TOWARDS AN UNDERSTANDING OF THE PATHOPHYSIOLOGY AND THE DEVELOPMENT OF THERAPEUTICS IN SPINAL MUSCULAR ATROPHY (SMA)

 

SMA is caused by mutations of the SMN1 gene. The pathogenic mechanism leading to motor neuron degeneration remains unclear and no curative treatment is available so far. Models of SMA have been created in our laboratory. Homozygous deletion of Smn exon 7 directed to neurons (“neuronal mutant”) leads to severe axonal degeneration contrasting with moderate and late loss of motor neuron cell bodies suggesting a primary involvement of axons in SMA. When directed to myotubes but not muscle progenitor cells, the Smn mutation results in progressive motor defect which is tightly correlated with the progressive loss of the regenerative capacity of the muscle. Different therapeutic strategies have been undertaken in SMA aiming at either upregulating SMN2 gene expression (a copy of SMN1), preventing exon 7 skipping of SMN2, protecting motor neurons from death or replacing damaged cells. We have provided the first evidence that the SMA disease course of neuronal mutant mice might be attenuated even after the onset of symptoms by using neuroprotective or neurotrophic agents which represent candidate therapeutic approaches in SMA. The potential of bone marrow derived stem cells alone or associated with physical training is currently evaluated in our mouse models. Several strategies have been undertaken to elucidate 1) the functions of SMN in motor neurons, 2) the putative relationship between motor neuron degeneration and fusion process, 3) the role of skeletal muscle in the motor neuron phenotype and finally 4) to test the hypothesis of a common molecular pathway involved in motor neuron diseases. Clarifying the SMA pathogenesis should lead to the design novel therapeutic avenues in SMA.