Serpina1 sirnas: compositions of matter and methods of treatment

Abstract

The technology described herein relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the Serpinal gene, and methods of using such dsRNA compositions to inhibit expression of Serpinal. In one embodiment, an iRNA for inhibiting expression of a Serpinal gene includes at least two sequences that are complementary to each other. The iRNA includes a sense strand having a first sequence and an antisense strand having a second sequence. The antisense strand includes a nucleotide sequence that is substantially complementary to at least part of an mRNA encoding Serpinal, and the region of complementarity is 30 nucleotides or less, and at least 15 nucleotides in length. Generally, the iRNA is 19 to 24, e.g., 19 to 21 nucleotides in length.

1 - 38 . (canceled) 
     
     
         39 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Serpinal, 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. 
     
     
         40 . The dsRNA of  claim 39 , 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. 
     
     
         41 . The dsRNA of  claim 39 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         42 . The dsRNA of  claim 39 , 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. 
     
     
         43 . The dsRNA of  claim 39 , 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. 
     
     
         44 . The dsRNA of  claim 39 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         45 . The dsRNA of  claim 39 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         46 . The dsRNA of  claim 45 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         47 . The dsRNA of  claim 39 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         48 . The dsRNA of  claim 39 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         49 . The dsRNA of  claim 39 , further comprising a ligand. 
     
     
         50 . The dsRNA of  claim 49 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     
     
         51 . The dsRNA of  claim 39 , wherein the region of complementarity consists of one of the antisense sequences of Tables 3 and 4. 
     
     
         52 . The dsRNA of  claim 39 , 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. 
     
     
         53 . A cell containing the dsRNA of  claim 39 . 
     
     
         54 . A vector encoding at least one strand of a dsRNA of  claim 39 . 
     
     
         55 . A pharmaceutical composition for inhibiting expression of a Serpinal gene comprising the dsRNA of  claim 39  or the vector of  claim 54 . 
     
     
         56 . The pharmaceutical composition of  claim 55 , further comprising a lipid formulation. 
     
     
         57 . The pharmaceutical composition of  claim 56 , wherein the lipid formulation is a SNALP, or XTC formulation. 
     
     
         58 . A method of inhibiting Serpinal 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 Serpinal gene, thereby inhibiting expression of the Serpinal gene in the cell.   
     
     
         59 . The method of  claim 58 , wherein the Serpinal expression is inhibited by at least 30%. 
     
     
         60 . A method of treating a disorder mediated by Serpinal 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. 
     
     
         61 . The method of  claim 60 , wherein the disorder is Alpha 1 anti-trypsin deficiency liver disease. 
     
     
         62 . The method of  claim 60 , wherein the administration of the dsRNA to the subject causes a decrease in cirrohsis, fibrosis, and/or Serpinal protein accumulation in the liver. 
     
     
         63 . The method of  claim 60 , wherein the likelihood of hepatocellular carcinoma occurring in the patient is reduced. 
     
     
         64 . The method of  claim 60 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the patient.