Base editing rescue of spinal muscular atrophy in cells and in mice

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from SMN protein insufficiency following SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2, an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild-type. AAV9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average lifespan, which was enhanced by one-time base editor+nusinersen co-administration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.