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 method of treating an Xanthine Dehydrogenase (XDH)-related disease in a subject in need thereof, wherein the XDH-related disease comprises hyperuricemia or gout, comprising:
providing 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; and
administering the subject the RNAi agent, thereby treating the XDH-related disease.
2 . The method 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 method of claim 2 , wherein the inverted abasic residue is coupled to an adjacent nucleoside via a phosphorothioate backbone.
4 . The method of claim 1 , wherein the 5′ end of the sense strand is coupled to a targeting ligand.
5 . The method of claim 4 , wherein the targeting ligand comprises:
6 . The method of claim 4 , wherein the targeting ligand is
7 . The method of claim 1 , wherein the RNAi agent is a pharmaceutically acceptable salt.
8 . The method of claim 7 , wherein the pharmaceutically acceptable salt is a sodium salt.
9 . The method of claim 1 , wherein the RNAi agent is administered intravenously or subcutaneously.
10 . The method of claim 1 , wherein the RNAi agent is administered to the subject in an effective amount that reduces XDH gene expression level, XDH mRNA expression level, XDH protein expression level, or XDH activity level in the subject at least about 30% relative to the expression levels of the subject prior to the administration.
11 . The method of claim 1 , wherein the RNAi agent is administered to the subject in an effective amount that reduces a level of serum uric acid level.
12 . The method of claim 1 , wherein the RNAi agent is administered at a dose of about 0.05 mg/kg to about 10.0 mg/kg of body weight of the subject.
13 . The method of claim 1 , wherein the RNAi agent is administered at an amount from about 50 to about 400 mg.
14 . The method of claim 1 , wherein the RNAi agent is administered in two or more doses.
15 . The method of claim 1 , wherein the subject is a human subject.
16 . A method of inhibiting Xanthine Dehydrogenase (XDH) gene expression, reducing XDH mRNA expression level, or reducing XDH protein expression level in a cell comprising:
contacting an RNAi agent to the cell, thereby inhibiting XDH gene expression, reducing XDH mRNA expression level, or reducing XDH protein expression level in the cell,
wherein the 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 cPrpusUfscCfauaauac UfcUfgAfgagsasg (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.
17 . The method of claim 16 , wherein the XDH gene expression, the XDH mRNA expression level, or the XDH protein expression level are reduced at least about 30% relative to a cell untreated with the RNAi agent.