Factor XII (Hageman Factor) (F12), KALLIKREIN B, PLASMA (FLETCHER FACTOR) 1 (KLKB1), and Kininogen 1 (KNG1) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1) gene, the Factor XII (Hageman Factor (F12) gene, or the Kininogen 1 (KNG1) gene, and methods of using such RNAi agents to inhibit expression of a KLKB1 gene, an F12 gene, and/or a KNG1 gene, and methods of treating subjects having an hereditary angioedema (HAE) and/or a contact activation pathway-associated disorder.

1 . A double stranded ribonucleic acid (dsRNA) agent selected from the group consisting of
 a) a dsRNA agent for inhibiting expression of Factor XII (Hageman Factor) (F12), wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:9 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:10;   b) a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Factor XII (Hageman Factor) (F12), wherein said dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 9, 10, 19C, 19D, 20, 21, 23, 24, 26, and 27;   c) a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1), wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:1 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2;   d) a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1), wherein said dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 3, 4, 19A, or 19B;   e) a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Kininogen 1 (KNG1), wherein said dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:17 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:18; and   f)_a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a Kininogen 1 (KNG1), wherein said dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 15, 16, 19E or 19F;   wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides.   
     
     
         2 . (canceled) 
     
     
         3 . The dsRNA agent of  claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a modification. 
     
     
         4 . The dsRNA agent of  claim 1 , wherein the at least one modified nucleotide is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxly-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     
     
         5 . The dsRNA agent of  claim 1 , further comprising at least one phosphorothioate internucleotide linkage. 
     
     
         6 . The dsRNA agent of  claim 1 , wherein the region of complementarity is 19 to 30 nucleotides in length; 21 to 23 nucleotides in length; 21 nucleotides in length; 19 nucleotides in length; or at least 17 nucleotides in length. 
     
     
         7 . The dsRNA agent of  claim 1 , wherein each strand is no more than 30 nucleotides in length; each strand is independently 19-30 nucleotides in length; or each strand is independently 19-25 nucleotides in length. 
     
     
         8 . The dsRNA agent of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides. 
     
     
         9 . The dsRNA agent of  claim 31 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent. 
     
     
         10 . The dsRNA agent of  claim 9 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         11 . The dsRNA agent of  claim 10 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The dsRNA agent of  claim 11 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
       
       and, wherein X is O or S. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A pharmaceutical composition for inhibiting expression of a KLKB1 gene, an F12 gene, or a KNG gene, comprising the dsRNA agent of  claim 1 . 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method of inhibiting expression of a KLKB1 gene, an F12 gene, or a KNG gene in a cell, the method comprising:
 (a) contacting the cell with the dsRNA agent of  claim 1 , or a pharmaceutical composition of  claim 15 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the contact activation pathway gene, thereby inhibiting expression of the contact activation pathway gene in the cell.   
     
     
         19 . The method of  claim 18 , wherein said cell is within a subject. 
     
     
         20 . The method of  claim 19 , wherein the subject is a human. 
     
     
         21 . A method of treating a subject having a disease or disorder that would benefit from reduction in expression of a contact activation pathway gene, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of  claim 1 , or a pharmaceutical composition of  claim 15 , thereby treating said subject. 
     
     
         22 .- 30 . (canceled) 
     
     
         31 . The dsRNA agent of  claim 1 , further comprising a ligand.