Spinal Muscular Atrophy Therapeutics Development

Abstract Spinal muscular atrophy (SMA) is a devastating genetic disease caused by mutations in the survival motor neuron 1 ( SMN1 ) gene that encodes SMN protein. Since mid-1990s when the SMN gene has been identified as the cause of SMA, the SMA field has made significant strides in understanding the disease's pathophysiology and has successfully generated important drug development tools such as screening assays, biomarkers, and animal models. Although a disease-modifying SMA drug has not yet been approved by the FDA and made available to patients, there are several promising therapeutics for SMA currently under clinical trials. SMA drug development efforts have been remarkable for the involvement of industry, academic researchers, advocacy groups, and government. Most therapeutic approaches for SMA focus on the upregulation of functional SMN protein levels, but other SMN-independent approaches, including neuroprotection and enhancement of muscle size and strength, are also being explored. This chapter presents an overview of the diverse strategies that are being and have previously been pursued in SMA therapeutic development, as well as some lessons learned from these efforts that may be applicable to drug development in other diseases.