Methods and compositions for treating a proprotein convertase subtilisin kexin (PCSK9) gene-associated disorder
AssigneeAlnylam Pharmaceuticals, Inc.
InventorKevin Fitzgerald
Life of this patent
Estimating the term…
Abstract
The invention relates to methods of inhibiting the expression of a PCSK9 gene in a subject, as well as therapeutic and prophylactic methods for treating subjects having a lipid disorder, such as a hyperlipidemia using RNAi agents, e.g., double-stranded RNAi agents, targeting the PCSK9 gene.
Claims30
A method of inhibiting the expression of a Proprotein convertase subtilisin kexin 9 (PCSK9) gene in a human subject, comprising subcutaneously administering to the subject a fixed dose of 275 mg to 325 mg of a double stranded ribonucleic acid (RNAi) agent, or salt thereof,
- wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-csusagacCfuGfudTuugcuuuugu-3′ (SEQ ID NO:
- 687) and the antisense strand comprises the nucleotide sequence of 5′-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3′ (SEQ ID NO:
- 688),
- wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U;
- Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U;
- dT is 2′-deoxythymidine;
- and s is a phosphorothioate linkage, and
- wherein the double stranded RNAi agent is conjugated to a N-acetylgalactosamine (GalNAc)3 ligand.
A method of treating a human subject having a hyperlipidemia, comprising subcutaneously administering to the subject a fixed dose of 275 mg to 325 mg of a double stranded ribonucleic acid (RNAi) agent, or salt thereof,
- wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-csusagacCfuGfudTuugcuuuugu-3′ (SEQ ID NO:
- 687) and the antisense strand comprises the nucleotide sequence of 5′-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3′ (SEQ ID NO:
- 688),
- wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U;
- Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U;
- dT is 2′-deoxythymidine;
- and s is a phosphorothioate linkage, and
- wherein the double stranded RNAi agent is conjugated to a N-acetylgalactosamine (GalNAc)3 ligand.
A method of decreasing levels of low density lipoprotein (LDLc) in serum of a human subject, comprising subcutaneously administering to the subject a fixed dose of 275 mg to 325 mg of a double stranded ribonucleic acid (RNAi) agent, or salt thereof,
- wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-csusagacCfuGfudTuugcuuuugu-3′ (SEQ ID NO:
- 687) and the antisense strand comprises the nucleotide sequence of 5′-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3′ (SEQ ID NO:
- 688),
- wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U;
- Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U;
- dT is 2′-deoxythymidine;
- and s is a phosphorothioate linkage, and
- wherein the double stranded RNAi agent is conjugated to a N-acetylgalactosamine (GalNAc)3 ligand.
A method of decreasing levels of low density lipoprotein (LDLc) in serum of a human subject having one or more risk factors associated with cardiovascular disease, comprising subcutaneously administering to the subject a fixed dose of 275 mg to 325 mg of a double stranded ribonucleic acid (RNAi) agent, or salt thereof,
- wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-csusagacCfuGfudTuugcuuuugu-3′ (SEQ ID NO:
- 687) and the antisense strand comprises the nucleotide sequence of 5′-asCfsaAfAfAfgCfaAfaAfcAfgGfuCfuagsasa-3′ (SEQ ID NO:
- 688),
- wherein a, g, c and u are 2′-O-methyl (2′-0Me) A, G, C, and U;
- Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U;
- dT is 2′-deoxythymidine;
- and s is a phosphorothioate linkage, and
- wherein the double stranded RNAi agent is conjugated to a N-acetylgalactosamine (GalNAc)3 ligand,
- wherein said one or more risk factors comprise diabetes, previous personal history of coronary heart disease (CHD) or noncoronary atherosclerosis, family history of cardiovascular disease, tobacco use, hypertension and/or obesity.
Dependencies are inferred from the claim text.