Relevance of the axonal SMN protein (a-SMN) for Spinal Muscular Atrophy: novel cell models, transgenic mice and therapeutic approaches

Spinal muscular atrophy (SMA) is a severe disease characterized by selective degeneration of spinal cord motor neurons and primarily affecting childhood. The clinical picture of SMA is a progressive paralysis involving all skeletal muscles. In more severe cases, it leads to respiratory insufficiency and death. SMA is one of the leading genetic causes of infant mortality, affecting about one child in 6000-10000 live births. The disease gene called Survival Motor Neuron (SMN) was identified in 1995 but the reason why the loss of this gene causes the disease is still debated, and no effective therapy is currently ready for affected patients. In 2007, our group has discovered a novel protein produced by the SMN gene, called a-SMN (for axonal SMN), which has interesting functional properties. It induces axon growth and may be involved in the pathogenesis of SMA. The final objective of the proposal is to establish the contribution of a-SMN deficiency to SMA pathogenesis, through cellular and animal models. Altogether, these experiments should provide definitive proof of the biological relevance of the a-SMN protein in SMA and lead to the development of effective therapeutic strategies for this devastating disease. We’re going to perform gene therapy experiments in SMA mice not only to verify the therapeutic value of a-SMN, but also to check whether co-administration of both SMN proteins represents a better therapeutic option than single administration of the FL-SMN counterpart.