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 double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Serpina1, wherein said dsRNA 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 one of the antisense sequences listed in Tables 3 and 4. 
     
     
         2 . The dsRNA of  claim 1 , wherein the sense and antisense strands comprise sequences selected from the group composed of AD-44715.1, AD-44722.1, AD-44734.1, AD-44717.1, AD-44723.1, AD-44735.1, AD-44724.1, AD-44719.1, and AD-44737.1 of Table 3. 
     
     
         3 . The dsRNA of  claim 1 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         4 . The dsRNA of  claim 1 , wherein at least one of said modified nucleotides is chosen from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     
     
         5 . The dsRNA of  claim 1 , wherein said modified nucleotide is chosen from the group of: a 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. 
     
     
         6 . The dsRNA of  claim 1 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         7 . The dsRNA of  claim 1 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         8 . The dsRNA of  claim 7 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         9 . The dsRNA of  claim 1 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         10 . The dsRNA of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         11 . The dsRNA of  claim 1 , further comprising a ligand. 
     
     
         12 . The dsRNA of  claim 11 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     
     
         13 . The dsRNA of  claim 1 , wherein the region of complementarity consists of one of the antisense sequences of Tables 3 and 4. 
     
     
         14 . The dsRNA of  claim 1 , wherein the dsRNA comprises a sense strand consisting of a sense strand sequence selected from Tables 3 and 4, and an antisense strand consisting of an antisense sequence selected from Tables 3 and 4. 
     
     
         15 . A cell containing the dsRNA of  claim 1 . 
     
     
         16 . A vector encoding at least one strand of a dsRNA of  claim 1 . 
     
     
         17 . A pharmaceutical composition for inhibiting expression of a Serpina1 gene comprising the dsRNA of  claim 1 . 
     
     
         18 . The pharmaceutical composition of  claim 17 , further comprising a lipid formulation. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the lipid formulation is a SNALP, or XTC formulation. 
     
     
         20 . A method of inhibiting Serpina1 expression in a cell, the method comprising:
 (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA) comprising 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 one of the antisense sequences listed in Tables 3 and 4; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a Serpina1 gene, thereby inhibiting expression of the Serpina1 gene in the cell.   
     
     
         21 . The method of  claim 20 , wherein the Serpina1 expression is inhibited by at least 30%. 
     
     
         22 . A method of treating a disorder mediated by Serpina1 expression comprising administering to a patient in need of such treatment a therapeutically effective amount of a double-stranded ribonucleic acid (dsRNA) comprising 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 one of the antisense sequences listed in Tables 3 and 4. 
     
     
         23 . The method of  claim 22 , wherein the disorder is Alpha 1 anti-trypsin deficiency liver disease. 
     
     
         24 . The method of  claim 22 , wherein the administration of the dsRNA to the subject causes a decrease in cirrohsis, fibrosis, and/or Serpina1 protein accumulation in the liver. 
     
     
         25 . The method of  claim 22 , wherein the likelihood of hepatocellular carcinoma occurring in the patient is reduced. 
     
     
         26 . The method of  claim 22 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the patient.