Methods and compositions for the specific inhibition of glycolate oxidase (HAO1) by double-stranded RNA

1. A nucleic acid comprising a first strand and a second strand forming a duplex structure, wherein the first strand is 21 nucleotides in length and the second strand is 23 nucleotides in length, wherein the second strand is 100% complementary along at least 15 nucleotides with the sequence as set forth in SEQ ID NO: 1823, wherein the second strand has a 3′ overhang of 2 nucleotides in length.

2. The nucleic acid of claim 1 , wherein the second strand comprises at least two phosphorothioate internucleotide linkages.

3. The nucleic acid of claim 1 , wherein the first strand and/or second strands comprise one or more modified nucleotides.

4. The nucleic acid of claim 3 , wherein each residue of the first strand and/or each residue of the second strand is a modified nucleotide.

5. The nucleic acid of claim 3 , wherein each modified nucleotide is independently a 2′-O-methyl or 2′-fluoro modified nucleotide.

6. The nucleic acid of claim 1 , wherein at least one nucleotide of the first strand is conjugated with one or more GalNac moieties.

7. The nucleic acid of claim 6 , wherein the at least one nucleotide is conjugated to the 3′ terminal nucleotide of the first strand.

8. The nucleic acid of claim 1 , wherein the second strand is a guide strand that complexes with RISC, binds a target mRNA as a component of the RISC complex, and promotes cleavage of a target RNA by RISC.

9. A nucleic acid comprising an oligonucleotide strand of 21-23 nucleotides in length, wherein the oligonucleotide is sufficiently complementary to a target region of HAO1 mRNA having a sequence as set forth in SEQ ID NO: 1823 along at least 15 nucleotides of the oligonucleotide strand length to reduce HAO1 target mRNA expression when the nucleic acid is introduced into a cell expressing the HAO1 mRNA, and wherein the nucleic acid comprises one or more modified nucleotides.

10. A pharmaceutical composition comprising the nucleic acid of claim 1 and a pharmaceutically acceptable carrier.

11. A method for reducing expression of a target HAO1 gene in a cell comprising contacting the cell with a nucleic acid of claim 1 in an amount sufficient to reduce expression of a target HAO1 mRNA in the cell.

12. A method for reducing expression of a target HAO1 mRNA in a subject comprising administering a nucleic acid of claim 1 to a subject in an amount sufficient to reduce expression of a target HAO1 mRNA in the subject.

13. The method of claim 12 , wherein the subject has primary hyperoxaluria 1 (PHI).

14. The method of claim 12 , wherein administration of the nucleic acid to the subject results in a reduction in glycolate oxidase in the subject.

15. The method of claim 12 , wherein administration of the nucleic acid to the subject results in a decrease in an accumulation of calcium oxalate deposits in the subject.

16. The method of claim 12 , wherein administration of the nucleic acid to the subject results in a decrease in an accumulation of calcium precipitates in the kidney in the subject.

17. The method of claim 12 , wherein administration of the nucleic acid to the subject results in an increase in a glycolate/creatinine ratio in urine of the subject.

18. The method of claim 12 , wherein administration of the nucleic acid to the subject is performed at a dose in a range of 0.3 to 10 mg/kg.

19. The method of claim 12 , wherein administration of the nucleic acid to the subject results in a reduction of HAO1 mRNA levels in the subject that are detectable at 29 days post-administration.

20. The method of claim 12 , wherein administration of the nucleic acid to the subject results in at least an 80% reduction of HAO1 mRNA levels.

21. The method of claim 12 , wherein administration of the nucleic acid to the subject is performed subcutaneously.

22. A pharmaceutical composition comprising the nucleic acid of claim 9 , and a pharmaceutically acceptable carrier.

23. A method for reducing expression of a target HAO1 gene in a cell comprising contacting a cell in vitro with a nucleic acid of claim 9 , in an amount sufficient to reduce expression of a target HAO1 mRNA in the cell.

24. A method for reducing expression of a target HAO1 mRNA in a subject comprising administering a nucleic acid of claim 9 , to a subject in an amount sufficient to reduce expression of a target HAO1 mRNA in the subject.

25. The method of claim 24 , wherein the subject has primary hyperoxaluria 1 (PHI).

26. The method of claim 24 , wherein administration of the nucleic acid to the subject is performed at a dose in a range of 0.3 to 10 mg/kg.

27. The method of claim 24 , wherein administration of the nucleic acid to the subject results in a reduction of HAO1 mRNA levels in the subject that are detectable at 29 days post-administration.

28. The method of claim 24 , wherein administration of the nucleic acid to the subject results in at least an 80% reduction of HAO1 mRNA levels.

29. The method of claim 24 , wherein administration of the nucleic acid to the subject is performed subcutaneously.

30. A method for treating a subject having primary hyperoxaluria 1 (PHI), the method comprising: administering to the subject a nucleic acid comprising a first strand and a second strand forming a duplex structure, wherein the first strand is 21 nucleotides in length and the second strand is 23 nucleotides in length, wherein the second strand is 100% complementary with the sequence as set forth in SEQ ID NO: 1823, wherein the second strand has a 3′ overhang of 2 nucleotides in length, wherein a GalNac moiety is conjugated to the 3′ terminal nucleotide of the first strand, and wherein administration of the nucleic acid to the subject results in a reduction of HAO1 mRNA levels in the subject.