NOGO Receptor-Mediated Blockade of Axonal Growth

Abstract

Disclosed are NgR proteins and biologically active Nogo (ligand) protein fragments. Also disclosed are compositions and methods for modulating the expression or activity of the Nogo and NgR protein. Also disclosed are peptides which block Nogo-mediated inhibition of axonal extension. The compositions and methods of the invention are useful in the treatment of cranial or cerebral trauma, spinal cord injury, stroke or a demyelinating disease.

What is claimed: 
     
         1 . A method of inhibiting CNS myelin-mediated neurite outgrowth inhibition or promoting axonal regeneration comprising contacting a neuron with a Nogo receptor (NgR) antagonist selected from the group consisting of:
 (a) an isolated NgR polypeptide; and   (b) an antibody or antigen binding fragment thereof that binds an NgR polypeptide;   wherein said NgR antagonist inhibits CNS myelin-induced neurite outgrowth inhibition or promotes axonal regeneration.   
     
     
         2 . A method of promoting neurite outgrowth or axonal regeneration in a mammal comprising administering to a mammal in need thereof an effective amount of a Nogo receptor (NgR) antagonist, wherein said NgR antagonist is selected from the group consisting of:
 (a) an isolated NgR polypeptide; and   (b) an antibody or antigen binding fragment thereof that binds an NgR polypeptide;   wherein said NgR antagonist inhibits CNS myelin-induced neurite outgrowth inhibition or promotes axonal regeneration.   
     
     
         3 . A method of treating a central nervous system disease, disorder or injury in a mammal, comprising administering to a mammal in need thereof an effective amount of an NgR antagonist selected from the group consisting of:
 (a) an isolated NgR polypeptide; and   (b) an antibody or antigen binding fragment thereof that binds an NgR polypeptide;   wherein said NgR antagonist inhibits CNS myelin-induced neurite outgrowth inhibition or promotes axonal regeneration.   
     
     
         4 . The method of  claim 3 , wherein said central nervous system disease, disorder or injury is selected from the group consisting of cranial or cerebral trauma, spinal cord injury, stroke, multiple sclerosis, monophasic demyelination, encephalomyelitis, multifocal leukoencephalopathy, panencephalitis, Marchiafava-Bignami disease, pontine myelinolysis, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Spongy degeneration, Alexander's disease, Canavan's disease, metachromatic leukodystrophy, and Krabbe's disease. 
     
     
         5 . An isolated polynucleotide comprising a first nucleic acid encoding a fragment of the polypeptide of SEQ ID NO:2, or a variant thereof, wherein said polypeptide inhibits NOGO-receptor-mediated neurite outgrowth inhibition. 
     
     
         6 . The polynucleotide of  claim 5 , wherein said polypeptide is selected from the group consisting of:
 (a) amino acids 27-309 of SEQ ID NO:2;   (b) amino acids 27-445 of SEQ ID NO:2;   (c) amino acids 1-348 of SEQ ID NO:2; and   (d) amino acids 1-309 of SEQ ID NO:2.   
     
     
         7 . The polynucleotide of  claim 6 , further comprising a second nucleic acid encoding a heterologous polypeptide fused to said polypeptide. 
     
     
         8 . A vector comprising the polynucleotide of  claim 5 . 
     
     
         9 . The vector of  claim 8 , wherein said polynucleotide is operably linked to one or more expression control elements. 
     
     
         10 . An isolated host cell comprising the polynucleotide of  claim 5 . 
     
     
         11 . The host cell of  claim 10 , wherein said polynucleotide is operably linked to one or more expression control elements. 
     
     
         12 . A method for producing a polypeptide comprising culturing the host cell of  claim 10  under conditions suitable for expression of the polypeptide and recovering the polypeptide from the culture medium. 
     
     
         13 . A composition comprising a polypeptide encoded by the polynucleotide of  claim 5  and a pharmaceutically acceptable carrier.