Polynucleotide agents targeting factor xii (hageman factor) (f12) and methods of use thereof

Abstract

The invention relates to polynucleotide agents targeting Factor XII (F12) gene, and methods of using such polynucleotide agents to inhibit expression of Factor XII and to treat subjects having a Factor XII-associated disease, e.g., heredity angioedema (HAE), prekallikrein deficiency, malignant essential hypertension, hypertension, end stage renal disease, or Fletcher Factor Deficiency.

1 . An antisense polynucleotide agent for inhibiting expression of a Factor XII (F12) gene, wherein the agent comprises 4 to 50 contiguous nucleotides, wherein at least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is 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 agent comprises 4 to 50 contiguous nucleotides, wherein at least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of residues 21-74, 87-106, 143-183, 209-239, 254-273, 287-315, 320-350, 352-392, 395-414, 352-414, 430-470, 472-568, 595-680, 595-669, 682-701, 736-899, 793-843, 793-899, 804-899, 901-942, 736-942, 968-987, 990-1097, 990-1042, 1100-1197, 1100-1206, 1210-1252, 1210-1240, 1253-1272, 1298-1406, 1308-1406, 1430-1515, 1430-1482, 1541-1560, 1583-1602, 1683-1714, 1727-1768, 1737-1756, 1781-1976, 1816-1868, 1902-1967, 1891-1957, 1992-2043, and 1992-2033 of SEQ ID NO:1. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The agent of  claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         8 . The agent of  claim 1 , wherein all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         9 . 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: 14 to 20 nucleotides in length: 14 nucleotides in length: or 20 nucleotides in length. 
     
     
         10 .- 16 . (canceled) 
     
     
         17 . 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, a bicyclic sugar moiety, a 5-methylcytosine, and a modified internucleoside linkage. 
     
     
         18 . The agent of  claim 17 , wherein the bicyclic sugar moiety has a (—CRH—)n group forming a bridge between the 2′ oxygen and the 4′ carbon atoms of the sugar ring, wherein n is 1 or 2 and wherein R is H, CH 3  or CH 3 OCH 3 . 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The agent of  claim 17 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         22 . The agent of  claim 1 , wherein the agent is a gapmer comprising a plurality of 2′-deoxynucleotides flanked on each of a 5′ and a 3′ side by a wing segment comprising at least one nucleotide having a modified sugar moiety. 
     
     
         23 . (canceled) 
     
     
         24 . The agent of  claim 22 , wherein the modified sugar moiety is 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. 
     
     
         25 . The agent of  claim 22 , wherein the 5′-wing segment is 1 to 6 nucleotides in length: 2 nucleotides in length: 3 nucleotides in length; 4 nucleotides in length: or 5 nucleotides in length. 
     
     
         26 . The agent of  claim 22 , wherein the 3′-wing segment is 1 to 6 nucleotides in length: 2 nucleotides in length: 3 nucleotides in length: 4 nucleotides in length: or 5 nucleotides in length. 
     
     
         27 . The agent of  claim 22 , wherein the gap segment is 5 to 14 nucleotides in length: or 10 nucleotides in length. 
     
     
         28 .- 42 . (canceled) 
     
     
         43 . The agent of  claim 1 , wherein the agent further comprises a ligand. 
     
     
         44 . The agent of  claim 43 , wherein the antisense polynucleotide agent is conjugated to the ligand at the 3′-terminus. 
     
     
         45 . The agent of  claim 43 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         46 . The agent of  claim 45 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         47 . A pharmaceutical composition for inhibiting expression of a Factor XII gene, comprising the agent of  claim 1 . 
     
     
         48 .- 55 . (canceled) 
     
     
         56 . A method of inhibiting expression of a Factor XII (F12) gene 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 a Factor XII (F12) gene, thereby inhibiting expression of the Factor XII gene in the cell.   
     
     
         57 .- 59 . (canceled) 
     
     
         60 . A method of treating a subject having a disease or disorder that would benefit from reduction in expression of a Factor XII (F12) gene, the method comprising administering to the subject a therapeutically effective amount of the agent of  claim 1 , thereby treating the subject. 
     
     
         61 .- 77 . (canceled)