Compositions and methods for inhibiting expression of mylip/idol gene

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the Mylip/Idol gene, and methods of using such dsRNA compositions to inhibit expression of Mylip/Idol.

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Mylip/Idol, wherein said dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 20 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the corresponding antisense nucleotide sequence of SEQ ID NO: 21. 
     
     
         2 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Mylip/Idol, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a Mylip/Idol transcript which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences listed in Tables 3, 4, 5 and 6. 
     
     
         3 . The dsRNA of  claim 1  or  2 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         4 . The dsRNA of  claim 3 , wherein at least one of said modified nucleotides is chosen from the group consisting 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 3 , wherein said modified nucleotide is chosen from the group consisting 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 2 , wherein the region of complementarity is at least 17 nucleotides in length. 
     
     
         7 . The dsRNA of  claim 2 , 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  or  2 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         10 . The dsRNA of  claim 1  or  2 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         11 . The dsRNA of  claim 1  or  2 , wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides. 
     
     
         12 . The dsRNA of  claim 1  or  2 , further comprising a ligand. 
     
     
         13 . The dsRNA of  claim 12 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     
     
         14 . The dsRNA of  claim 2 , wherein the region of complementarity consists of one of the antisense sequences of Tables 3, 4, 5, or 6. 
     
     
         15 . The dsRNA of  claim 2 , wherein the sense strand consists of SEQ ID NO: 20 and the antisense strand consists of SEQ ID NO: 21. 
     
     
         16 . The dsRNA of  claim 1  or  2 , wherein the dsRNA comprises a sense strand consisting of a sense strand sequence selected from Tables 3, 4, 5 and 6, and an antisense strand consisting of an antisense sequence selected from Tables 3, 4, 5 and 6. 
     
     
         17 . A cell containing the dsRNA of  claim 1  or  2 . 
     
     
         18 . A pharmaceutical composition for inhibiting expression of a Mylip/Idol gene comprising the dsRNA of  claim 1  or  2 . 
     
     
         19 . The pharmaceutical composition of  claim 18 , further comprising a lipid formulation. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the lipid formulation is a SNALP, or XTC formulation 
     
     
         21 . A method of inhibiting Mylip/Idol expression in a cell, the method comprising:
 (a) introducing into the cell the dsRNA of  claim 1  or  2 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a Mylip/Idol gene, thereby inhibiting expression of the Mylip/Idol gene in the cell.   
     
     
         22 . The method of  claim 21 , wherein the Mylip/Idol expression is inhibited by at least 30%. 
     
     
         23 . A method of treating a disorder mediated by Mylip/Idol expression comprising administering to a human in need of such treatment a therapeutically effective amount of the dsRNA of  claim 1  or  2  or a pharmaceutical composition of  claims 18 - 20 . 
     
     
         24 . The method of  claim 23 , wherein the human has a lipid disorder. 
     
     
         25 . The method of  claim 23 , wherein the human has a disorder associated with cholesterol metabolism. 
     
     
         26 . The method of  claim 23 , wherein the human has diabetes or atherosclerosis. 
     
     
         27 . The method of  claim 25 , wherein the administration of the dsRNA to the subject causes a decrease in Low Density Lipoprotein cholesterol (LDLc) in the serum of the subject by at least 10%. 
     
     
         28 . The method of  claim 23 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject. 
     
     
         29 . A vector encoding at least one strand of a dsRNA, wherein said dsRNA comprises a region of complementarity to at least a part of an mRNA encoding Mylip/Idol, wherein said dsRNA is 30 base pairs or less in length, and wherein said dsRNA targets said mRNA for cleavage. 
     
     
         30 . The vector of  claim 29 , wherein the region of complementarity is at least 15 nucleotides in length. 
     
     
         31 . The vector of  claim 29 , wherein the region of complementarity is 19 to 21 nucleotides in length. 
     
     
         32 . A cell comprising the vector of  claim 29 .