Claims for Patent: 10,465,195

Summary for Patent: 10,465,195

Title:	Methods and compositions for the specific inhibition of glycolate oxidase (HAO1) by double-stranded RNA
Abstract:	This invention relates to compounds, compositions, and methods useful for reducing Glycolate Oxidase (HAO1) target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.
Inventor(s):	Brown; Bob D. (Littleton, MA), Dudek; Henryk T. (Wellesley, MA)
Assignee:	Dicerna Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	16/297,316
Patent Claims:	1. A double stranded nucleic acid (dsNA), wherein the dsNA comprises: (a) a first nucleic acid strand, wherein: (i) the first nucleic acid strand is 15-27 nucleotides in length; and (ii) the first nucleic acid strand comprises one or more modified nucleotides; and (b) a second nucleic acid strand, wherein: (i) the second nucleic acid strand is 19-27 nucleotides in length; (ii) the second nucleic acid strand comprises one or more modified nucleotides; and (iii) the second nucleic acid strand is complementary to SEQ ID NO: 1823 along at least 19 consecutive nucleotides in length. 2. The dsNA of claim 1, wherein the second nucleic acid strand comprises 1-5 single-stranded nucleotides at its 3' terminus. 3. The dsNA of claim 2, wherein each of the single stranded nucleotides is modified. 4. The dsNA of claim 1, wherein the one or more modified nucleotides of the first nucleic acid strand and the one or more modified nucleotides of the second nucleic acid strand are each selected from the group consisting of: a 2'-O-methyl modified nucleotide and a 2'-fluoro modified nucleotide. 5. The dsNA of claim 2, wherein the second nucleic acid strand comprises two single-stranded nucleotides at its 3' terminus. 6. The dsNA of claim 1, wherein the second nucleic acid strand comprises at least one phosphorothioate linkage. 7. The dsNA of claim 6, wherein the at least one phosphorothioate linkage is located at the final internucleotide linkage of the 3' terminus of the second nucleic acid strand and/or at the final internucleotide linkage of the 5' terminus of the second nucleic acid strand. 8. The dsNA of claim 1, wherein the second nucleic acid strand is complementary to SEQ ID NO: 1823 along 21 consecutive nucleotides in length. 9. The dsNA of claim 1, wherein the second nucleic acid is 21, 22, 23, 24, 25, 26, or 27 nucleotides in length. 10. The dsNA of claim 9, wherein the second nucleic acid strand comprises 23 consecutive nucleotides of a sequence a set forth in SEQ ID NO: 5035. 11. The dsNA of claim 1, wherein starting from the first nucleotide (position 1) at the 3' terminus of the first nucleic acid strand, position 1, 2, and/or 3 is substituted with a modified nucleotide. 12. The dsNA of claim 11, wherein the modified nucleotide is a 2'-O-methyl modified nucleotide. 13. The dsNA of claim 1, wherein the first nucleic acid strand comprises at least one phosphorothioate linkage. 14. The dsNA of claim 13, wherein the at least one phosphorothioate linkage is located at the final internucleotide linkage of the 3' terminus of the first nucleic acid strand and/or at the final internucleotide linkage of the 5' terminus of the first nucleic acid strand. 15. The dsNA of claim 1, wherein the first nucleic acid strand comprises SEQ ID NO: 1823. 16. The dsNA of claim 15, wherein the first nucleic acid strand is 21, 22, 23, 24, 25, 25, 26, or 27 nucleotides in length. 17. The dsNA of claim 1, wherein the 3' terminus of the first nucleic acid strand and the 5' terminus of the second nucleic acid strand form a blunt end. 18. The dsNA of claim 1, comprising a duplex region of 19-21 base pairs. 19. The dsNA of claim 1, wherein at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more of nucleotides of the dsNA are modified. 20. The dsNA of claim 1, wherein each of the modified nucleotides is independently selected from a 2'-O-methyl modified nucleotide, a 2'-methoxyethoxy modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-allyl modified nucleotide, a 2'-O[2-(methylamino)-2-oxoethyl] modified nucleotide, a 2'-amino modified nucleotide, and a 2'-O-(N-methylcarbamate) modified nucleotide. 21. The dsNA of claim 20, wherein each of the modified nucleotides is independently selected from a 2'-O-methyl modified nucleotide and a 2'-fluoro modified nucleotide. 22. The dsNA of claim 21, wherein the 3' terminus of the first nucleic acid is conjugated to a GalNAc moiety. 23. A pharmaceutical composition comprising the dsNA of claim 1 and a pharmaceutically acceptable carrier. 24. A method of inhibiting expression of an HAO1 gene in a mammalian cell, the method comprising contacting the mammalian cell with the dsNA of claim 1 in an amount sufficient to reduce an amount of HAO1 mRNA in the mammalian cell. 25. The method of claim 24, wherein mammalian cell is in a subject. 26. The method of claim 25, wherein the subject is human. 27. The method of claim 26, wherein the subject has primary hyperoxaluria 1 (PH1). 28. The method of claim 27, wherein the method further comprises administering the dsNA via an intravenous, intramuscular, intraperitoneal, or subcutaneous route.