAGCUCGG f Uf cgga 1252- 12 1250- 12 108 AGUUUGG 196 Gf Uf uug 72 1272ausasuaa (vinu) sGfsuccAfaac AAUAUAAG gCfuCfG uccgAf gCf uuauasusu CUCGGAGU f Gf aguu 1255- 1253- 13 109 UUGGACG 197 Uf Gf gac 1275 1275auscsagg (vinu) sGfsuacUfguc UUUCAGGA aCf cUf G ugcaGf gUf ccugasasa CCUGCAGA f Cf agac 14 1932- 1930- CAGUACA A 1952 110 1952 198 f Gf uacacsasgac (vinu) sUfsaucUfagc UGCAGACA aGfuAfC cuguAf cUf gucugscsa GUACAGGC f Af ggcu 1942- 15 111 1940- UAGAUAA 199 Af Gf aua 1962 1962aasgsaca (vinu) sUfsuauCfuag GCAGACAG gUf aCf A ccugUf aCf ugucusgsc UACAGGCU f Gf gcua 1943- 1941- 16 112 AGAUAAC 200 Gf Af uaa 1963 1963agsusauc (vinu) sUfsccgAfgcu CAGUAUCU uAf aUf A 1247- uauaUf uAf gauacsusg 1245- AAUAUAAG f Uf aagc 17 113 1941267 1267 CUCGGAG ucggaacsusaau (vinu) sAfsaacUfccg AUCUAAUA aUf aAf G 1251- agcuUf aUf auuagsasu 1249- UAAGCUCG f Cf ucgg 18 114 1951271 1271 GAGUUUG aguuuausasuaa (vinu) sGfsuccAfaac AAUAUAAG gCfuCfG 1255- uccgAf gCf uuauasusu 1253- CUCGGAGU f Gf aguu 19 115 191275 1275 UUGGACG 7 uggacauscsagg (vinu) sGfsuacUfguc UUUCAGGA aCf cUf G 1932- ugcaGf gUf ccugasasa 1930- CCUGCAGA f Cf agac 20 116 CAGUACA 1981952 1952aguacacsasgac (vinu) sUfsaucUfagc UGCAGACA aGfuAfC 1942- cuguAf cUf gucugscsa21 1940- GUACAGGC f Af ggcu 1962 117 1962 UAGAUAA 199 agauaaasgsaca (vinu) sUfsuauCfuag GCAGACAG gUf aCf A 1943- ccugUf aCf ugucusgsc 1941- UACAGGCU f Gf gcua 22 118 2001963 1963 AGAUAAC gauaaagsusauc (vinu) sUfsccgAfgcu CAGUAUCU uAf aUf A 1247- uauaUf uagauac sus g 1245- AAUAUAAG f Uf aagc 23 119 1941267 1267 CUCGGAG ucggaacsusaau (vinu) sAfsaacUfccg AUCUAAUA aUf aAf G 24 1251- agcuUf auauuagsasu 1249- 120 UAAGCUCG 195 f Cf ucgg 1271 1271GAGUUUGAttorney Docket No. 62801.91W001aguuuausasaua (vinu) sCfsaaaCfucc UCUAAUAU uAf aGf C 1252- gagcUf uauauuasgsa AAGCUCGG f Uf cgga 25 121 1250- 196 1272 1272 AGUU...

Claims

Attorney Docket No. 62801.91W001CLAIMSWhat is claimed is:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death inducing DNA fragmentation factor alpha like effector (CIDEB) (e.g., human CIDEB (hCIDEB)),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1. 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

2. The dsRNA agent of claim 1, wherein the nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96. or 321-323.

3. The dsRNA agent of claim 1 or 2, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

4. The dsRNA agent of any one of claims 1-3, wherein the nucleotide sequence of the antisense strand comprises the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and the nucleotide sequence of the sense strand comprises the nucleotide sequence of the corresponding sense strand set forth in Table 2 or 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

5. A dsRNA agent for inhibiting expression of CIDEB (e.g., hCIDEB),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, andAttorney Docket No. 62801.91W001wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3: andthe nucleotide sequence of the sense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2 or 3.

