NOGO Receptor-Mediated Blockade of Axonal Growth
AssigneeYale University
InventorSTEPHEN M. STRITTMATTER
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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.
Claims43
A nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising:
- (a) amino acid residues 27-309 of SEQ ID NO:2 (human NgR NTLRRCT domain), or amino acid residues 27-309 of SEQ ID NO:2 with 1-20 conservative amino acid substitutions;
- and (b) and less than a complete CTS domain, provided that a partial CTS domain, if present, consists of no more than the first 39 consecutive amino acid residues.
A polypeptide comprising:
- (a) amino acid residues 27-30 9 of SEQ ID NO:2 (human NgR NTLRRCT domain), or amino acid residues 27-309 if SEQ ID NO:2 with 1-20 conservative amino acid substitutions;
- and (b) fewer than 115 consecutive amino acids from amino acids 310-445 of SEQ ID NO 2.
An antibody that binds to an epitope in the CTS domain of NgR.
A method of inhibiting binding of a Nogo polypeptide to a NgR, comprising contacting the NgR with an antibody that binds to the amino acid sequence con sting of SEQ ID NO:2 (NgR polypeptide).
A method of treating a central nervous system disease, disorder or injury, comprising administering to a mammal an effective amount of an agent selected from the group consisting of:
- (a) an agent that inhibits binding of a Nogo polypeptide to a NgR;
- and (b) an agent that inhibits NgR-dependent signal transduction in a central nervous system neuron.
A method for identifying a molecule that decreases Nogo-dependent inhibition of axonal growth, the method comprising:
- (a) providing a NgR polypeptide;
- (b) contacting the NgR polypeptide with a candidate molecule;
- and
- (c) detecting a decrease in binding of the Nogo polypeptide to the NgR in the presence of the candidate molecule, as compared to the binding of the Nogo polypeptide to the NgR in the absence of the candidate molecule.
A nucleic acid comprising a nucleotide sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of:
- (a) IYKGVIQAI and (b) EELV, the polypeptide comprising 40 amino acids or fewer.
A polypeptide comprising an amino acid sequence selected from the group consisting of:
- (a) IYKGVIQAI and (b) EELV, the polypeptide comprising 40 amino acids or fewer.
A method of identifying a molecule that decreases axonal Nogo-dependent inhibition of axonal growth, the method comprising:
- (a) providing a polypeptide comprising a target sequence consisting of an amino acid sequence selected from the group consisting of IYKGVIQAI and EELV;
- (b) contacting the polypeptide with a candidate molecule;
- and
- (c) detecting binding of the candidate molecule to a target sequence in the polypeptide.
Dependencies are inferred from the claim text.