Inhibition of choroidal neovascularization

Abstract

Methods of treatment of diseases that include or are characterized by inappropriate or pathological neovascularization are disclosed. These diseases include diseases of the eye, such as diabetic retinopathy, retinopathy of prematurity, and choroidal neovascularization which can occur in age-related macular degeneration (AMD). Disclosed methods include administering agents that cause directly or indirectly upregulation of the ABCA1 transporter protein in macrophages. These agents include, without limitation, LXR agonists. In some embodiments, inhibitors of CETP expression or activity can also be effective. Administration routes can include, without limitation, intraocular, periocular, or systemic administration.

1 . A method of treating an ocular disease characterized by choroidal neovascularization (CNV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an activator of an ATP-binding cassette (ABC) transporter. 
     
     
         2 . A method in accordance with  claim 1 , wherein the activator of an ABC transporter is an agonist of an ABC transporter selected from the group consisting of PPARα, PPARγ and PPARδ. 
     
     
         3 . A method in accordance with  claim 1 , wherein the activator of an ATP-binding cassette (ABC) transporter is an LXR agonist. 
     
     
         4 . A method in accordance with  claim 3 , wherein the LXR agonist is selected from the group consisting of N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-tri-fluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-benzenesulfonamide), N,N-dimethyl-3beta-hydroxy-cholenamide, methyl-3β-hydroxy-5α,6α-epoxycholanate and 2-[3-[3-[[2-chloro-3-(trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]propoxy]phenyl]acetic acid. 
     
     
         5 . A method in accordance with  claim 1 , wherein the administering a therapeutically effective amount of an activator of an ABC transporter comprises administering the activator intraocularly, periocularly or systemically. 
     
     
         6 . A method in accordance with  claim 1 , wherein the administering a therapeutically effective amount of an activator of an ABC transporter comprises administering to an eye of the subject a pharmaceutically acceptable eye drop formulation comprising the activator. 
     
     
         7 . A method in accordance with  claim 1 , wherein the administering a therapeutically effective amount of an activator of an ABC transporter comprises intraocularly injecting a pharmaceutically acceptable injectable formulation comprising the activator. 
     
     
         8 . A method in accordance with  claim 1 , wherein the administering a therapeutically effective amount of an activator of an ABC transporter comprises administering the activator orally or parenterally in a pharmaceutically acceptable formulation. 
     
     
         9 . A method of treating an ocular disease characterized by choroidal neovascularization (CNV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an inhibitor of cholesteryl ester transfer protein (CETP) activity. 
     
     
         10 . A method in accordance with  claim 9 , wherein the inhibitor of CETP activity is selected from the group consisting of ethyl (2R,4S)-4-({[3,5-bis(trifluoromethyl)phenyl]methyl}(methoxycarbonyl)amino)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (Torcetrapib), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one (Anacetrapib) and S-[2-({[1-(2-ethylbutyl)cyclohexyl]carbonyl}amino)phenyl] 2-methylpropanethioate (Dalcetrapib). 
     
     
         11 . A method in accordance with  claim 9 , wherein the administering a therapeutically effective amount of an inhibitor of CETP activity comprises intraocularly injecting a pharmaceutically acceptable formulation comprising the inhibitor. 
     
     
         12 . A method in accordance with  claim 9 , wherein the administering a therapeutically effective amount of an inhibitor of CETP activity comprises administering to an eye of the subject a pharmaceutically acceptable eye drop formulation comprising the inhibitor. 
     
     
         13 . A method in accordance with  claim 9 , wherein the administering a therapeutically effective amount of inhibitor of CETP activity comprises administering the inhibitor orally or parenterally in a pharmaceutically acceptable formulation. 
     
     
         14 . A method of treating an ocular disease characterized by choroidal neovascularization (CNV) in a subject in need thereof, comprising:
 providing a cell culture comprising macrophages;   adding an activator of an ATP-binding cassette (ABC) transporter to the culture in an amount sufficient to stimulate ABC transporter expression and/or activity in the macrophages; and   administering the macrophages to the subject.   
     
     
         15 . A method in accordance with  claim 14 , wherein the activator is selected from the group consisting of N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-tri-fluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]benzenesulfonamide, methyl-3β-hydroxy-5α,6α-epoxycholanate and (2-[3-[3-[[2-chloro-3-(trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]propoxy]phenyl]acetic acid). 
     
     
         16 . A method in accordance with  claim 14 , wherein the providing a cell culture comprising macrophages comprises providing a cell culture comprising peripheral blood mononuclear cells (PBMCs). 
     
     
         17 . A method in accordance with  claim 16 , wherein the cell culture comprising peripheral blood mononuclear cells (PBMCs) comprises PBMCs autologous to the subject. 
     
     
         18 . A method in accordance with  claim 16 , wherein the providing a cell culture comprising macrophages comprises growing macrophages comprised by the culture 
     
     
         19 . A method of treating an ocular disease characterized by choroidal neovascularization (CNV), comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of miR33. 
     
     
         20 . A method in accordance with  claim 19 , wherein the inhibitor of miR33 is a single-stranded RNA which inhibits miR33.