Claims for Patent: 10,738,311

Summary for Patent: 10,738,311

Title:	Therapeutic inhibition of lactate dehydrogenase and agents therefor
Abstract:	This invention relates to compounds, compositions, and methods useful for reducing lactact dehydrogenase target RNA and protein levels via use of ds RNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.
Inventor(s):	Bob D. Brown, Henryk T. Dudek, Cheng Lai
Assignee:	Novo Nordisk Health Care AG
Application Number:	US16/355,566
Patent Claims:	1. A method for reducing expression of the lactate dehydrogenase (LDHA) gene in one or more tissues of a subject, comprising administering to the subject an effective amount of a double stranded nucleic acid (dsNA) comprising a sense strand and an antisense strand, wherein the antisense strand is 19-35 nucleotides in length, wherein the antisense strand is complementary to a target lactate dehydrogenase mRNA sequence as set forth in SEQ ID NO: 401 along at least 19 nucleotides of said antisense strand length, and wherein the dsNA comprises one or more modified nucleotides, thereby reducing expression of the LDHA gene in one or more tissues of the subject. 2. The method of claim 1, wherein the subject has a lactate dehydrogenase knockdown treatable disease or disorder, wherein the disease or disorder is chronic kidney disease or pyruvate dehydrogenase complex deficiency. 3. The method of claim 2, wherein the disease or disorder is selected from the group consisting of PH1, PH2, PH3 and idiopathic hyperoxaluria. 4. The method of claim 1, wherein the dsNA is administered in a lipid nanoparticle. 5. The method of claim 1, wherein the one or more tissues comprises liver. 6. The method of claim 1, wherein the sense strand and antisense strand form a duplex such that the antisense strand comprises a two nucleotide overhang at its 3′ end. 7. The method of claim 1, wherein the dsNA comprises a duplex of 19 to 25 base pairs in length. 8. The method of claim 6, wherein the sense strand is 25 to 53 nucleotides in length. 9. The method of claim 6, wherein the sense strand is 36 nucleotides in length and/or wherein the antisense strand is 22 nucleotides in length. 10. The method of claim 1, wherein the sense strand and the antisense strand are each in the range of 21 to 23 nucleotides in length. 11. The method of claim 1, wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. 12. The method of claim 11, wherein the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand form a blunt end. 13. The method of claim 1, wherein the sense strand comprises a tetraloop at its 3′ end. 14. The method of claim 10, wherein the sense strand comprises a tetraloop at its 3′ end. 15. The method of claim 13, wherein the tetraloop comprises a single stranded loop having a sequence of GAAA. 16. The method of claim 1, wherein the dsNA comprises at least one phosphorothioate linkage. 17. The method of claim 15, wherein the dsNA comprises at least one phosphorothioate linkage. 18. The method of claim 1, wherein the one or more modified nucleotides contains a 2′ modification. 19. The method of claim 18, wherein the one or more modified nucleotides are selected from a 2′-O-methyl nucleotide and a 2′-fluoro nucleotide. 20. The method of claim 19, wherein the dsNA comprises at least one 2′-fluoro nucleotide and at least one 2′-O-methyl nucleotide. 21. The method of claim 1, wherein the dsNA is attached to a moiety selected from the group consisting of a GalNAc moiety, a cholesterol moiety, and a cholesterol targeting ligand. 22. The method of claim 19, wherein the dsNA is attached to a GalNAc moiety. 23. The method of claim 22, wherein the dsNA is administered in a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 24. A method for reducing expression of the lactate dehydrogenase (LDHA) gene in one or more tissues of a subject, comprising administering to the subject an effective amount of a nucleic acid comprising an oligonucleotide strand of 19-35 nucleotides in length, wherein said oligonucleotide strand is complementary to a target lactate dehydrogenase mRNA sequence as set forth in SEQ ID NO: 401 along at least 19 nucleotides of said oligonucleotide strand length, and wherein the nucleic acid comprises one or more modified nucleotides, thereby reducing expression of the LDHA gene in one or more tissues of the subject. 25. A method for reducing expression of the lactate dehydrogenase (LDHA) gene in a mammalian cell comprising administering to the mammalian cell an effective amount of a nucleic acid comprising an oligonucleotide strand of 19-35 nucleotides in length, wherein said oligonucleotide strand is complementary to a target lactate dehydrogenase mRNA sequence as set forth in SEQ ID NO: 401 along at least 19 nucleotides of said oligonucleotide strand length, and wherein the nucleic acid comprises one or more modified nucleotides, in an amount sufficient to reduce expression of a target lactate dehydrogenase mRNA in said cell, thereby reducing expression of the LDHA gene in the mammalian cell. 26. The method of claim 24, wherein the nucleic acid is in a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 27. A method of reducing expression of the lactate dehydrogenase gene (LDHA) in one or more tissues of a subject comprising administering to the subject a double stranded nucleic acid (dsNA) comprising a sense strand and an antisense strand, wherein the antisense strand is 19-35 nucleotides in length, wherein the antisense strand is complementary to a target lactate dehydrogenase mRNA sequence as set forth in SEQ ID NO: 401 along at least 19 nucleotides of said antisense strand length, wherein the complementary region of the antisense strand contains between one and four mismatched nucleotide residues relative to SEQ ID NO: 401, and wherein the dsNA comprises one or more modified nucleotides, thereby reducing expression of the LDHA gene in one or more tissues of the subject. 28. The method of claim 27, wherein the complementary region of the antisense strand contains three, two, or one mismatched nucleotide residues relative to SEQ ID NO: 401. 29. The method of claim 27, wherein the sense strand and antisense strand form a duplex such that the antisense strand comprises a two nucleotide overhang at its 3′ end. 30. The method of claim 27, wherein the dsNA comprises a duplex of 19 to 25 base pairs in length. 31. The method of claim 29, wherein the sense strand is 25 to 53 nucleotides in length. 32. The method of claim 29, wherein the sense strand is 36 nucleotides in length and/or wherein the antisense strand is 22 nucleotides in length. 33. The method of claim 27, wherein the sense strand and the antisense strand are each in the range of 21 to 23 nucleotides in length. 34. The method of claim 27, wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. 35. The method of claim 34, wherein the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand form a blunt end. 36. The method of claim 27, wherein the sense strand comprises a tetraloop at its 3′ end. 37. The method of claim 33, wherein the sense strand comprises a tetraloop at its 3′ end. 38. The method of claim 36, wherein the tetraloop comprises a single stranded loop having a sequence of GAAA. 39. The method of claim 3, wherein the disease or disorder is PH1.