Composition and methods of rnai therapeutics for treatment of cancer and other neovascularization diseases

Abstract

Compositions and methods are provided for treatment of diseases involving unwanted neovascularization (NV). The invention provides treatments that control NV through selective inhibition of pro-angiogenic biochemical pathways, including inhibition of the VEGF pathway gene expression and inhibition localized at pathological NV tissues. Tissue targeted nanoparticle compositions comprising polymer conjugates and nucleic acid molecules that induce RNA interference (RNAi) are provided. The nanoparticle compositions of the invention can be used alone or in combination with other therapeutic agents such as VEGF pathway antagonists. The compositions and methods can be used for the treatment of NV diseases such as cancer, ocular disease, arthritis, and inflammatory diseases.

1 .- 11 . (canceled) 
     
     
         12 . A 25 base pair, blunt-ended small interfering RNA (siRNA) molecule that is double-stranded and comprises a sense strand and an antisense strand, wherein the antisense strand consists of the complement of the sequence in any one of SEQ ID NOs: 303-322. 
     
     
         13 . The siRNA molecule of  claim 12 , comprising at least one nucleotide that is chemically modified. 
     
     
         14 . The siRNA molecule of  claim 13 , wherein the at least one chemically modified nucleotide is a nucleotide comprising a 2′-O-methyl ribose. 
     
     
         15 . A composition comprising the siRNA molecule of  claim 12  and a pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 15 , further comprising one or more additional nucleic acid molecules that induce RNA interference and decrease the expression of a gene of interest. 
     
     
         17 . The composition of  claim 16 , wherein at least one of the one or more additional nucleic acid molecules decreases the expression of a gene selected from the group consisting of; VEGF, VEGFR1, VEGFR2, VEGFR3, PDGF, PDGFR-α, PDGFR-β, EGF, EGFR, RAF-a, RAF-c, AKT, RAS, NFkB, HIF, bFGF, bFGFR, Her-2, c-Met, c-Myc and HGF. 
     
     
         18 . The composition of  claim 15 , wherein the carrier is a nucleic acid delivery vehicle. 
     
     
         19 . The composition of  claim 18 , wherein the nucleic acid delivery vehicle is synthetic. 
     
     
         20 . The composition of  claim 19  wherein the synthetic nucleic acid delivery vehicle comprises a cationic polymer-siRNA complex. 
     
     
         21 . The composition of  claim 20 , wherein the cationic polymer is a histidine-lysine co-polymer. 
     
     
         22 . The composition of  claim 19 , wherein the synthetic nucleic acid delivery vehicle further comprises a hydrophilic polymer. 
     
     
         23 . The composition of  claim 22 , wherein the hydrophilic polymer comprises a component selected from the group consisting of: polyethylene glycol, a polyacetal and a polyoxazoline. 
     
     
         24 . The composition of  claim 19 , wherein the synthetic nucleic acid vehicle further comprises a targeting moiety. 
     
     
         25 . The composition of  claim 24 , wherein the targeting moiety binds a tumor specific molecule or an angiogenesis-specific molecule. 
     
     
         26 . The composition of  claim 15  comprising an additional therapeutic agent selected from the group consisting of: an anti-cancer agent, an anti-inflammatory agent and an anti-infective agent. 
     
     
         27 . The composition of  claim 15  comprising an additional anti-angiogenic agent. 
     
     
         28 . A method of reducing tumor growth in a subject in need thereof, comprising the step of administering the siRNA molecule of  claim 12  to the subject. 
     
     
         29 . A method for decreasing the EGF or EGFR protein level in a cell, comprising the step of introducing into the cell the siRNA molecule of  claim 12 .