Polynucleotide agents targeting hydroxyacid oxidase (glycolate oxidase, hao1) and methods of use thereof

Abstract

The invention relates to polynucleotide agents targeting an hydroxyacid oxidase (HAO1) gene, and methods of using such polynucleotide agents to inhibit expression of HAO1 and to treat subjects having an HAO1-associated disease, e.g., hyperoxaluria.

1 . A single-stranded antisense polynucleotide agent for inhibiting expression of hydroxyacid oxidase (HAO1),
 wherein the agent comprises about 4 to about 50 contiguous nucleotides,   wherein at least one of the contiguous nucleotides is a modified nucleotide, and   wherein the nucleotide sequence of the agent is about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of SEQ ID NOs:1-4.   
     
     
         2 . The agent of  claim 1 , wherein the equivalent region is any one of the regions of SEQ ID NO:1 targeted by the agents provided in Table 3 or Table 4. 
     
     
         3 . (canceled) 
     
     
         4 . The agent of  claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides; or wherein all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         5 . The agent of  claim 1 , wherein the agent is 10 to 40 nucleotides in length: 10 to 30 nucleotides in length: 18 to 30 nucleotides in length: 10 to 24 nucleotides in length: 18 to 24 nucleotides in length; or 20 nucleotides in length. 
     
     
         6 . The agent of  claim 1 , wherein the modified nucleotide comprises a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 
     
     
         7 . The agent of  claim 1 , wherein the modified nucleotide is a 5-methylcytosine; or a modified internucleoside linkage. 
     
     
         8 - 10 . (canceled) 
     
     
         11 . The agent of  claim 1 , comprising
 a gap segment consisting of linked deoxynucleotides;   a 5′-wing segment consisting of linked nucleotides;   a 3′-wing segment consisting of linked nucleotides;   wherein the gap segment is positioned between the 5′-wing segment and the 3′-wing segment and wherein each nucleotide of each wing segment comprises a modified sugar.   
     
     
         12 . (canceled) 
     
     
         13 . The agent of  claim 1 , wherein the agent further comprises a ligand at the 3′-terminus. 
     
     
         14 . The agent of  claim 13 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         15 . A pharmaceutical composition for inhibiting expression of an hydroxyacid oxidase (HAO1) gene comprising the agent of  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising the agent of  claim 1 , and a lipid formulation. 
     
     
         17 . A method of inhibiting hydroxyacid oxidase (HAO1) expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 1 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain antisense inhibition of an HAO1 gene, thereby inhibiting expression of the HAO1 gene in the cell.   
     
     
         18 . The method of  claim 17 , wherein the cell is within a subject. 
     
     
         19 . The method of  claim 18 , wherein the subject is a human. 
     
     
         20 . A method of preventing at least one symptom or treating a subject having a disease or disorder that would benefit from reduction in hydroxyacid oxidase (HAO1) expression, the method comprising administering to the subject a prophylactically effective amount or a therapeutically effective amount of the agent of  claim 1  or the pharmaceutical composition of  claim 15 , thereby preventing at least one symptom or treating the subject. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 20 , wherein the disorder is an hydroxyacid oxidase (HAO1)-associated disease. 
     
     
         23 . The method of  claim 22 , wherein the HAO1-associated disease is selected from the group consisting of primary hyperoxaluria and secondary hyperoxaluria.