Use of VEGF and homologues to treat neuron disorders

Abstract

The present invention relates to neurological and physiological dysfunction associated with neuron disorders. In particular, the invention relates to the involvement of vascular endothelial growth factor (VEGF) and homologues in the aetiology of motor neuron disorders. The invention further concerns a novel, mutant transgenic mouse (VEGF m/m ) with a homozygous deletion in the hypoxia responsive element (HRE) of the VEGF promoter which alters the hypoxic upregulation of VEGF. These mice suffer severe adult onset muscle weakness due to progressive spinal motor neuron degeneration which is reminiscent of amyotrophic lateral sclerosis (ALS)—a fatal disorder with unknown aetiology. Furthermore, the neuropathy of these mice is not caused by vascular defects, but is due to defective VEGF-mediated survival signals to motor neurons. The present invention relates in particular to the isoform VEGF 165 which stimulates survival of motor neurons via binding to neuropilin-1, a receptor known to bind semaphorin-3A which is implicated in axon retraction and neuronal death, and the VEGF Receptor-2. The present invention thus relates to the usage of VEGF, in particular VEGF 165 , for the treatment of neuron disorders and relates, in addition, to the usage of polymorphisms in the VEGF promotor for diagnosing the latter disorders.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a neuron disorder in a mammal, the method comprising administering to the mammal a VEGF protein. 
     
     
         17 . The method of  claim 16 , wherein the neuron disorder is a neuropathy. 
     
     
         18 . The method of  claim 17 , wherein the neuropathy is a motor neuron disorder. 
     
     
         19 . The method of  claim 18 , wherein the motor neuron disorder is amyotrophic lateral sclerosis (ALS) or an ALS-like disorder. 
     
     
         20 . The method of  claim 16 , wherein the VEGF is selected from the group consisting of VEGF-A and VEGF-B. 
     
     
         21 . The method of  claim 20 , wherein the VEGF-A is isoform VEGF165. 
     
     
         22 . The method of  claim 16 , wherein the VEGF is adminstered intrathecally. 
     
     
         23 . A method of enhancing survival of a motor neuron in a mammal, the method comprising contacting a motor neuron of the mammal with an amount of a VEGF protein effective to enhance survival of the motor neuron. 
     
     
         24 . The method of  claim 23 , wherein the motor neuron is hypoxic. 
     
     
         25 . The method of  claim 23 , wherein the motor neuron is contacted in vitro. 
     
     
         26 . The method of  claim 23 , wherein the VEGF is selected from the group consisting of VEGF-A and VEGF-B. 
     
     
         27 . The method of  claim 26 , wherein the VEGF-A is isoform VEGF 165. 
     
     
         28 . The method of  claim 23 , wherein contacting the motor neuron is through intrathecal administration. 
     
     
         29 . A method of treating a neuron disorder in a mammal, the method comprising administering to the mammal a nucleic acid sequence encoding VEGF. 
     
     
         30 . The method of  claim 29 , wherein the VEGF is selected from the group consisting of VEGF-A and VEGF-B. 
     
     
         31 . The method of  claim 30 , wherein the VEGF-A is isoform VEGF 165. 
     
     
         32 . A method of enhancing survival of a motor neuron in a mammal, the method comprising contacting a motor neuron of the mammal with a nucleic acid sequence encoding an amount of a VEGF protein effective to enhance survival of the motor neuron. 
     
     
         33 . The method of  claim 32 , wherein the motor neuron is hypoxic. 
     
     
         34 . The method of  claim 32 , wherein the motor neuron is contacted in vitro. 
     
     
         35 . The method of  claim 32 , wherein the VEGF is selected from the group consisting of VEGF-A and VEGF-B. 
     
     
         36 . The method of  claim 35 , wherein the VEGF-A is isoform VEGF 165. 
     
     
         37 . A method for identifying a molecule which stimulates survival of motor neurons, wherein the method comprises exposing a neuropilin-1 receptor and a VEGF Receptor-2 to at least one molecule thought to modulate motor neurons, and monitoring survival of the motor neurons. 
     
     
         38 . The method of  claim 37 , wherein said monitoring comprising determining inhibition of semaphorin 3A-induced death of the motor neurons. 
     
     
         39 . A method of producing a pharmaceutical composition comprising mixing a molecule identified as stimulating survival of motor neurons with a pharmaceutically acceptable carrier.