RNAi agents for inhibiting expression of xanthine dehydrogenase (XDH), pharmaceutical compositions thereof, and methods of use
The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit xanthine dehydrogenase (XDH) gene expression. Also disclosed are pharmaceutical compositions that include XDH RNAi agents and methods of use thereof. The XDH RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Delivery of the XDH RNAi agents in vivo provides for inhibition of XDH gene expression. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms mediated in part by XDH gene expression, such as gout and hyperuricemia.
1. A pharmaceutical composition for inhibiting expression of an XDH gene, comprising an RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleic acid sequence of cucucucaGfaGfuAfuuauggaa (SEQ ID NO: 1663) and the antisense strand comprises a nucleic acid sequence of cPrpusUfscCfauaauacUfcUfgAfgagsasg (SEQ ID NO: 1146), wherein lower case (n)=2′-O-Me modified nucleotide; Nf=2′-F modified nucleotide; cPrpn=5′-cyclopropyl phosphonate-2′-O-methyl modified nucleotide; and s=phosphorothioate backbone modification.
2. The pharmaceutical composition of claim 1 , wherein the sense strand further comprises an inverted abasic residue at each of the 5′ end and the 3′ end.
3. The pharmaceutical composition of claim 2 , wherein the inverted abasic residue is coupled to an adjacent nucleoside via a phosphorothioate backbone.
4. The pharmaceutical composition of claim 1 , wherein the 5′ end of the sense strand is coupled to a targeting ligand.
5. The pharmaceutical composition of claim 4 , wherein the targeting ligand comprises:
6. The pharmaceutical composition of claim 4 , wherein the targeting ligand is
7. The pharmaceutical composition of claim 1 , wherein the sense strand consists of a nucleic acid sequence of (invAb)scucucucaGfaGfuAfuuauggaas(invAb) (SEQ ID NO: 1680) and the antisense strand consists of a nucleic acid sequence of cPrpusUfscCfauaauacUfcUfgAfgagsasg (SEQ ID NO: 1146), wherein lower case (n)=2′-O-Me modified nucleotide; Nf=2′-F modified nucleotide; cPrpn=5′-cyclopropyl phosphonate-2′-O-methyl; (invAb)=inverted abasic residue; and s=phosphorothioate backbone modification.
8. The pharmaceutical composition of claim 7 , wherein the 5′ end of the sense strand is coupled to a targeting ligand.
9. The pharmaceutical composition of claim 8 , wherein the targeting ligand comprises:
10. The pharmaceutical composition of claim 8 , wherein the targeting ligand is
11. The pharmaceutical composition of claim 7 , wherein the RNAi agent is a pharmaceutically acceptable salt.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable salt is a sodium salt.
13. The pharmaceutical composition of claim 10 , wherein the RNAi agent is a pharmaceutically acceptable salt.
14. The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable salt is a sodium salt.