Project 1: Therapeutic Gene Editing for Spinal Muscular Atrophy (Trailblazer)

PROJECT SUMMARY PROJECT 1 (SMA) Spinal Muscular Atrophy (SMA) is a progressive motor neuron disease (MND) and the leading genetic cause of infant mortality across all ethnic groups. SMA is caused by the homozygous loss of the essential survival motor neuron 1 (SMN1) gene and while one or more copies of the highly similar SMN2 gene partially compensates for the loss of SMN1 in SMA patients, SMN1, in contrast to SMN2, contains a C·G-to-T·A change at position 6 of exon 7 (C6T). This change leads to skipping of exon 7 during mRNA splicing and the resulting truncated SMNΔ7 protein is rapidly degraded in cells. This rapid degradation results in SMN protein insufficiency, loss of motor neurons, paralysis, and death. Patients with the most common form of SMA, type I, have a ~10-fold reduction in SMN protein levels and live to a median age of 6 months if untreated. In this trailblazer project, we aim to (1) Optimize base editing treatment protocols in Δ7 SMA mice; (2) Assess biodistribution, off-targets, and toxicity profiles in SMA mice; and (3) Conduct large-scale efficacy studies. We will work closely with the Gene Editing core to generate rigorous analyses of gene editing outcomes for the IND submission of our trailblazer project, and we will coordinate closely with the Preclinical Mouse Model Core to analyze samples from large-scale efficacy studies. The successful outcomes of this trailblazer project will also inform the strategies used to develop genome editing-based therapeutic leads in all Follower Projects.