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