Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death, occurring in ~1:6,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). SMN2 is nearly identical to SMN1, however, mutations in SMN2 have no clinical consequence if SMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated and unstable protein. While increasing SMN levels may be sufficient for many forms of SMA, an effective treatment regimen for the breadth of the clinical SMA spectrum may require a combinatorial approach that includes ?SMN-independent? approaches to address the complexity of the disease. SMN-independent therapeutics can be envisioned as a means to augment an SMN-associated function or compensate for a secondary defect/pathway, each of which would not necessarily require an increase in SMN protein levels. Consistent with this notion, two compounds have entered clinical trials for SMA that are mechanistically distinct from the potential therapeutics that increase SMN: a neuroprotectant being developed by Roche (Olesoxime); and a skeletal muscle activator being developed by Cytokinetics (CK-2127107) (10, 11). Going forward, novel SMN-independent targets for drug development will likely play an important role in treating SMA, and genetic modifiers of SMA are a likely source for SMN-independent drug targets. The objective of this proposal is to identify SMN-independent modifiers of disease as a means to identify functional and druggable targets for SMA.
Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disease that is the leading genetic cause of infantile death worldwide. In this proposal, the objective is to identify genes that can reduce the severity of the disease and potentially become therapeutic targets.
