Selective induction of apoptosis to treat ocular disease

Abstract

The invention is directed to a method of prophylactically or therapeutically treating choroidal neovascularization, wherein the method comprises directly administering to the eye a therapeutic factor or a nucleic acid sequence that encodes a therapeutic factor, which he expressed to produce the therapeutic factor, to selectively induce apoptosis of endothelial cells associated with neovascularization of the choroid such that choroidal neovascularization is treated prophylactically or therapeutically. The invention also provides a method of prophylactically or therapeutically treating ocular neovascularization, wherein the method comprises directly administering to the eye a nucleic acid sequence encoding a therapeutic factor to promote apoptosis of endothelial cells associated with neovascularization, such that the nucleic acid is expressed thereby producing the therapeutic factor to treat ocular neovascularization prophylactically or therapeutically.

What is claimed is:  
     
         1 . A method of prophylactically or therapeutically treating choroidal neovascularization, wherein the method comprises directly administering a therapeutic factor or a nucleic acid sequence encoding a therapeutic factor, which is expressed to produce the therapeutic factor, to the eye to selectively induce apoptosis of endothelial cells associated with neovascularization of the choroid, such that choroidal neovascularization is treated prophylactically or therapeutically.  
     
     
         2 . The method of  claim 1 , wherein apoptosis induced by the therapeutic factor in endothelial cells associated with neovascularization of the choroid is 5-times greater than apoptosis induced by the therapeutic factor in endothelial cells associated with existing vasculature in the eye.  
     
     
         3 . The method of  claim 1 , wherein apoptosis induced by the therapeutic factor in endothelial cells associated with neovascularization of the choroid is 10-times greater than apoptosis induced by the therapeutic factor in endothelial cells associated with existing vasculature in the eye.  
     
     
         4 . The method of  claim 3 , wherein apoptosis induced by the therapeutic factor in endothelial cells associated with neovascularization of the choroid is 50-times greater than apoptosis induced by the therapeutic factor in endothelial cells associated with existing vasculature in the eye.  
     
     
         5 . The method of  claim 1 , wherein the therapeutic factor does not affect endothelial cells of existing vasculature.  
     
     
         6 . The method of  claim 3 , wherein the existing vasculature is retinal vasculature.  
     
     
         7 . The method of  claim 1 , wherein the method comprises contacting an ocular cell with an expression vector comprising a nucleic acid sequence encoding the therapeutic factor.  
     
     
         8 . The method of  claim 7 , wherein the nucleic acid sequence encoding the therapeutic factor is operably linked to a regulatable promoter.  
     
     
         9 . The method of  claim 7 , wherein the expression vector is a viral vector.  
     
     
         10 . The method of  claim 9 , wherein the viral vector is an adeno-associated vector.  
     
     
         11 . The method of  claim 9 , wherein the viral vector is a  herpes simplex  viral vector.  
     
     
         12 . The method of  claim 9 , wherein the viral vector is an adenoviral vector.  
     
     
         13 . The method of  claim 12 , wherein the adenoviral vector is replication deficient.  
     
     
         14 . The method of  claim 13 , wherein the adenoviral vector is deficient in one or more gene functions of the E1 region required for viral replication.  
     
     
         15 . The method of  claim 14 , wherein the adenoviral vector is deficient in one or more gene functions of the E4 region required for viral replication.  
     
     
         16 . The method of  claim 13 , wherein the adenoviral vector is deficient in one or more gene functions of the E4 region required for viral replication.  
     
     
         17 . The method of  claim 16 , wherein the adenoviral vector is deficient in all gene functions required for viral replication.  
     
     
         18 . The method of  claim 1 , wherein the therapeutic factor is an inhibitor of angiogenesis.  
     
     
         19 . The method of  claim 1 , wherein the therapeutic factor is a neurotrophic factor.  
     
     
         20 . The method of  claim 19 , wherein the therapeutic factor has both antiangiogenic and neurotrophic properties.  
     
     
         21 . The method of  claim 20 , wherein the therapeutic factor is pigment epithelium-derived factor.  
     
     
         22 . The method of  claim 1 , wherein the therapeutic factor is administered topically, subconjunctivally, retrobulbarly, periocularly, subretinally, suprachoroidally, or intraocularly.  
     
     
         23 . A method of prophylactically or therapeutically treating ocular neovascularization, wherein the method comprises directly administering a nucleic acid sequence encoding a therapeutic factor, which is expressed to produce the therapeutic factor to the eye to selectively induce apoptosis of endothelial cells associated with neovascularization, such that ocular neovascularization is treated prophylactically or therapeutically.  
     
     
         24 . The method of  claim 23 , wherein apoptosis induced by the therapeutic factor in endothelial cells associated with neovascularization is 10-times greater than apoptosis induced by the therapeutic factor in endothelial cells associated with existing vasculature in the eye.  
     
     
         25 . The method of  claim 24 , wherein apoptosis induced by the therapeutic factor in endothelial cells associated with neovascularization is 50-times greater than apoptosis induced by the therapeutic factor in endothelial cells associated with existing vasculature in the eye.  
     
     
         26 . The method of  claim 24 , wherein the existing vasculature is retinal vasculature.  
     
     
         27 . The method of  claim 23 , wherein the neovascularization is retinal neovascularization.  
     
     
         28 . The method of  claim 27 , wherein the neovascularization is associated with diabetic retinopathy.  
     
     
         29 . The method of  claim 23 , wherein the nucleic acid is in a viral vector.  
     
     
         30 . The method of  claim 29 , wherein the viral vector is an adeno-associated viral vector.  
     
     
         31 . The method of  claim 29 , wherein the viral vector is a  herpes simplex  viral vector.  
     
     
         32 . The method of  claim 29 , wherein the viral vector is an adenoviral vector.  
     
     
         33 . The method of  claim 32 , wherein the adenoviral vector is replication deficient.  
     
     
         34 . The method of  claim 33 , wherein the adenoviral vector is deficient in one or more gene functions of the E1 region required for viral replication.  
     
     
         35 . The method of  claim 34 , wherein the adenoviral vector is deficient in one or more gene functions of the E4 region required for viral replication.  
     
     
         36 . The method of  claim 33 , wherein the adenoviral vector is deficient in one or more gene functions of the E4 region required for viral replication.  
     
     
         37 . The method of  claim 36 , wherein the adenoviral vector is deficient in all gene functions required for viral replication.  
     
     
         38 . The method of  claim 23 , wherein the nucleic acid sequence encoding the therapeutic factor is operably linked to a regulatable promoter.  
     
     
         39 . The method of  claim 23 , wherein the therapeutic factor is an inhibitor of angiogenesis.  
     
     
         40 . The method of  claim 23 , wherein the therapeutic factor is a neurotrophic factor.  
     
     
         41 . The method of  claim 40 , wherein the therapeutic factor has both anti-angiogenic and neurotrophic properties.  
     
     
         42 . The method of  claim 41 , wherein the therapeutic factor is pigment epithelium derived factor.  
     
     
         43 . The method of  claim 23 , wherein the therapeutic factor is administered topically, subconjunctivally, retrobulbarly, periocularly, subretinally, suprachoroidally, or intraocularly.  
     
     
         44 . A method of prophylactically or therapeutically treating a target tissue for neovascularization, wherein the method comprises directly administering a nucleic acid sequence encoding a therapeutic factor, which is expressed to produce the therapeutic factor, to the target tissue to selectively induce apoptosis of endothelial cells associated with neovascularization of the target tissue, such that neovascularization is treated prophylactically or therapeutically.