6. The dsRNA agent of claim 5, wherein the nucleotide sequence of the antisense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202 set forth in Table 2 or 3; and the nucleotide sequence of the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the sense strand of the corresponding dsRNA agent set forth in Table 2 or 3.

7. A dsRNA agent for inhibiting expression of CIDEB (e.g., hCIDEB),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, andwherein the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4 or 5 (e.g., 3 (e.g., 0, 1, 2, or 3))) nucleotides from nucleotides 1225-1285, 1235-1275, 1240-1270, 1245-1265, 1227-1287, 1237-1277, 1242-1272, 1247-1267, 1231-1291, 1241-1261, 1246-1276. 1251-1271, 1235-1295, 1245-1265, 1250-1280, 1255-1275, 1353-1411, 1363-1381, 1368-1396, 1373-1391, 1762-1820, 1772-1810, 1757-1805, 1782-1800, 1912-1972, 1922-1942, 1927-1957, 1932-1952, 1922-1982, 1932-1972, 1937-1967, 1942-1962, 1923-1983, 1933-1973, 1938-1968. or 1943-1963 of SEQ ID NO: 1;wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., 2 or 3)) nucleotides from the nucleotide sequence of the corresponding complementary nucleotide sequence of SEQ ID NO: 2.

8. The dsRNA agent of claim 7, wherein the nucleotide sequence of the antisense strand differs by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5 (e.g., 3 (e.g., 0, 1, 2, or 3))) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.Attorney Docket No. 62801.91W0019. The dsRNA agent of claim 7 or 8, wherein the sense strand differs by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the sense strands set forth in Table 2 or 3 or set forth in any one of SEQ ID NOS: 299-308, 4-96, or 321-323.

10. A dsRNA agent for inhibiting expression of CIDEB (e.g., hCIDEB),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324.

11. The dsRNA agent of claim 10, wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 (e.g., 0, 1, 2, 3. 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308. 4-96, or 321-323.

12. The dsRNA agent of claim 10 or 11, wherein the nucleotide sequence of the antisense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and wherein the nucleotide sequence of the sense strand comprises at least 15 (e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 (e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

13. The dsRNA agent of any one of claims 10-12, wherein the nucleotide sequence of the antisense strand comprises at least 21 (e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands set forth in Table 2 or Table 3 or set forth in any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324; and wherein the nucleotide sequence of the sense strand comprises at least 18 (e.g., 18, 19, 20, 21) contiguous nucleotides ofAttorney Docket No. 62801.91W001the nucleotide sequence of the corresponding sense strand set forth in Table 2 or Table 3 or the corresponding sense strand set forth in one of SEQ ID NOS: 299-308, 4-96, or 321-323.

14. A dsRNA agent for inhibiting expression of CIDEB {e.g., hCIDEB),wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,wherein the nucleotide sequence of the antisense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 5 {e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-202.

15. The dsRNA agent of claim 14, wherein the nucleotide sequence of the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 5 e.g., 0, 1, 2, 3, 4, or 5) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

16. The dsRNA agent of claim 14 or 15. wherein the nucleotide sequence of the antisense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21, 22, or 23) contiguous nucleotides of and differing by no more than 3 {e.g., 0, 1, 2, or 3) nucleotides from the nucleotide sequence of any one of the antisense strand of any one of dsRNA agents 1-202; and wherein the nucleotide sequence of the sense strand comprises at least 15 {e.g., 16, 17, 18, 19, 20, 21) contiguous nucleotides of and differing by no more than 3 {e.g., 0, 1.2, or 3) nucleotides from the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

17. The dsRNA agent of any one of claims 14-16, wherein the nucleotide sequence of the antisense strand comprises at least 21 {e.g., 21, 22, or 23) contiguous nucleotides of the nucleotide sequence of any one of the antisense strands of any one of dsRNA agents 1-202; and wherein the nucleotide sequence of the sense strand comprises at least 18 {e.g., 18. 19, 20, 21) contiguous nucleotides of the nucleotide sequence of the corresponding sense strand of the dsRNA agent.

18. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified nucleotide and / or the antisense strand comprises at least one modified nucleotide.Attorney Docket No. 62801.91W00119. The dsRNA agent of any one of the preceding claims, wherein at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the nucleotides of the sense strand and / or antisense strand are modified.

