Serpina1 sirnas: compositions of matter and methods of treatment

Abstract

The technology described herein relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the Serpina1 gene, and methods of using such dsRNA compositions to inhibit expression of Serpina1.

What is claimed herein is: 
     
         1 . A Serpina-1 inhibiting double stranded ribonucleic acid (dsRNA) comprising:
 i. a sense strand molecule which is 19-23 nucleotides in length comprising at least 19 contiguous nucleotides of SEQ ID NO:62, said sense strand comprising at least 10 nucleotides comprising a 2′-O-methyl modification;   ii. a separate antisense strand molecule which is 19-23 nucleotides in length comprising at least 19 contiguous nucleotides of SEQ ID NO: 106, said antisense strand comprising at least 3 nucleotides comprising a 2′O-methyl modification; and   iii. at least 19 of the nucleotides in each strand are modified; and   wherein the sense strand and antisense strand are two separate molecules.   
     
     
         2 . The dsRNA of  claim 1 , wherein the nucleotides in said antisense strand are all modified nucleotides. 
     
     
         3 . The dsRNA of  claim 1 , wherein said modified nucleotides comprise a modification selected from the group consisting of: 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         4 . The dsRNA of  claim 1 , wherein said sense strand comprises at least one phosphorothioate linkage. 
     
     
         5 . The dsRNA of  claim 4 , wherein said sense strand comprises three phosphorothioate linkages. 
     
     
         6 . The dsRNA of  claim 1 , wherein said antisense strand comprises at least one phosphorothioate linkage. 
     
     
         7 . The dsRNA of  claim 6 , wherein said antisense strand comprises three phosphorothioate linkages. 
     
     
         8 . The dsRNA of  claim 1 , wherein said dsRNA comprises a ligand. 
     
     
         9 . The dsRNA of  claim 8 , wherein said ligand comprises at least one carbohydrate conjugate. 
     
     
         10 . The dsRNA of  claim 8 , wherein said ligand is attached to the 5′ end of said sense strand. 
     
     
         11 . The dsRNA of  claim 1 , wherein said sense strand comprises at least one inverted nucleotide linkage. 
     
     
         12 . The dsRNA of  claim 11 , wherein said sense strand comprises at least two inverted nucleotide linkages. 
     
     
         13 . The dsRNA of  claim 1 , wherein said sense strand comprises a 2′-O-methyl modified nucleotide at positions 1, 3, 4, 5, 9, 11, 13, 14, 15, and 18 of the 19 contiguous nucleotides of SEQ ID NO 62. 
     
     
         14 . The dsRNA of  claim 1 , wherein said antisense strand comprises a 2′-O-methyl modified nucleotide at position 8 of the 19 contiguous nucleotides of SEQ ID NO:106. 
     
     
         15 . The dsRNA of  claim 1 , wherein all uridine nucleotides of the sense strand comprise a 2′-O-methyl modification. 
     
     
         16 . The dsRNA of  claim 1 , wherein all adenine nucleotides of the sense strand comprise a 2′-O-methyl modification. 
     
     
         17 . The dsRNA of  claim 1 , wherein said antisense strand comprises at least one cytosine nucleotide comprising a 2′-O-methyl modification. 
     
     
         18 . The dsRNA of  claim 17 , wherein said antisense strand comprises a 2′-O-methyl modified cytosine nucleotide at position 8 of said antisense strand. 
     
     
         19 . A Serpina-1 inhibiting double stranded ribonucleic acid (dsRNA) comprising:
 i. a sense strand molecule which is 19-23 nucleotides in length comprising:
 A. at least 19 contiguous nucleotides of SEQ ID NO:62; 
 B. three phosphorothioate linkages; 
 C. a ligand attached to the 5′ end wherein said ligand comprises at least one carbohydrate conjugate; 
 D. at least one inverted base; 
 E. all modified nucleotides; 
 F. at least 10 nucleotides comprising a 2′-O-methyl modification; and 
   ii. a separate antisense strand molecule which is 19-23 nucleotides in length comprising:
 A. at least 19 contiguous nucleotides of SEQ ID NO: 106; 
 B. three phosphorothioate linkages; 
 C. all modified nucleotides; 
 D. at least 3 nucleotides comprising a 2′-O-methyl modification; and 
   wherein the sense strand and antisense strand are two separate molecules.   
     
     
         20 . The dsRNA of  claim 19 , wherein said antisense strand comprises at least one cytosine nucleotide comprising a 2′-O-methyl modification. 
     
     
         21 . The dsRNA of  claim 20 , wherein said antisense strand comprises a 2′-O-methyl modified cytosine nucleotide at position 8 of said antisense strand.