BETA-CATENIN (CTNNB1) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsAkin Akinc, Jeffrey Zuber
Life of this patent
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Abstract
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the beta-catenin (CTNNB1) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a CTNNB1 gene and to methods of preventing and treating a CTNNB1-associated disorder, e.g., cancer, e.g., hepatocellular carcinoma.
Claims30
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.
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.
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.
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.
Dependencies are inferred from the claim text.