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.

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 the LDLR binding domain of apolipoprotein B (apoB). 
     
     
         3 . The interfering RNA delivery conjugate of  claim 1 , wherein the ligand comprises the LDLR binding domain of apolipoprotein E (apoE). 
     
     
         4 . The interfering RNA delivery conjugate of  claim 1 , wherein the ligand comprises an LDLR-specific antibody or a fragment thereof. 
     
     
         5 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is linked to the ligand via a nucleic acid binding protein. 
     
     
         6 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is linked to the ligand via a polycation. 
     
     
         7 . The interfering RNA delivery conjugate of  claim 6 , wherein the polycation is polylysine. 
     
     
         8 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is linked to the ligand via a 7xArg peptide, 8xArg peptide, 9xArg peptide, 10xArg peptide, or 11xArg peptide. 
     
     
         9 . The interfering RNA delivery conjugate of  claim 8 , wherein the interfering RNA molecule is linked to the ligand via a 9xArg peptide. 
     
     
         10 . The interfering RNA delivery conjugate of  claim 1 , wherein the conjugate comprises an HA2 peptide. 
     
     
         11 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is a siRNA, miRNA, or shRNA. 
     
     
         12 . The interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule is covalently linked to the ligand. 
     
     
         13 . A method of delivering an interfering RNA molecule to an eye of a patient, comprising administering to the patient the interfering RNA delivery conjugate of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the interfering RNA delivery conjugate is administered by intraocular injection, ocular topical application, subconjunctival injection, intravitreal injection, anterior or posterior juxtascleral injection, intravenous injection, oral administration, intramuscular injection, intraperitoneal injection, transdermal application, intranasal application, or transmucosal application. 
     
     
         15 . The method of  claim 13 , wherein the interfering RNA delivery conjugate is administered to the patient in the presence of an HA2 peptide. 
     
     
         16 . A method of treating or preventing an ocular disorder in a patient, comprising administering to the patient the interfering RNA delivery conjugate of  claim 1 , wherein the interfering RNA molecule can attenuate expression of a gene associated with the ocular disorder. 
     
     
         17 . The method of  claim 16 , wherein the interfering RNA delivery conjugate is administered by intraocular injection, ocular topical application, subconjunctival injection, intravitreal injection, anterior or posterior juxtascleral injection, intravenous injection, oral administration, intramuscular injection, intraperitoneal injection, transdermal application, intranasal application, or transmucosal application. 
     
     
         18 . The method of  claim 16 , wherein the interfering RNA delivery conjugate is administered to the patient in the presence of an HA2 peptide. 
     
     
         19 . The method of  claim 16 , wherein the ocular disorder is associated with ocular angiogenesis, dry eye, ocular inflammatory conditions, ocular hypertension, or glaucoma.