Spinal muscular atrophy (SMA) is a common childhood autosomal recessive disease caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene. One of the primary features of SMA is the progressive loss of neuromuscular function that is often fatal, making SMA the leading genetic cause of death in infants and young children. Motor neuron death is a significant feature of this disease, but some recent information suggests that muscle dysfunction or malformation may also occur. While SMN appears to have multiple cellular roles, and it is not yet clear which of them support neuromuscular development and health, a reasonable amount of patient information indicates that higher levels of SMN expression are associated with less severe cases of disease. This suggests a clear therapeutic strategy: namely, identifying the pathways and, ultimately, drug classes that increase SMN levels. However, there are alternate strategies, one of which is finding pathways that function independently of SMN and are corrective when SMN levels are reduced. To accomplish this, we and our collaborators have carried out two sets of screens. The first set used chemical and biological libraries to search for compounds that increase amounts of SMN in mouse motor neurons and other cells. The second set used genetic methods to find genes that can ameliorate SMA phenotypes in fly and worm models. We will establish a set of key phenotypic assays to test all of the compounds and genes that come out of the screens. These will include mouse motor neuron survival, skeletal muscle development and neuromuscular junction formation. In addition, we will test these compounds and genes on human motor neurons produced from induced pluripotent stem (iPS) cells made from an SMA patient. Targets identified from chemical screens will be cross-validated in genetic models. Thus, hits from all the screens will be evaluated and compared rigorously. Finally, compounds indentified from these screens will be tested in mouse SMA models. The end result of this work should be thoroughly characterized compounds that can potentially be used to develop therapeutics for this childhood disease.

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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Harvard Medical School
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