LOW DENSITY LIPOPROTEIN RECEPTOR-MEDIATED siRNA DELIVERY

Abstract

The invention provides interfering RNA molecule-ligand conjugates useful as a delivery system for delivering interfering RNA molecules to a cell in vitro or in vivo. The conjugates comprise a ligand that can bind to a low density lipoprotein receptor (LDLR) or LDLR family member. Therapeutic uses for the conjugates are also provided.

What is claimed is: 
     
         1 . An interfering RNA delivery conjugate comprising an interfering RNA molecule and a ligand that can bind to a receptor in the low density lipoprotein receptor (LDLR) family. 
     
     
         2 . The interfering RNA delivery conjugate of  claim 1  wherein the ligand comprises an LDLR-binding domain of apolipoprotein B 
     
     
         3 . The interfering RNA delivery conjugate of  claim 1  wherein the ligand comprises an antibody that can bind LDLR. 
     
     
         4 . The interfering RNA delivery conjugate of  claim 1  wherein the ligand comprises an antibody fragment that can bind LDLR. 
     
     
         5 . The interfering RNA delivery conjugate of  claim 1  wherein the ligand comprises a fusion protein comprises antibody or antibody fragment that can bind LDLR fused to a second ligand that can also bind to LDLR. 
     
     
         6 . The interfering RNA delivery conjugate of  claim 5  wherein the second ligand comprises second antibody, an apoB, an apoE, or an LDLR binding fragment of an apoB or apoE. 
     
     
         7 . The interfering RNA delivery conjugate of  claim 1  wherein the conjugate further comprises a nucleic acid binding protein. 
     
     
         8 . The interfering RNA delivery conjugate of  claim 7  wherein the nucleic acid binding protein comprises a protamine. 
     
     
         9 . The interfering RNA delivery conjugate of  claim 1  wherein the conjugate further comprises a polycation. 
     
     
         10 . The interfering RNA delivery conjugate of  claim 9  wherein the polycation is selected from the group consisting of: polylysine, polyarginine, and polyethyleneimine. 
     
     
         11 . The interfering RNA delivery conjugate of  claim 10  wherein the polyarginine comprises 7×Arg peptide, 8×Arg peptide, 9×Arg peptide, 10×Arg peptide, or 11×Arg peptide. 
     
     
         12 . The interfering RNA delivery conjugate of  claim 1  wherein the conjugate further comprises an HA2 peptide or TAT-HA2 peptide, or a retro-inverso TAT-HA2 peptide. 
     
     
         13 . The interfering RNA delivery conjugate of  claim 7 , wherein the interfering RNA molecule is linked to the ligand via a nucleic acid binding protein. 
     
     
         14 . The interfering RNA delivery conjugate of  claim 13 , wherein the interfering RNA molecule is linked to the ligand via a polycation. 
     
     
         15 . The interfering RNA delivery conjugate of  claim 10 , wherein the interfering RNA molecule is linked to the ligand via a polyarginine. 
     
     
         16 . The interfering RNA delivery conjugate of  claim 15  wherein the polyarginine comprises 7×Arg peptide, 8×Arg peptide, 9×Arg peptide, 10×Arg peptide, or 11×Arg peptide. 
     
     
         17 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is a siRNA, miRNA, or shRNA. 
     
     
         18 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is covalently linked to the ligand.