Modulation of aqueous humor outflow by targeting vascular-endothelial-cadherin in schlemm's canal cells

Abstract

The present invention provides methods of inhibiting cadherins between Schlemm's canal cells, to a patient suffering from glaucoma as well as screening for substances that inhibit cadherins between the Schlemm's canal cells.

1 . A method of treating glaucoma comprising, administering one or more cadherin inhibitors to a mammalian patient in need thereof, in an amount sufficient to inhibit a cadherin between Schlemm's canal cells to treat glaucoma in the mammalian patient.  
     
     
         2 . The method of  claim 1 , wherein the cadherin is VE-cadherin.  
     
     
         3 . The method of  claim 1 , wherein the mammalian patient is a human patient.  
     
     
         4 . The method of  claim 1 , wherein the administering comprises intravenous injection.  
     
     
         5 . The method of  claim 1 , wherein the administering comprises ocular administration.  
     
     
         6 . The method of  claim 5 , wherein the administration is topical.  
     
     
         7 . The method of  claim 5 , wherein the administration is ocular injection.  
     
     
         8 . The method of  claim 1 , wherein the one or more cadherin inhibitors is an antibody or antibody fragment.  
     
     
         9 . The method of  claim 1 , wherein the one or more cadherin inhibitors is a peptide.  
     
     
         10 . The method of  claim 9 , wherein the peptide comprises the amino acid sequence HAV.  
     
     
         11 . The method of  claim 9 , wherein the peptide comprises the amino acid sequence VIV.  
     
     
         12 . The method of  claim 9 , wherein the peptide comprises the amino acid sequence HAV and VIV.  
     
     
         13 . A method for screening for a substance that inhibits a cadherin between Schlemm's canal cells, comprising contacting the Schlemm's canal cells with the substance; and detecting the inhibition of the cadherin between the Schlemm's canal cells, which is indicative that the substance inhibits a cadherin between Schlemm's canal cells.  
     
     
         14 . The method of  claim 13 , wherein the Schlemm's canal cells are cultured cells.  
     
     
         15 . The method of  claim 13 , wherein the Schlemm's canal cells are cells obtained from a live tissue sample.  
     
     
         16 . The method of  claim 13 , wherein the Schlemm's canal cells are obtained from a post mortem eye.  
     
     
         17 . The method of  claim 13 , wherein the detecting comprises measuring an increase in hydraulic conductivity between the Schlemm's canal cells, wherein an increase in hydraulic conductivity is indicative that the substance inhibits a cadherin between Schlemm's canal cells.  
     
     
         18 . The method of  claim 13 , wherein the detecting comprises measuring transendothelial electrical resistance between the Schlemm's canal cells, wherein an increase in transendothelial electrical resistance is indicative that the substance inhibits a cadherin between Schlemm's canal cells.  
     
     
         19 . The method of  claim 13 , wherein the detecting comprises measuring transendothelial electrical resistance and hydraulic conductivity between the Schlemm's canal cells, wherein an increase in transendothelial electrical resistance and hydraulic conductivity is indicative that the substance inhibits a cadherin between Schlemm's canal cells.  
     
     
         20 . The method of  claim 13 , wherein the detecting comprises measuring outflow facility using a human anterior chamber perfusion model and increase in outflow facility is indicative that the substance inhibits cadherins between Schlemm's canal cells.  
     
     
         21 . The method of  claim 13 , wherein the detecting comprises measuring outflow facility using a live monkey and increase in outflow facility or decrease in intraocular pressure is indicative that the substance inhibits cadherins between Schlemm's canal cells.  
     
     
         22 . The method of  claim 13 , wherein the detecting comprises measuring the ability of the substance to affect adhesion of cultured Schlemm's canal cells to microtiter plates that have been precoated with a fusion protein comprising all or a portion of a extracellular domain of VE-cadherin.