Restoration of the UPS through enhancement of UBA1 levels Elaine Pityn
Spinal Muscular Atrophy (SMA) is a disease caused by mutations in survival motor neuron 1 gene (SMN1), inherited through an autosomal recessive pattern. Mutations in SMN1 reduce levels of survival motor neuron (SMN) protein, which causes muscle atrophy and death in severe cases. The reduction of SMN results in aberrant molecular pathways that may be targeted for therapeutic approaches like the ubiquitin pathway. Research shows the depletion of ubiquitin activating enzyme 1 (UBA1) across all SMA models and patient’s cells (Powis et al. 2016). Replenishment of UBA1 prevents SMA pathogenesis; for instance in SMA zebrafish, motor axon and motor performance were improved (Powis et al. 2016) . UBA1 levels were replenished by a gene therapy approach with adeno-associated virus serotype 9-UBA1 (AAV9-UBA1). In mouse models it was shown that mice could withstand AAV-UBA1 levels over long periods and secondly, systemic restoration of UBA1 resulted in less organ pathology and improved neuromuscular outcomes, overall weight, survival, and motor performance (Powis et al. 2016). The findings suggest UBA1 restoration has potential as a therapy for SMA.
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