Ffa1 (gpr40) as a therapeutic target for neural angiogenesis diseases or disorders

Abstract

The instant invention provides methods and compositions related to discovery of Free Fatty Acid Receptor 1 (FFA1) as a therapeutic target for treatment or prevention of diseases or disorders of neurons that are characterized by angiogenesis, or of vascular diseases of the eye, retinal degeneration and/or tumors more generally. Therapeutic and/or prophylactic uses and compositions of known FFA1 inhibitors, including small molecules and nucleic acid agents, are described. Methods for identification of novel FFA1 inhibitors are also provided.

1 . A method for treating or preventing angiogenesis in neural cells of a subject, treating or preventing cancer in a subject, and/or treating or preventing retinal angiomatous proliferation (RAP) vascular lesions in a subject, the method comprising:
 (a) identifying a subject having or at risk of neural cell angiogenesis, and/or having or at risk of developing cancer, and/or having or at risk of developing RAP vascular lesions; and   (b) administering a FFA1 inhibitor to the subject,   
       thereby treating or preventing angiogenesis in the neural cells of the subject, treating or preventing cancer in the subject, and/or treating or preventing RAP vascular lesions in the subject. 
     
     
         2 . The method of  claim 1 , wherein the neural cells are retinal cells, optionally photoreceptor cells. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the subject has macular telangiectasia (MacTel) or neovascular age-related macular degeneration (AMD). 
     
     
         5 . The method of  claim 1 , wherein the cells of the subject are impaired for lipid uptake, as compared to the cells of an appropriate control subject. 
     
     
         6 . The method of  claim 1 , wherein the subject has dyslipidemia or mitochondrial dysfunction. 
     
     
         7 . The method of  claim 1 , wherein the FFA1 inhibitor is a small molecule antagonist or an RNAi agent. 
     
     
         8 . The method of  claim 1 , wherein the FFA1 antagonist is GW1100. 
     
     
         9 . The method of  claim 1 , wherein the FFA1 inhibitor is administered to the eye of the subject. 
     
     
         10 . The method of  claim 9 , wherein the FFA1 inhibitor is administered by intravitreal injection. 
     
     
         11 . The method of any  claim 1 , wherein administering the FFA1 inhibitor enhances GLUT1 expression in the retinal cells of the subject. 
     
     
         12 . A method for increasing glucose uptake in a retinal cell, the method comprising obtaining a retinal cell and contacting the retinal cell with a FFA1 inhibitor, thereby increasing glucose uptake in the retinal cell. 
     
     
         13 . The method of  claim 12 , wherein the retinal cell is a retinal cell in vitro. 
     
     
         14 . The method of  claim 12 , wherein GLUT1 expression is enhanced in the retinal cell contacted with the FFA1 inhibitor. 
     
     
         15 . A method for identifying a test compound as a FFA1 inhibitor, the method comprising contacting a retinal cell with a test compound; and measuring glucose uptake in the retinal cell, wherein measurement of increased glucose uptake in the retinal cell in the presence of the test compound identifies the test compound as a FFA1 inhibitor. 
     
     
         16 . The method of  claim 15 , wherein the retinal cell has a mutation or deletion of the very low-density lipoprotein receptor (Vldlr) gene that suppresses fatty acid uptake in the retinal cell. 
     
     
         17 . The method of  claim 15 , wherein GLUT1 expression is enhanced in the retinal cell contacted with the test compound. 
     
     
         18 . A method for treating or preventing a vascular disease of the eye, retinal degeneration and/or cancer in a subject, the method comprising:
 (a) identifying a subject having or at risk of developing a vascular disease of the eye, retinal degeneration and/or cancer; and   (b) administering a GPR84 inhibitor, or a GPR120 inhibitor to the subject, thereby treating or preventing the vascular disease of the eye, retinal degeneration and/or cancer in the subject.   
     
     
         19 . The method of  claim 18 , wherein the GPR84, or the GPR120 inhibitor is a small molecule antagonist or an RNAi agent. 
     
     
         20 . The method of  claim 18 , wherein the GPR84 inhibitor is GLPG1205, or the GPR120 inhibitor is 4-Methyl-N-9H-xanthen-9-yl-benzenesulfonamide. 
     
     
         21 . The method of  claim 18 , wherein the vascular disease of the eye is age-related macular degeneration (AMD) or retinopathy of prematurity (ROP). 
     
     
         22 .- 25 . (canceled)