20. The dsRNA agent of any one of the preceding claims, wherein all of the nucleotides in the sense strand and / or antisense strand are modified.

21. The dsRNA agent of any one of the preceding claims, wherein all of the nucleotides in the sense strand and the antisense strand are modified.

22. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified sugar (e.g., ribose moiety).

23. The dsRNA agent of any one of the preceding claims, wherein (a) the sense strand comprises at least one 2'-O-methyl and / or the antisense strand comprises at least one 2'-O-methyl and / or (b) the sense strand comprises at least one 2'-deoxy-2'-fluoro and / or the antisense strand comprises at least one 2'-deoxy-2'-fluoro.

24. The dsRNA agent of any one of the preceding claims, wherein (a) the sense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro; and the antisense strand comprises at least one 2'-O-methyl and at least one 2'-deoxy-2'-fluoro.

25. The dsRNA agent of any one of the preceding claims, wherein at least one of the modified nucleotides comprises a modified nucleobase.

26. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one modified internucleoside linkage and / or the antisense strand comprises at least one modified intemucleoside linkage.

27. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one vinyl-phosphonate and / or the antisense strand comprises at least one vinyl-phosphonate.

28. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 5' vinyl-phosphonate.

29. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one vinyl-phosphonate-2'-0-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) and / or the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine) (e.g., wherein the antisense strand comprises at least one vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine).Attorney Docket No. 62801.91W00130. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 5' vinyl-phosphonate-2'-O-methyl (e.g., vinyl-phosphonate-2'-O-methyluridine).

31. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one phosphorothioate and / or the antisense strand comprises at least one phosphorothioate.

32. The dsRNA agent of any one of the preceding claims, wherein the sense strand comprises at least one phosphorothioate and the antisense strand comprises at least one phosphorothioate.

33. The dsRNA agent of any one of the preceding claims, wherein each of the antisense strand and the sense strand are not more than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 nucleotides in length.

34. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-3020-30, 21-30, 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides; and / or the sense strand comprises from about 15-30, 16-30, 17-30, 18-30, 19-30, 20-30. 21-30. 22-30, 23-30, 24-30, 25-30, 36-30, 27-30, 28-30, 29-30, 19-20, 19-21, 19-22, 19-23, 19-24, or 19-25 nucleotides.

35. The dsRNA agent of any one of the preceding claims, wherein antisense strand comprises from about 19-23 nucleotides; and / or the sense strand comprises from about 19-23 nucleotides.

36. The dsRNA agent of any one of the preceding claims, wherein antisense strand comprises or consists of about 23 nucleotides; and / or the sense strand comprises or consists of about 21 nucleotides.

37. The dsRNA agent of any one of the preceding claims, wherein the sense strand and / or the antisense strand comprises a 3' and / or 5' overhang of 1, 2, or 3 nucleotides.

38. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 3' overhang of 1. 2, or 3 nucleotides (e.g., 2 nucleotides).

39. The dsRNA agent of any one of the preceding claims, wherein the antisense strand comprises a 3' overhang of 2 nucleotides.

40. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is from about 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-20, 19-21, 23-30, 23-29, 23-28, 23-27, 23-26. 23-25, 23-24, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25. 21-24.21-23, or 21-22 nucleotide pairs in length.Attorney Docket No. 62801.91W00141. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is from about 19-23 or 19-21 nucleotide pairs in length.

42. The dsRNA agent of any one of the preceding claims, wherein the double stranded region is about 21 nucleotide pairs in length.

43. The dsRNA agent of any one of the preceding claims, wherein the sense strand and the antisense strand are part of a single nucleic acid molecule (e.g., wherein a hairpin loop is between the sense strand and the antisense strand of the single nucleic acid molecule.

44. The dsRNA agent of any one of the preceding claims, wherein the sense strand and the antisense strand are separate nucleic acid molecules {i.e., connected only through the double stranded region).

