Dual Targeting siRNA Agents

Abstract

The invention relates to dual targeting siRNA agents targeting a PCSK9 gene and a second gene, and methods of using dual targeting siRNA agents to inhibit expression of PCSK9 and to treat PCSK9 related disorders, e.g., hyperlipidemia.

1 . A dual targeting siRNA agent comprising a first dsRNA targeting a PCSK9 gene and a second dsRNA targeting a second gene, wherein the first dsRNA and the second dsRNA are linked with a covalent linker. 
     
     
         2 . (canceled) 
     
     
         3 . The dual targeting siRNA agent of  claim 1 , wherein the second gene is selected from the group consisting of XBP-1, PCSK9, PCSK5, ApoC3, SCAP, and MIG12. 
     
     
         4 . (canceled) 
     
     
         5 . The dual targeting siRNA agent of  claim 1 , wherein the first dsRNA comprises at least 15 contiguous nucleotides of an antisense strand of one of Tables 1, 2, or 4-8, or comprises an antisense strand of one of Tables 1, 2, or 4-8, or comprises a sense strand and an antisense strand of one of Tables 1, 2, or 4-8. 
     
     
         6 . The dual targeting siRNA agent of  claim 1 , wherein the first dsRNA comprises AD-9680 or AD-10792. 
     
     
         7 . The dual targeting siRNA agent of  claim 1 , wherein the second dsRNA comprises at least 15 contiguous nucleotides of an antisense strand of one of Tables 3 or 9-13, or comprises an antisense strand of one of Tables 3 or 9-13, or comprises a sense strand and an antisense strand of one of Tables 3 or 9-13. 
     
     
         8 . The dual targeting siRNA agent of  claim 1 , wherein the second dsRNA comprises AD-18038. 
     
     
         9 . The dual targeting siRNA agent of  claim 1 , wherein the first and second dsRNA comprises at least one modified nucleotide. 
     
     
         10 . The dual targeting siRNA agent of  claim 9 , wherein the modified nucleotide 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. 
     
     
         11 . The dual targeting siRNA agent of  claim 9 , wherein the 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, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         12 . The dual targeting siRNA agent of  claim 1 , wherein each strand of each dsRNA is 19-23 bases in length. 
     
     
         13 . The dual targeting siRNA agent of  claim 1 , wherein the first and second dsRNAs are linked with a disulfide linker. 
     
     
         14 . The dual targeting siRNA agent of  claim 1 , wherein the covalent linker links the sense strand of the first dsRNA to the sense strand of the second dsRNA. 
     
     
         15 . The dual targeting siRNA agent of  claim 1 , wherein the covalent linker links the antisense strand of the first dsRNA to the antisense strand of the second dsRNA. 
     
     
         16 . The dual targeting siRNA agent of  claim 1 , further comprising a ligand. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising the dual targeting siRNA agent of  claim 1  and a pharmaceutical carrier. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the pharmaceutical carrier is a lipid formulation. 
     
     
         21 .- 23 . (canceled) 
     
     
         24 . A method of inhibiting expression of the PCSK9 gene and a second gene in a cell, the method comprising (a) introducing into the cell the dual targeting siRNA agent of  claim 1 ; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the PCSK9 gene and the second gene, thereby inhibiting expression of the PCSK9 gene and the second gene in the cell. 
     
     
         25 . A method of treating a disorder mediated by PCSK9 expression or of reducing total serum cholesterol in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition of  claim 19 . 
     
     
         26 .- 30 . (canceled)