Claims for Patent: 9,631,193

Summary for Patent: 9,631,193

Title:	Compositions and methods for inhibiting expression of the ALAS1 gene
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.
Inventor(s):	Bettencourt; Brian (Groton, MA), Fitzgerald; Kevin (Brookline, MA), Querbes; William (Cambridge, MA), Yasuda; Makiko (New York, NY), Desnick; Robert J. (New York, NY)
Assignee:	ALNYLAM PHARMACEUTICALS, INC. (Cambridge, MA) ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI (New York, NY)
Application Number:	14/391,392
Patent Claims:	1. A method of treating a disorder related to ALAS1 expression, comprising administering to a subject in need of such treatment a therapeutically effective amount of a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand, each of which are 15-30 nucleotides in length, wherein the antisense strand comprises a region of complementarity to an ALAS1 RNA and comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 1296, and wherein the antisense strand is complementary to at least nucleotides 871-889 of SEQ ID NO: 1. 2. A method of treating a porphyria comprising administering to a subject in need of such treatment a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand each of which are 15-30 nucleotides in length, and wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 1296. 3. The method of claim 2, wherein the subject is at risk for developing, or is diagnosed with, a porphyria. 4. The method of claim 3, wherein the dsRNA is administered before, during or after an acute attack of porphyria, or is administered prophylactically to prevent an acute attack of porphyria. 5. The method of claim 2, wherein the dsRNA is in the form of a GalNAc conjugate. 6. The method of claim 2, wherein the dsRNA is administered at a dose of 0.05-50 mg/kg. 7. The method of claim 2, wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg. 8. The method of claim 2, wherein the method decreases a level of a porphyrin or a porphyrin precursor in the subject. 9. The method of claim 8, wherein the porphyrin precursor is 6-aminolevulinic acid (ALA) or porphopilinogen (PBG). 10. The method of claim 2, wherein the dsRNA has an 10.sub.50 in the range of 0.01-1 nM. 11. The method of claim 2, wherein said method: (i) ameliorates a symptom associated with a porphyria, (ii) inhibits ALAS1 expression in the subject, (iii) decreases a level of a porphyrin precursor or a porphyrin in the subject, (iv) decreases frequency of acute attacks of symptoms associated with a porphyria in the subject, or (v) decreases incidence of acute attacks of symptoms associated with a porphyria in the subject when the subject is exposed to a precipitating factor. 12. The method of claim 2, wherein the dsRNA comprises modifications on the nucleotides and the modifications are selected from the group consisting of LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy, 2'-hydroxyl, and combinations thereof. 13. The method of claim 12, wherein the modifications on the nucleotides are 2'-O-methyl, 2'-fluoro or both. 14. The method of claim 2, wherein the dsRNA comprises a carbohydrate ligand. 15. The method of claim 14, wherein the ligand is attached via a linker. 16. The method of claim 15, wherein the linker is a bivalent or trivalent branched linker. 17. The method of claim 14, wherein the ligand is ##STR00028## 18. The method of claim 15, wherein the ligand and linker are as shown in Formula XXIV: ##STR00029## 19. The method of claim 18, wherein the ligand is attached to the 3' end of the sense strand. 20. The method of claim 2, wherein the porphyria is a hepatic porphyria selected from the group consisting of acute intermittent porphyria (AIP) hereditary coproporphyria (HCP), variegate porphyria (VP), ALA deyhdratase deficiency porphyria (ADP), and hepatoerythropoietic porphyria. 21. The method of claim 2, wherein the dsRNA is administered during a prodrome. 22. The method of claim 2, wherein the subject has an elevated level of ALA, PBG, or both. 23. The method of claim 22, wherein the subject suffers from chronic pain. 24. A method of treating a subject with an elevated level of ALA, PBG, or both ALA and PBG, the method comprising administering to the subject a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand each of which are 15-30 nucleotides in length and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 1296. 25. The method of claim 24, wherein the method is effective to decrease the level of ALA, PBG, or both ALA and PBG. 26. The method of claim 14, wherein the ligand comprises one or more N-acetylgalactosamine (GalNAc) derivatives. 27. The method of claim 2, wherein the dsRNA comprises one or more phosphorothioate linkages. 28. The method of claim 12, wherein the dsRNA comprises at least 20 modified nucleotides. 29. The method of claim 28, wherein the dsRNA comprises nucleotide modifications on the entire length of the sense and antisense strands. 30. The method of claim 2, wherein the dsRNA comprises at least one blunt end. 31. The method of claim 2, wherein the dsRNA comprises a 3' overhang of at least one nucleotide on the antisense strand or the sense strand. 32. The method of claim 31, wherein the 3' overhang is two nucleotides in length. 33. The method of claim 31, wherein the 3' overhang is present on the 3' ends of both the antisense strand and the sense strand. 34. The method of claim 31, wherein the 3' overhang is present on the antisense strand. 35. The method of claim 34, wherein one or more of the nucleotides in the overhang is a nucleoside thiophosphate. 36. The method of claim 2, wherein the region of complementarity is 19 to 24 nucleotides in length. 37. The method of claim 2, wherein the dsRNA comprises a duplex region that is 17-23 nucleotide pairs in length. 38. The method of claim 2, wherein each strand of the dsRNA is 19-24 nucleotides in length. 39. A method of treating a subject having a porphyria, the method comprising administering to the subject a double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand each of which are 19-24 nucleotides in length, wherein (i) the antisense strand comprises at least 15 contiguous nucleotides of SEQ ID NO: 1296, (ii) the sense strand comprises at least 15 contiguous nucleotides of SEQ ID NO:1295, (iii) the dsRNA comprises a ligand attached to the 3' end of the sense strand and having the structure ##STR00030## (iv) the nucleotides of the dsRNA are modified on the entire length of the sense strand and the antisense strand with 2'-O-methyl and 2'-fluoro modifications, and (v) the antisense strand comprises a 3'-overhang of two nucleotides. 40. The method of claim 39, wherein the dsRNA comprises one or more phosphorothioate linkages. 41. The method of claim 39, wherein the ligand is attached via a linker as shown in Formula XXIV: ##STR00031## 42. The method of claim 2, wherein the sense strand comprises at least 15 contiguous nucleotides of SEQ ID NO: 1295. 43. The method of claim 2, wherein the antisense strand is complementary to at least nucleotides 871-889 of SEQ ID NO: 1. 44. The method of claim 24, wherein the antisense strand is complementary to at least nucleotides 871-889 of SEQ ID NO: 1. 45. The method of claim 39, wherein the antisense strand is complementary to at least nucleotides 871-889 of SEQ ID NO: 1.