45. The dsRNA agent of the any one of the preceding claims, wherein:the nucleotide sequence of the antisense strand consists of 23 nucleotides;the nucleotide sequence of the sense strand consists of 21 nucleotides;the double stranded region is 21 nucleotide pairs in length;the antisense strand comprises a 3' overhang of 2 nucleotides;the antisense strand comprises a 5’ vinyl-phosphonate-2’-O-methyl (e.g., vinyl-phosphonate-2'-0-methyluridine), at least one 2'-O-methyl, at least one 2'-deoxy-2'-fluoro and at least one phosphorothioate; andthe sense strand comprises at least one 2'-O-methyl, at least one 2'-deoxy-2'-fluoro and at least one phosphorothioate.

46. A conjugate comprising the dsRNA agent of any one of claims 1-45 and a heterologous moiety.

47. The conjugate of claim 46, wherein the heterologous moiety is a peptide, protein, carbohydrate, lipid, polymer, or small molecule.

48. The conjugate of claim 46 or 47, wherein the heterologous moiety is carbohydrate.

49. The conjugate of any one of claims 46-48, wherein the heterologous moiety comprises one or more GalNac.

50. The conjugate of claim 49, wherein the GalNac is triantennary GalNac.

51. The conjugate of any one of claims 46-50, wherein the heterologous moiety is a targeting moiety.Attorney Docket No. 62801.91W00152. The conjugate of claim 51, wherein the targeting moiety specifically binds to a moiety expressed by hepatocytes (e.g., on the surface of the hepatocytes).

53. The conjugate of any one of claims 50-52, wherein the targeting moiety comprises GalNac.

54. The conjugate of claim 53, wherein the GalNac is triantennary GalNac.

55. The conjugate of any one of claims 50-54, wherein the targeting moiety directs the agent to hepatocytes through specific binding to the asialoglycoprotein receptor (e.g., expressed on the surface of hepatocytes).

56. The conjugate of any one of claims 46-55, wherein the heterologous moiety is attached to the dsRNA agent via a linker.

57. The conjugate of claim 56, wherein the linker comprises triethylene glycol (TEG).

58. The conjugate of claim 57, wherein the heterologous moiety comprises GalNac and the linker is TEG.

59. The conjugate of claim 57 or 58, wherein the heterologous moiety comprises triantennary GalNac and the linker is TEG.

60. The conjugate of any one of claims 56-59, wherein the heterologous moiety and linker comprises Formula XXXIX below:

461. The conjugate of any one of claims 46-60, wherein the heterologous moiety attached to the 3' end of the sense and / or antisense strand and / or the 5' end of the sense and / or antisense strand, and / or at an internal site of the sense and / or antisense strand.

62. The conjugate of any one of claims 46-61, wherein the heterologous moiety attached to the 3' end of the sense strand.

63. The conjugate of any one of claims 46-62, wherein the conjugate is set forth in Table 5.Attorney Docket No. 62801.91W00164. The conjugate of any one of claims 46-63, wherein the nucleotide sequence of the sense strand comprises the nucleotide sequence set forth in any one of SEQ ID NOS: 203-298; and the nucleotide antisense strand comprises the nucleotide sequence set forth in the corresponding antisense strand (any one of SEQ ID NOS: 309-318, 97-141, 143-192, or 324).

65. A vector (e.g., a viral vector, a non-viral vector) encoding the antisense strand, the sense strand, or both the antisense and sense strand of any one of claims 1-45.

66. A carrier comprising the dsRNA agent of any one of claims 1-45, the conjugate of any one of claims 46-64, or the vector of claim 65.

67. The carrier of claim 66, wherein the carrier comprises a nanoparticle, a polymer, a lipid-based delivery system, a dendrimer, a cationic delivery system, or a hydrogel.

68. The carrier of claim 67, wherein the lipid-based delivery system is a lipid nanoparticle (LNP), liposome, lipoplex, nanoliposome, an exosome, or a micelle.

69. A cell (or population of cells) comprising the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, or the carrier of any one of claims 66-68.

70. A pharmaceutical composition comprising the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the earner of any one of claims 66-68, or the cell (or population of cells) of claim 69, and a pharmaceutically acceptable excipient.

