Modulation of Activity of Neurotrophins

Abstract

The present invention relates to methods for modulating the activity of one or more neurotrophins, such as neural growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4 (NT-4), in an animal and methods for treatment of a disease or disorder in an individual by modulation of neurotrophin activity. The modulation is carried out by interfering with binding between a neurotrophin and a receptor of the Vps10p-domain receptor family or modulating the expression of a receptor of the Vps10p-domain receptor family. Methods for screening for agents capable of modulating neurotrophin activity and agents selected using these screening methods are also disclosed, as are methods for determining the effect of an agent on one or more neurotrophins in cells. The present invention also pertains to methods for modulating the transport of one or more neurotrophins.

What is claimed is: 
     
         1 . A method of treating a tumour in an animal in need of such treatment, said method comprising administering to said animal a therapeutically effective amount of an agent capable of binding a receptor of the Vps10p-domain receptor family and inhibiting binding of a pro-neurotrophin to said receptor. 
     
     
         2 . The method of  claim 1 , wherein said agent is an antibody that binds an extracellular part of a Sortilin receptor comprising amino acids 612-740 of SEQ ID NO:1, and thereby inhibits binding of a pro-neurotrophin to said receptor. 
     
     
         3 . The method of  claim 1 , wherein said agent is a peptide comprising amino acid residues selected from the group consisting of residues 24-77 of SEQ ID NO:1; residues 29-81 of SEQ ID NO:2; residues 19-121 of SEQ ID NO:6, residues 19-127 of SEQ ID NO:7, residues 17-124 of SEQ ID NO:8, and residues 25-80 of SEQ ID NO:9. 
     
     
         4 . The method of  claim 1 , wherein said pro-neurotrophin is selected from the group consisting of pro-NGF, pro-BDNF, pro-NT-3 and pro-NT-4/5. 
     
     
         5 . The method of  claim 1 , wherein said antibody is administered in a therapeutically effective amount of from about 1 μg/kg to about 100 mg/kg per day. 
     
     
         6 . The method of  claim 1 , wherein the animal is a mammal. 
     
     
         7 . The method of  claim 6 , wherein the mammal is a human being. 
     
     
         8 . The method of  claim 1 , wherein said animal has cancer and wherein said treatment reduces toxic effects of a chemotherapeutic agent used to treat said cancer. 
     
     
         9 . The method of  claim 8 , wherein said agent is an antibody that binds an extracellular part of a Sortilin receptor comprising amino acids 612-740 of SEQ ID NO:1, and thereby inhibits binding of a pro-neurotrophin to said receptor. 
     
     
         10 . The method of  claim 8 , wherein said agent is a peptide comprising amino acid residues selected from the group consisting of residues 24-77 of SEQ ID NO:1; residues 29-81 of SEQ ID NO:2; residues 19-121 of SEQ ID NO:6, residues 19-127 of SEQ ID NO:7, residues 17-124 of SEQ ID NO:8, and residues 25-80 of SEQ ID NO:9. 
     
     
         11 . The method of  claim 8 , wherein said pro-neurotrophin is selected from the group consisting of pro-NGF, pro-BDNF, pro-NT-3 and pro-NT-4/5. 
     
     
         12 . The method of  claim 8 , wherein said antibody is administered in a therapeutically effective amount of from about 1 μg/kg to about 100 mg/kg per day. 
     
     
         13 . The method of  claim 8 , wherein the animal is a mammal. 
     
     
         14 . The method of  claim 13 , wherein the mammal is a human being. 
     
     
         15 . A pharmaceutical composition comprising:
 (a) a therapeutically effective amount of:
 (1) an antibody directed against a peptide comprising a sequence comprising amino acids 612-740 of SEQ ID NO:1; or 
 (2) a soluble receptor of the Vps10p-domain receptor family or a fragment or a variant thereof, 
 wherein said therapeutically effective amount is effective for the treatment of a tumour in an animal in need of such treatment; and 
   (b) a pharmaceutically acceptable carrier.   
     
     
         16 . A pharmaceutical composition comprising:
 (a) a therapeutically effective amount of:
 (1) an antibody directed against a peptide comprising a sequence comprising amino acids 612-740 of SEQ ID NO:1; or 
 (2) a soluble receptor of the Vps10p-domain receptor family or a fragment or a variant thereof, 
 wherein said therapeutically effective amount is effective for the treatment of toxic effects of a chemotherapeutic agent used to treat cancer; and 
   (b) a pharmaceutically acceptable carrier.