Promotion of axonal regeneration

Abstract

The present invention concerns a method of promoting axonal regeneration. In particular, the invention concerns a method of promoting the growth or regeneration of neurons, and treating disease or conditions associated with the loss, loss of function or dysfunction of nerve cells, in particular thalamic nerve cells, by administering a polypeptide having a high degree of sequence identity with a native sequence Netrin G1 (NGL-1) or an agonist thereof.

1 . A method of promoting axonal growth or regeneration comprising delivering to an injured neuron an effective amount of a polypeptide having at least about 80% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1 and comprising a transmembrane region, or an agonist thereof. 
     
     
         2 . The method of  claim 1  wherein said polypeptide has at least about 85% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1. 
     
     
         3 . The method of  claim 1  wherein said polypeptide has at least about 90% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1. 
     
     
         4 . The method of  claim 1  wherein said polypeptide has at least about 95% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1. 
     
     
         5 . The method of  claim 1  wherein said polypeptide has at least about 99% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1. 
     
     
         6 . The method of  claim 1  wherein said polypeptide further comprises a C-terminal PDZ domain-binding motif. 
     
     
         7 . The method of  claim 6  wherein said PDZ domain-binding motif has the sequence of VQETQI (SEQ ID NO: 7). 
     
     
         8 . The method of  claim 1  wherein said polypeptide comprises an extracellular domain (ECD) comprising nine leucine-rich repeats (LRRs). 
     
     
         9 . The method of  claim 1  wherein said polypeptide further comprises an N-terminal signal sequence. 
     
     
         10 . The method of  claim 1  wherein said polypeptide comprises amino acids 44-352 of SEQ ID NO: 1. 
     
     
         11 . The method of  claim 1  wherein said polypeptide comprises amino acids 44-428 of SEQ ID NO: 1. 
     
     
         12 . The method of  claim 1  wherein said polypeptide comprises amino acids 44-546 of SEQ ID NO: 1. 
     
     
         13 . The method of  claim 1  wherein said polypeptide is human NGL-1 (SEQ ID NO: 1), with or without the N-terminal signal sequence and with or without an immunoglobulin-like region. 
     
     
         14 . The method of  claim 1  wherein said polypeptide is a non-human homologue of human NGL-1 (SEQ ID NO: 1), with or without an N-terminal signal sequence and with or without an immunoglobulin-like region. 
     
     
         15 . The method of  claim 14  wherein said non-human homologue is mouse NGL-1 (SEQ ID NO: 4). 
     
     
         16 . The method of  claim 14  wherein said non-human homologue is chicken NLG-1 (SEQ ID NO: 5). 
     
     
         17 . The method of  claim 1  wherein said agonist is an agonist antibody. 
     
     
         18 . The method of  claim 1  wherein said agonist is an antibody fragment. 
     
     
         19 . The method of  claim 17  or  18  wherein said antibody or antibody fragment is chimeric, humanized or human. 
     
     
         20 . The method of  claim 1  wherein said agonist is a peptide. 
     
     
         21 . A method for treating a disease or condition associated with the loss, loss of function or dysfunction of nerve cells comprising delivering to said nerve cells an effective amount of a polypeptide having at least 80% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1 and comprising a transmembrane region, or an agonist thereof. 
     
     
         22 . The method of  claim 21  wherein said nerve cells are thalamic nerve cells. 
     
     
         23 . The method of  claim 21  wherein said disease or condition is a neurodegenerative disease. 
     
     
         24 . The method of  claim 21  wherein said disease or condition is characterized by nerve cell injury. 
     
     
         25 . The method of  claim 24  wherein said injury is due to mechanical trauma. 
     
     
         26 . The method of  claim 24  wherein said injury is associated with diabetes, stroke, liver or kidney dysfunction, other endocrine or metabolic derangements, chemotherapy or radiation, or chemical intoxication of the nervous system. 
     
     
         27 . The method of  claim 21  wherein said disease or condition is associated with spinal cord injury. 
     
     
         28 . The method of  claim 27  wherein said disease or condition is allodynia or pain following spinal cord injury. 
     
     
         29 . The method of  claim 21  wherein said disease or condition is associated with neural dysfunction. 
     
     
         30 . The method of  claim 29  wherein said disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's chorea, amylotrophic lateral sclerosis (ALS), and peripheral neuropathies. 
     
     
         31 . The method of  claim 21  wherein said disease or condition is a congenital or hereditary abnormality. 
     
     
         32 . The method of  claim 31  wherein said congenital or hereditary abnormality is a Charcot-Marie-Tooth disease. 
     
     
         33 . The method of  claim 21  wherein said disease or condition is an autoimmune disease attacking axons of the central or peripheral nervous system. 
     
     
         34 . The method of  claim 33  wherein said autoimmune disease is multiple sclerosis or Gulliam-Barre syndrome. 
     
     
         35 . A method for treating a disease or condition associated with the loss, loss of function or dysfunction of nerve cells comprising delivering to said nerve cells an effective amount of a nucleic acid encoding a polypeptide having at least 80% sequence identity with amino acid residues 44-352 of SEQ ID NO: 1 and comprising a transmembrane region, or a peptide or polypeptide agonist thereof. 
     
     
         36 . The method of  claim 35  wherein said nerve cells are thalamic nerve cells.