Compositions and methods for inhibiting expression of the ALAS1 gene
AssigneesAlnylam Pharmaceuticals, Inc., Icahn School of Medicine at Mount Sinai
InventorsBrian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda
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Abstract
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.
Claims78
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an ALAS1 RNA transcript,
- wherein the sense strand comprises the sequence and all of the modifications of csasgaaaGfaGfuGfuCfuCfaucuuaL96 (SEQ ID NO:
- 4160), and wherein the antisense strand comprises the sequence and all of the modifications of usAfsAfGfaUfgAfgAfcAfcUfcUfuUfcUfgsgsu (SEQ ID NO:
- 4161),
- wherein c, a, g, u=2′-OMe ribonucleosides;
- Af, Cf, Gf, Uf=2′F ribonucleosides;
- s=phosphorothioate, and
- wherein
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand comprising SEQ ID NO. 4160 and an antisense strand comprising SEQ ID NO:
- 4161, the antisense strand comprising a region of complementarity to an ALAS1 RNA transcript,
- wherein said dsRNA is in the form of a conjugate having the structure of:
- or a pharmaceutically acceptable salt thereof,
- wherein Af, Cf, Gf, Uf=2′F ribonucleosides;
- Am, Cm, Gm, Um=2′-OMe ribonucleosides;
- =phosphorothioate;
- =phosphodiester, and
- wherein
A pharmaceutical composition for inhibiting expression of an ALAS1 gene, the composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand comprising SEQ ID NO:
- 4160 and an antisense strand comprising SEQ ID NO:
- 4161, the antisense strand comprising a region of complementarity to an ALAS1 RNA transcript, wherein said dsRNA is in the form of a conjugate having the structure of:
- pharmaceutically acceptable salt thereof,
- wherein Af, Cf, Gf, Uf=2′F ribonucleosides;
- Am, Cm, Gm, Um=2′-OMe ribonucleosides;
- =phosphorothioate;
- =phosphodiester, and
- wherein
A method of treating a porphyria, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand comprising SEQ ID NO:
- 4060 and an antisense strand comprising SEQ ID NO:
- 4161, the antisense strand comprising a region of complementarity to an ALAS1 RNA transcript, wherein said dsRNA is in the form of a conjugate having the structure of:
- pharmaceutically acceptable salt thereof,
- wherein Af, Cf, Gf, Uf=2′F ribonucleosides;
- Am, Cm, Gm, Um=2′-OMe ribonucleosides;
- =phosphorothioate;
- =phosphodiester, and
- wherein
- thereby treating the porphyria.
A pharmaceutically acceptable salt of a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to an ALAS1 RNA transcript,
- wherein the sense strand comprises the sequence and all of the modifications of csasgaaaGfaGfuGfuCfuCfaucuuaL96 (SEQ ID NO:
- 4160), and wherein the antisense strand comprises the sequence and all of the modifications of usAfsAfGfaUfgAfgAfcAfcUfcUfuUfcUfgsgsu (SEQ ID NO:
- 4161),
- wherein c, a, g, u=2 ′-OMe ribonucleosides;
- Af, Cf, Gf, Uf=2 ′F ribonucleosides;
- s=phosphorothioate, and
- wherein
Dependencies are inferred from the claim text.