Awarded to Professor Mimoun Azzouz, Sheffield University, March 2007.
Abstract
Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease.
Gene therapy approaches involving the use of viral vectors offer a promising strategy for delivery of genes to enhance motor neuron survival. We have previously demonstrated that lentiviral vectors encoding for human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. The same vector system was used to treat the SMA type 1 mouse model. The treatment restored SMN protein to motor neurons, reduced motor neuron death and increased the life expectancy by an average of 3 to 5 days compared control groups. Taken together, these data report the first preclinical proof-of-concept of the potential use of viral vectors as a therapeutic strategy for SMN replacement and represent, therefore, a powerful method to prevent motor neuron degeneration in SMA.
Further extension of survival by SMN replacement will likely require knowledge of when and/or where high levels of SMN protein are needed. Further pre-clinical studies are needed before entering clinical application in SMA patients. It has been shown that systemic administration of adeno-associated vectors (serotype 6) (AAV6) in rodent led to a wide spread expression of the reporter gene in spinal and brain motor neurons.
We therefore propose to undertake experiments aiming to optimise the therapeutic vectors. AAV6 vectors expressing codon optimised SMN will be used to generate efficacy data in SMA mouse models.
We gratefully acknowledge the contribution of the SMA Trust towards the funding of this project. | 
