BETA-CATENIN (CTNNB1) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

1 . A double stranded RNA (dsRNA) agent for inhibiting expression of beta-catenin (CTNNB1) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand differing by no more than 4 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and an antisense strand differing by no more than 4 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf, and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; VP is a vinyl phosphonate; dT is 2′-deoxythimidine-3′-phosphate; dG is 2′-deoxyguanosine-3′-phosphate; and dA is 2′-deoxyadenosine-3′-phosphate.

2 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

3 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand differs by no more than 2 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 2 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

4 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand differs by no more than 1 base from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 1 base from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

5 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand comprises the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

6 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand consists of the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

7 . A double stranded RNA (dsRNA) agent for inhibiting expression of beta-catenin (CTNNB1) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand comprising the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and an antisense strand comprising the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U respectively; s is a phosphorothioate linkage; VP is a vinyl phosphonate; dT is 2′-deoxythimidine-3′-phosphate; dG is 2′-deoxyguanosine-3′-phosphate; and dA is 2′-deoxyadenosine-3′-phosphate.

8 . A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 and a pharmaceutically acceptable carrier.

9 . The pharmaceutical composition of claim 8 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in an unbuffered solution.

10 . The pharmaceutical composition of claim 9 , wherein the unbuffered solution is saline or water.

11 . The pharmaceutical composition of claim 8 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in a buffer solution.

12 . The pharmaceutical composition of claim 11 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.

13 . The pharmaceutical composition of claim 11 , wherein the buffer solution is phosphate buffered saline (PBS).

14 . A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 and a lipid.

15 . The pharmaceutical composition of claim 14 , wherein the lipid is a cationic lipid.

16 . The pharmaceutical composition of claim 15 , wherein the cationic lipid comprises one or more biodegradable groups.

17 . The pharmaceutical composition of claim 16 , wherein the lipid comprises the structure

18 . The pharmaceutical composition of claim 17 , comprising

(a)

(b) cholesterol;

(c) distearoylphosphatidylcholine (DSPC); and

(d) 1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (PEG-DMG).

19 . The pharmaceutical composition of claim 18 , wherein the

DSPC, cholesterol, and PEG-DMG are present in a molar ratio of 50:12:36:2, respectively.

20 . A pharmaceutical composition comprising a dsRNA agent for inhibiting expression of a gene encoding beta-catenin (CTNNB1), or a pharmaceutically acceptable salt thereof,

wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand differing by no more than 4 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and an antisense strand differing by no more than 4 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U respectively; s is a phosphorothioate linkage; VP is a vinyl phosphonate; dT is 2′-deoxythimidine-3′-phosphate; dG is 2′-deoxyguanosine-3′-phosphate; and dA is 2′-deoxyadenosine-3′-phosphate; and

a lipid.

21 . The pharmaceutical composition of claim 20 , wherein the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

22 . The pharmaceutical composition of claim 20 , wherein the sense strand differs by no more than 2 bases from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 2 bases from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

23 . The pharmaceutical composition of claim 20 , wherein the sense strand differs by no more than 1 base from the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand differs by no more than 1 base from the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

24 . The pharmaceutical composition of claim 20 , wherein the sense strand comprises the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20 and the antisense strand comprises the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21.

25 . The pharmaceutical composition of claim 20 , wherein the lipid is a cationic lipid.

26 . The pharmaceutical composition of claim 25 , wherein the cationic lipid comprises one or more biodegradable groups.

27 . The pharmaceutical composition of claim 26 , wherein the lipid comprises the structure

28 . The pharmaceutical composition of claim 27 , comprising

(a)

(b) cholesterol;

(c) distearoylphosphatidylcholine (DSPC); and

(d) 1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (PEG-DMG).

29 . The pharmaceutical composition of claim 28 , wherein the

DSPC, cholesterol, and PEG-DMG are present in a molar ratio of 50:12:36:2 respectively.

30 . A pharmaceutical composition comprising

(a) a dsRNA agent for inhibiting expression of a gene encoding beta-catenin (CTNNB1), or a pharmaceutically acceptable salt thereof,

wherein the dsRNA agent consists of a sense strand consisting of the nucleotide sequence 5′-usascuguugGfAfUfugauucgasasa-3′ of SEQ ID NO: 20) and an antisense strand consisting of the nucleotide sequence 5′-VPudTucdGadAucaadTcCfaacaguasgsc-3′ of SEQ ID NO: 21,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U respectively; s is a phosphorothioate linkage; VP is a vinyl phosphonate; dT is 2′-deoxythimidine-3′-phosphate; dG is 2-deoxyguanosine-3′-phosphate; and dA is 2-deoxyadenosine-3′-phosphate;

(b) a lipid comprising the structure

(c) cholesterol;

(d) distearoylphosphatidylcholine (DSPC); and

(e) 1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (PEG-DMG), wherein the

DSPC, cholesterol, and PEG-DMG are present in a molar ratio of 50:12:36:2 respectively.