71. A kit comprising the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70.

72. A method of delivering a dsRNA, conjugate, vector, carrier, or pharmaceutical composition to a cell, the method comprising introducing into a cell the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68. or the pharmaceutical composition of claim 70, to thereby deliver the dsRNA, conjugate, vector, carrier, or pharmaceutical composition into the cell.

73. The method of claim 72, wherein the cell is in vitro, ex vivo, or in vivo.

74. The method of claim 72 or 73, wherein the cell is in a subject (e.g., a human subject).

75. A method of delivering a dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the earnerAttorney Docket No. 62801.91W001of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70, to thereby deliver the dsRNA, conjugate, vector, carrier, cell, or pharmaceutical composition to the subject.

76. A method of reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in a cell, the method comprising delivering into the cell the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68. or the pharmaceutical composition of claim 70, to thereby reduce or inhibit expression of CIDEB (e.g., hCIDEB) in the cell.

77. A method of reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in a cell in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the earner of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70, to thereby reduce or inhibit expression of CIDEB (e.g., hCIDEB) in the cell in the subject.

78. A method of treating, ameliorating, or preventing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70, to thereby treat, ameliorate, or prevent the CIDEB (e.g., hCIDEB) associated disease in the subject.

79. The method of claim 78, wherein the treating, ameliorating, or preventing of the CIDEB (e.g., hCIDEB) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

80. The method of claim 78 or 79, wherein the CIDEB (e.g., hCIDEB) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

81. The method of claim 78 or 79, wherein the CIDEB (e.g., hCIDEB) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.Attorney Docket No. 62801.91W00182. A method of treating, ameliorate, or preventing a liver disease in a subject, the method comprising administering to the subject the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65. the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70, to thereby treat, ameliorate, or prevent the liver disease in the subject.

83. The method of claim 82, wherein the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

84. The method of claim 82 or 83, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

85. The method of claim 82 or 83, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

86. A method of diagnosing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein,wherein the presence of the one or more somatic mutation indicates that the subject has a CIDEB (e.g., hCIDEB) associated disease.

87. The method of claim 86, wherein the CIDEB (e.g., hCIDEB) associated disease is a liver disease.

88. The method of any one of claims 86-87. wherein the CIDEB (e.g., hCIDEB) associated disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD, MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

89. The method of any one of claims 86-87, wherein the CIDEB (e.g., hCIDEB) associated disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

90. A method of diagnosing a liver disease in a subject, the method comprisingAttorney Docket No. 62801.91W001(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein,wherein the presence of the one or more somatic mutation indicates that the subject has a liver disease.

91. The method of claim 90, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD. MASH, MAFLD, MetALD, SLD, or cryptogenic SLD.

92. The method of claim 90, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

93. The method of any one of claims 86-92, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.

94. The method of any one of claims 86-93, further comprising administering to the subject an inhibitory nucleic acid molecule that inhibits expression of CIDEB if a CIDEB somatic mutation is detected in the DNA, RNA, or protein.

95. The method of claim 94, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70.

96. A method of selecting a subject for administration of an inhibitory nucleic acid molecule that inhibits expression of CIDEB, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein,wherein the subject is selected for administration of the inhibitory nucleic acid molecule if the one or more somatic mutation is present.Attorney Docket No. 62801.91W00197. The method of claim 96, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.

98. The method of any one of claims 96-97, further comprising administering to the subject the inhibitory nucleic acid molecule if the subject is selected.

99. The method of claim 98, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70.

100. A method of treating, ameliorating, or preventing a CIDEB (e.g., hCIDEB) associated disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, and(c) administering to the subject an inhibitory nucleic acid that inhibits expression of CIDEB if the one or more CIDEB somatic mutation is detected in the DNA, RNA, or protein.

101. The method of claim 100. wherein the CIDEB (e.g., hCIDEB) associated disease is a liver disease.

102. The method of any one of claims 100-101, wherein the liver disease is fatty liver disease, steatotic liver disease, liver inflammation, NASH, NAFLD, MASLD. MASH, MAFLD.MetALD, SLD, or cryptogenic SLD.

