Xanthine dehydrogenase (XDH) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12091666-B2
Application number	US-202217709529-A
Country	US
Kind code	B2
Filing date	Mar 31, 2022
Priority date	Jul 27, 2015
Publication date	Sep 17, 2024
Grant date	Sep 17, 2024

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting a xanthine dehydrogenase (XDH) gene, and methods of using such double stranded RNAi agents to inhibit expression of an XDH gene and methods of treating subjects having an XDH-associated disease.

First claim

We claim:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a xanthine dehydrogenase (XDH) gene,
wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,
wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 3606-3624 of the nucleotide sequence of SEQ ID NO:1 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2,
wherein the dsRNA agent comprises at least one nucleotide comprising a nucleotide modification and
wherein a ligand is conjugated to the sense strand of the dsRNA agent.

2. The dsRNA agent of claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a nucleotide modification.

3. The dsRNA agent of claim 2 , wherein the nucleotide modification is independently selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy-nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino-modified nucleotide modification, a 2′-O-allyl-nucleotide modification, 2′-C-alkyl-nucleotide modification, 2′-hydroxly-nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, and a nucleotide comprising a 5′-phosphate mimic modification.

4. The dsRNA agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.

5. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least 2 nucleotides.

6. The dsRNA agent of claim 1 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

7. The dsRNA agent of claim 6 , wherein the ligand is

8. The dsRNA agent of claim 7 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

9. The dsRNA agent of claim 8 , wherein the X is O.

10. The dsRNA agent of claim 1 , wherein the double stranded region is 17-30 nucleotide pairs in length; 17-23 nucleotide pairs in length; 17-25 nucleotide pairs in length; 23-27 nucleotide pairs in length; 19-21 nucleotide pairs in length; or 21-23 nucleotide pairs in length.

11. The dsRNA agent of claim 1 , wherein each strand is 15-30 nucleotides in length; or 19-30 nucleotides in length.

12. The dsRNA agent of claim 1 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

13. A pharmaceutical composition for inhibiting expression of an XDH gene comprising the dsRNA agent of claim 1 .

14. A method of inhibiting xanthine dehydrogenase (XDH) expression in a cell, the method comprising contacting the cell with the dsRNA agent of claim 1 , thereby inhibiting expression of the XDH gene in the cell.

15. A method of treating a subject having a disease or disorder that would benefit from reduction in XDH expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating said subject.

16. The dsRNA agent of claim 2 , wherein the nucleotide modifications are independently selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and an abasic nucleotide modification.

17. The dsRNA agent of claim 1 , wherein the ligand is conjugated to the 5′ end of the sense strand of the dsRNA agent.

18. The dsRNA agent of claim 12 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

19. The dsRNA agent of claim 18 , wherein the strand is the antisense strand.

20. The dsRNA agent of claim 12 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.

21. The dsRNA agent of claim 20 , wherein said strand is the antisense strand.

22. The dsRNA agent of claim 12 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at both the 5′- and 3′-terminus of one strand.

23. The dsRNA agent of claim 22 , wherein said strand is the antisense strand.

24. The dsRNA agent of claim 1 , wherein the antisense strand comprises at least 16 contiguous nucleotides differing by no more than three nucleotides from the nucleotide sequence of the complement of nucleotides 3606-3624 of SEQ ID NO:1.

25. The dsRNA agent of claim 1 , wherein the sense strand comprises at least 16 contiguous nucleotides from the nucleotide sequence 5′-GCACAGAUAUUGUCAUGGA-3′ (SEQ ID NO: 562) and the antisense strand comprises at least 16 contiguous nucleotides from the nucleotide sequence 5′-UCCAUGACAAUAUCUGUGC-3′ (SEQ ID NO: 876).

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Fitzgerald Kevin
• Hinkle Gregory
• Mooney Timothy Ryan

Classifications

• C12N2310/351

  Conjugate · CPC title

• C12N2310/3125

  Methylphosphonates · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title