Modulation of Activity of Proneurotrophins

Abstract

The present invention provides agents for inhibiting binding of a pro-neurotrophin to a Vps10p-domain receptor, in particular the binding of a pro-NGF or a pro-BDNF to a Sortilin receptor. The invention thus provides agents for the manufacture of a medicament, for treating and/or preventing disease or disorders such as but not limited to neurological, neuropsychiatric and ocular diseases, disorders, and degeneration as well as obesity, diabetes, pain and/or nociception in an individual.

What is claimed is: 
     
         1 . An in vitro screening method for selecting a compound which alters the binding of at least one pro-neurotrophin to a binding site on Sortilin, comprising:
 (a) providing an assay for measuring the binding of a pro-neurotrophin to a binding site on Sortilin, wherein said binding site comprises SEQ ID N0:25 or variant or fragment thereof;   (b) adding the compound to be tested to the assay;   (c) determining the amount of a pro-neurotrophin bound to the binding site on Sortilin;   (d) comparing the amount determined in step c) with an amount determined in the absence of the compound to be tested; and   (e) selecting a compound having a difference in the two amounts as a compound which alters the binding of pro-neurotrophins to the Sortilin.   
     
     
         2 . The method of  claim 1 , wherein the pro-neurotrophin is selected from proNGF of SEQ ID NO:6, pro-BDNF of SEQ ID NO:7, pro-NT-3 of SEQ ID NO:8 or proNT-4/5 of SEQ ID NO:9. 
     
     
         3 . The method of  claim 1 , wherein said binding site on Sortilin receptor comprises SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28. 
     
     
         4 . A method for determining the degree of inhibition of an agent on the activity of pro-neurotrophins in cells expressing a receptor selected from the Vps10p-domain receptors of SEQ ID NOs: 1 to 5 or any fragment of variant thereof, said variant having at least 70% sequence identity to any of said SEQ ID NOs: 1 to 5, said method comprising the steps of:
 (a) administering said agent to a mammal expressing said receptor,   (b) measuring the activity of said pro-neurotrophins in said mammal; and   (c) determining the degree of inhibition by comparing the measurement of step (b) with a measurement obtained in the absence of said agent being tested,   wherein the difference in the two measurements identifies the degree of inhibition of said agent on the activity of pro-neurotrophins on cells expressing said receptor.   
     
     
         5 . A pharmaceutical composition comprising:
 (a) (1) an agent capable of binding any of SEQ ID NOs. 25 to 28 or a variant or fragment thereof; or
 (2) an agent comprising any of SEQ ID NOs. 25 to 28 or a variant or fragment thereof capable of binding a proneurotrophin selected from the group consisting of proNGF, proBDNF, proNT3 and proNT4/5; or 
 (3) an antibody capable of binding to any of SEQ ID NOs: 25 to 28; and 
   (b) a pharmaceutically acceptable carrier.   
     
     
         6 . A kit in parts comprising:
 (a) a composition of  claim 5 ;   (b) a medical instrument or other means for administering the composition; and   (c) instructions on how to use the kit in parts.   
     
     
         7 . The kit of  claim 6 , further comprising a second active ingredient.