103. The method of any one of claims 100-101, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

104. The method of any one of claims 100-103, wherein the treating, ameliorating, or preventing of the CIDEB (e.g., hCIDEB) associated disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).Attorney Docket No. 62801.91W001105. A method of treating, ameliorating, or preventing a liver disease in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein, and(c) administering to the subject an inhibitory nucleic acid that inhibits expression of CIDEB if the one or more CIDEB somatic mutation is detected in the DNA, RNA, or protein.

106. The method of claim 105, wherein the liver disease is fatty liver, liver inflammation, NASH, NAFLD, obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, AFLD, cirrhosis, MASLD, MASH, MetALD, SLD, or cryptogenic SLD.

107. The method of claim 105, wherein the liver disease is liver fibrosis, cirrhosis, liver failure, jaundice, AFLD, obesity-induced metabolic syndrome, insulin insensitivity, or type-2 diabetes.

108. The method of any one of claims 105-107, wherein (a) comprises isolating and purifying DNA, or having DNA isolated and purified, from a sample obtained from the subject; and (b) comprises detecting, or having detected, the presence or absence of the one or more somatic CIDEB mutation in the DNA.

109. The method of any one of claims 105-108, wherein the inhibitory nucleic acid molecule comprises the dsRNA of any one of claims 1-45, the conjugate of any one of claims 46-64, the vector of claim 65, the carrier of any one of claims 66-68, the cell (or population of cells) of claim 69, or the pharmaceutical composition of claim 70.

110. The method of any one of claims 105-109, wherein the treating, ameliorating, or preventing of the liver disease is mediated (at least in part) through the by reducing or inhibiting expression of CIDEB (e.g., hCIDEB) in the subject (e.g., a population of cells within the subject).

111. An in vitro method of screening a sample from a subject for one or more somatic CIDEB mutation, the method comprising;(a) isolating and purifying DNA, RNA, or protein from a sample obtained from the subject; andAttorney Docket No. 62801.91W001(b) detecting the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein.

112. The method of any one of claims 86-111, wherein the sample is a blood, tissue, or cell sample.

113. The method of any one of claims 86-112, wherein the sample is biopsy.

114. The method of any one of claims 86-113, wherein the sample is a liver biopsy.

115. The method of any one of claims 86-114, wherein at least one of the one or more somatic mutation is a loss of function mutation.

116. The method of any one of claims 86-115, wherein at least one of the one or more somatic mutation is a gain of function mutation.

117. The method of any one of claims 86- 116, wherein the subject is a human.

118. A dsRNA of any one of claims 1-45, conjugate of any one of claims 46-64, vector of claim 65, carrier of any one of claims 66-68, cell (or population of cells) of claim 69, or pharmaceutical composition of claim 70 for use in a method of treating, ameliorating, or preventing a CIDEB associated disease (e.g., a CIDEB associated disease described herein) in a subject.

119. A dsRNA of any one of claims 1-45, conjugate of any one of claims 46-64, vector of claim 65, carrier of any one of claims 66-68, cell (or population of cells) of claim 69, or pharmaceutical composition of claim 70 for use in a method of treating, ameliorating, or preventing a liver disease (e.g., a liver disease described herein) in a subject.

120. Use of a dsRNA of any one of claims 1-45, conjugate of any one of claims 46-64, vector of claim 65, earner of any one of claims 66-68, cell (or population of cells) of claim 69, or pharmaceutical composition of claim 70 for the manufacture of a medicament for the treatment, amelioration, or prevention of a CIDEB associated disease (e.g., a CIDEB associated disease described herein) in a subject.

121. Use of a dsRNA of any one of claims 1-45, conjugate of any one of claims 46-64, vector of claim 65, earner of any one of claims 66-68, cell (or population of cells) of claim 69, or pharmaceutical composition of claim 70 for the manufacture of a medicament for the treatment, amelioration, or prevention of a liver disease (e.g., a liver disease described herein) in a subject.

122. A method of treating, ameliorating, or preventing a liver disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising:Attorney Docket No. 62801.91W001(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, andadministering a therapy to the subject if the one or more TM6SF2 germline mutation is present.

123. A method of treating, ameliorating, or preventing a CIDEB associated disease in a subject, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, andadministering a therapy to the subject if the one or more TM6SF2 germline mutation is present.

