Targeting Ligands For Therapeutic Compounds

Abstract

Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.

1 . A targeting ligand selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein n is an integer from 1 to 20 and Targeting Moiety is selected from the group consisting of: carbohydrates, glycans, haptens, vitamins, folate, biotin, aptamers, peptides, insulin, EGF and transferrin. 
       
     
     
         2 . The targeting ligand of  claim 1 , wherein the Targeting Moiety is a carbohydrate. 
     
     
         3 . The targeting ligand of  claim 1 , wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound. 
     
     
         4 . The targeting ligand of  claim 3 , wherein the expression-inhibiting oligomeric compound is an RNAi agent. 
     
     
         5 . The targeting ligand of  claim 4 , wherein the RNAi agent is double-stranded. 
     
     
         6 . The targeting ligand of  claim 4 , wherein the RNAi agent comprises one or more modified nucleotides. 
     
     
         7 . The targeting ligand of  claim 4 , wherein the targeting ligand is linked at the 3′ or 5′ terminal end of the RNAi agent. 
     
     
         8 . The targeting ligand of  claim 5 , wherein the double-stranded RNAi agent is linked to the targeting ligand at the 5′ terminal end of the sense strand of the RNAi agent. 
     
     
         9 . The targeting ligand of  claim 4 , wherein the RNAi agent is linked to the targeting ligand via a phosphate group, phosphorothioate group, or a phosphonate group. 
     
     
         10 . The targeting ligand of  claim 1 , wherein the targeting ligand comprises the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is an integer from 1 to 20. 
     
     
         11 . The targeting ligand of  claim 10 , wherein n is 6. 
     
     
         12 . The targeting ligand of  claim 1 , wherein the targeting ligand is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A method of inhibiting expression of a target nucleic acid in a cell, the method comprising administering to the cell an effective amount of an expression-inhibiting oligomeric compound conjugated to the targeting ligand of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the cell is present in a subject and the effective amount is a therapeutically effective amount. 
     
     
         15 . The method of  claim 14 , wherein the subject is a human. 
     
     
         16 . The method of  claim 13 , wherein the expression-inhibiting oligomeric compound is an RNAi agent. 
     
     
         17 . A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the targeting ligand of  claim 1  linked to an expression-inhibiting oligomeric compound to a subject in need thereof. 
     
     
         18 . The method of  claim 17 , wherein the expression-inhibiting oligomeric compound is an RNAi agent. 
     
     
         19 . A composition comprising the targeting ligand of  claim 3  and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the composition of  claim 19  to a subject in need of treatment therefor.