Use of VEGF and homologuest 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 amyotrophic lateral sclerosis (ALS) in a mammal, the method comprising administering to the mammal an expression vector comprising a nucleic acid sequence encoding vascular endothelial growth factor (VEGF), wherein expression of VEGF in a motor neuron treats ALS in the mammal.  
     
     
         17 . The method of  claim 16 , wherein VEGF is a VEGF-A.  
     
     
         18 . The method of  claim 17 , wherein VEGF-A is isoform VEGF 165 .  
     
     
         19 . A method of enhancing survival of a motor neuron in a mammal, the method comprising administering to the mammal an expression vector comprising a nucleic acid sequence encoding vascular endothelial growth factor (VEGF), wherein expression of VEGF in a motor neuron enhances survival of the motor neuron in the mammal.  
     
     
         20 . The method of  claim 19 , wherein VEGF is a VEGF-A.  
     
     
         21 . The method of  claim 20 , wherein VEGF-A is isoform VEGF 165 .