124. A method of treating, ameliorating, or preventing a liver disease in a subject, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein, andadministering a CIDEB inhibitor to the subject if the one or more TM6SF2 germline mutation is present.

125. A method of selecting a subject for administration of a CIDEB inhibitor, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the subject is selected for administration of the CIDEB inhibitor if the one or more TM6SF2 germline mutation is present.Attorney Docket No. 62801.91W001126. The method of claim 125, further comprising administering the CIDEB inhibitor to the subject if the subject is selected.

127. A method of predicting the presence of a disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a disease (e.g., liver disease) characterized by the presence of one or more somatic CIDEB mutation.

128. A method of predicting the presence of a disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates a higher likelihood that the subject has a disease (e.g., liver disease) characterized by the presence of one or more somatic CIDEB mutation (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).

129. A method of predicting the likelihood that a subject will develop a disease characterized by the presence of one or more somatic mutations in CIDEB, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject is more likely to develop a disease characterized by the presence of one or more somatic mutations in CIDEB (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).Attorney Docket No. 62801.91W001130. A method of predicting the likelihood that a subject will develop a CIDEB associated disease, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject is more likely to develop a CIDEB associated disease (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).

131. A method of diagnosing a disease characterized by the presence of one or more somatic CIDEB mutation in a subject, the method comprising:(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a disease characterized by the presence of one or more somatic CIDEB mutation.

132. A method of diagnosing a CIDEB associated disease in a subject, the method comprising (a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject; and(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA. RNA, or protein,wherein the presence of the one or more germline TM6SF2 mutations indicates that the subject has a CIDEB associated disease.

133. An in vitro method of screening a sample from a subject, the method comprising(a) isolating and purifying DNA, RNA, or protein, or having DNA, RNA, or protein isolated and purified, from a sample obtained from the subject;(b) detecting, or having detected, the presence or absence of one or more germline TM6SF2 mutation in the DNA, RNA, or protein; and(c) detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein.Attorney Docket No. 62801.91W001134. The method of any one of claims 122- 133, wherein the germline TN6F2 mutation is a loss of function mutation.

135. The method of any one of claims 122-134, wherein the one or more germline TM6SF2 mutation comprises a single nucleotide polymorphism.

136. The method of any one of claims 122-137, wherein the one or more germline TM6F2 mutation comprises a non-synonymous mutation (e.g., a non-synonymous single nucleotide polymorphism).

137. The method of any one of claims 122-136, wherein the one or more germline TM6SF2 mutation comprises a missense mutation, a nonsense mutation, a truncation, an insertion, or a deletion.

138. The method of any one of claims 122-137, wherein the germline TM6F2 mutation comprises the rs58542926 single nucleotide polymorphism.

139. The method of any one of claims 122-138, wherein the germline TM6F2 mutation comprises the rs58542926 C> T single nucleotide polymorphism.

140. The method of any one of claims 122-139, wherein the germline TM6F2 mutation comprises the rs58542926 OT single nucleotide polymorphism in one or both TM6F2 alleles.

141. The method of any one of claims 122-140, wherein the germline TM6SF2 mutation results in expression of a TNF6F2 protein comprising an E167K amino acid substitution, amino acid numbering relative to the amino acid sequence set forth in SEQ ID NO: 1188.

142. The method of claim 141, wherein the encoded TNF6F2 protein comprising the E167K amino acid substitution exhibits reduced function (e.g., relative to a reference TNF6F2 protein (e.g., the TNF6F2 protein comprising the amino acid sequence set forth in SEQ ID NO: 1188)).

143. The method of any one of claims 122-142, wherein the presence of the one or more germline TM6SF2 mutation indicates that the subject has a disease (e.g., a liver disease) characterized by the presence of one or more somatic CIDEB mutation.

144. The method of any one of claims 122-143, wherein the presence of the one or more germline TM6SF2 mutation indicates that the subject is more likely to develop a disease (e.g., a liver disease) characterized by the presence of one or more somatic CIDEB mutation (e.g., relative to a subject wherein the one or more genetic TM6SF2 mutation was not determined to be present).Attorney Docket No. 62801.91W001145. The method of any one of claims 122- 144, further comprising detecting, or having detected, the presence or absence of one or more somatic CIDEB mutation in the DNA, RNA, or protein.

