Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof

Abstract

The invention relates to polynucleotide agents targeting the Serpinc1 (AT3) gene, and methods of using such polynucleotide agents to inhibit expression of Serpinc1 and to treat subjects having a bleeding disorder, e.g., a hemophilia.

1 . An antisense polynucleotide agent for inhibiting expression of Serpinc1 (AT3), 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 . (canceled) 
     
     
         3 . An antisense polynucleotide agent for inhibiting expression of Serpinc1, wherein the agent comprises at least 8 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences listed in Tables 3 and 4. 
     
     
         4 . The agent of  claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides; or all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         5 . (canceled) 
     
     
         6 . The agent of  claim 1 , which 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. 
     
     
         7 .- 11 . (canceled) 
     
     
         12 . 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′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety; a 5-methylcytosine; or a modified internucleoside linkage. 
     
     
         13 .- 31 . (canceled) 
     
     
         32 . An antisense polynucleotide agent for inhibiting Serpinc1 (AT3), 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.   
     
     
         33 .- 37 . (canceled) 
     
     
         38 . The agent of any one of  claim 1  or  32 , wherein the agent further comprises a ligand. 
     
     
         39 . (canceled) 
     
     
         40 . The agent of  claim 38 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         41 . (canceled) 
     
     
         42 . A pharmaceutical composition for inhibiting expression of a Serpinc1 (AT3) gene comprising the agent of  claim 1  or  32 . 
     
     
         43 .- 50 . (canceled) 
     
     
         51 . A method of inhibiting Serpinc1 (AT3) expression in a cell, the method comprising:
 (a) contacting the cell with the agent of  claim 1  or  32 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain antisense inhibition of a Serpinc1 gene, thereby inhibiting expression of Serpinc1 gene in the cell.   
     
     
         52 - 54 . (canceled) 
     
     
         55 . A method of treating a subject having a disease or disorder that would benefit from reduction in Serpinc1 (AT3) expression, the method comprising administering to the subject a therapeutically effective amount of the agent of  claim 1  or  32 . 
     
     
         56 . A method of preventing at least one symptom in a subject having a disease or disorder that would benefit from reduction in Serpinc1 (AT3) expression, the method comprising administering to the subject a prophylactically effective amount of the agent of  claim 1  or  32 , thereby preventing at least one symptom in the subject having a disorder that would benefit from reduction in Serpinc1 expression. 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 55  or  56 , wherein the disorder is a bleeding disorder. 
     
     
         59 - 74 . (canceled)