Method For Treatment Of Macular Degeneration By Modulating P2Y12 or P2X7 Receptors

Abstract

Provided is a method of treating or preventing age-related macular degeneration (AMD) in a patient subject to, or symptomatic of the disease, wherein the method comprises restoring normal lysosomal pH (pH L ), or acidifying an abnormally elevated pH L , thus decreasing or preventing a damaging accumulation of lipofuscin or waste products in the retinal pigment epithelium (RPE) cells of the eye of the patient. Further, this method is achieved by modulating the action of the P2X7 and/or P2Y12 receptors of the RPE cells, specifically decreasing the acidity (pH L ) of the RPE lysosomes by administering selected receptor antagonists affecting the action of the P2X7 and/or P2Y12 receptors of the RPE. Methods for selecting and quantifying the effectiveness of drugs to restore pH L and determine outer segment clearance rates is also provided using a high through-put screening protocol.

What is claimed is: 
     
         1 . A method of reducing, treating or preventing age-related macular degeneration (AMD) in a patient subject to or symptomatic of age-related macular AMD, the method comprising modulating P2X7 receptor activity, thereby acidifying lysosomal pH (pH L ) in the retinal pigment epithelium (RPE) cell(s) of the patient's eyes. 
     
     
         2 . The method for quantifying the effectiveness of the inhibitor or antagonist of the P2X7 receptor to restore pH L  of  claim 1 , and to determine outer segment clearance rates, comprising using a high through-put screening protocol. 
     
     
         3 . A method of reducing, treating or preventing age-related macular degeneration (AMD) in a patient subject to or symptomatic of age-related macular AMD, the method comprising modulating P2Y12 receptor activity, thereby acidifying lysosomal pH (pH L ) in the retinal pigment epithelium (RPE) cell(s) of the patient's eyes. 
     
     
         4 . The method for quantifying the effectiveness of the inhibitor or antagonist of the P2Y12 receptor to restore pH L  of  claim 3 , and to determine outer segment clearance rates, comprising using a high through-put screening protocol. 
     
     
         5 . A method of providing RPE cells having lysosomes with elevated pH L  to permit the efficient screening of compounds capable of reducing or restoring lysosomal function (acidic pH L ), the method comprising stimulating endogenous expression in the RPE cell of endogenous ATP as an agonist of the P2X7 receptor, or by stimulating the P2X7 receptor by administering exogenous BzATP. 
     
     
         6 . A method of providing RPE cells having lysosomes with elevated pH L  to permit the efficient screening of compounds capable of reducing or restoring lysosomal function (acidic pH L ), the method comprising stimulating endogenous expression in the RPE cell of endogenous ADP as an agonist of the P2Y12 receptor, or by administering meSADP, each in an amount sufficient to elevate the pH L  to a level equivalent to long-term exposure of the RPE cells to A2E, or to levels representative of AMD.