146. The method of any one of claims 122-145, wherein at least one of the one or more somatic CIDEB mutation is a loss of function mutation.

147. The method of claims 122-146, wherein the one or more somatic CIDEB mutation comprises a single nucleotide polymorphism.

148. The method of claims 122-147, wherein the one or more somatic CIDEB mutation comprises a non-synonymous mutation (e.g., a non-synonymous single nucleotide polymorphism).

149. The method of claims 122-148, wherein the one or more somatic CIDEB mutation comprises a missense mutation, a nonsense mutation, a truncation, an insertion, or a deletion.

150. The method of claims 122-149, wherein the therapy comprises a CIDEB inhibitor.

151. The method of any one of claims 122-150, wherein the CIDEB inhibitor is an inhibitory nucleic acid molecule that inhibits expression of CIDEB.

152. The method of any one of claims 122-151, wherein the inhibitory nucleic acid molecule comprises an siRNA agent, antisense oligonucleotide, or miRNA agent.

153. The method of any one of claims 151-152, wherein the inhibitory nucleic acid molecule comprises an agent described herein.

154. The method of any one of claims 151-153, wherein the inhibitory nucleic acid molecule comprises a dsRNA agent described herein.

155. The method of any one of claims 122-154, wherein the therapy is a standard of care therapy for the treatment, prevention, and / or amelioration of the disease.

156. The method of any one of claims 122-155, wherein the therapy is an anti-diabetic therapy (e.g., described herein), an anti-obesity therapy (e.g., described herein), an anti-hypertension therapy, an anti-dyslipidemia therapy, a therapy to increase HDL (e.g., described herein), a therapy to decrease LDL and / or triglycerides (e.g., described herein), diet, and / or exercise, or any combination of the foregoing.

157. The method of any one of claims 122-156, wherein the therapy is a GLP1 agonist (e.g., described herein (e.g., semaglutide)).Attorney Docket No. 62801.91W001158. The method of any one of claims 122- 157, wherein the therapy is a thyroid hormone receptor beta (NR1A2) agonist (e.g., described herein (e.g., resmetirom)).

159. The method of any one of claims 122-158, wherein the subject is at high risk for a disease, is suspected of having a disease, is predicted to have a disease, has one or more risk factors for a disease, or has been diagnosed with a disease.

160. The method of any one of claims 122-159, wherein the subject is overweight or obese (defined as described herein), is a type-2 diabetic, has hypertension, has a high body mass index (defined as described herein), has dyslipidemia, has low HDL (defined as described herein), has high LDL (defined as described herein), has high triglycerides (defined as described herein), or any combination of the foregoing.

161. The method of any one of claims 122-160, wherein the disease is a liver disease.

162. The method of any one of claims 122-161, wherein the disease is a CIDEB associated disease.

163. The method of any one of claims 122-162, wherein the disease is characterized by the presence of one or more somatic CIDEB mutation.

164. The method of any one of claims 122-163, wherein the disease comprises fatty liver, liver inflammation, liver steatosis, and / or liver fibrosis.

165. The method of any one of claims 122-164, wherein the disease is nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), obesity-induced metabolic syndrome, insulin insensitivity, obesity, type-2 diabetes, alcoholic fatty liver disease (AFLD), cirrhosis, metabolic dysfunction associated steatotic liver disease (MASLD), metabolic-associated steatohepatitis (MASH), metabolic dysfunction associated fatty liver disease (MAFLD), metabolic dysfunction and alcohol associated steatotic liver disease (MetALD), steatotic liver disease (SLD), or cryptogenic SLD.

166. The method of any one of claims 122-165, wherein the disease is fatty liver.

167. The method of any one of claims 122-166, wherein the disease is MASH.

168. The method of any one of claims 122-167, wherein the disease is MAFLD.

169. The method of any one of claims 122-168, wherein the sample is a blood, tissue, or cell sample.

170. The method of any one of claims 122-169, wherein the sample is a biopsy.

171. The method of any one of claims 122-170, wherein the sample is a liver biopsy.

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