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

Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from survival motor neuron (SMN) protein insufficiency resulting from <i>SMN1</i> loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of <i>SMN2</i>, an insufficient copy of <i>SMN1</i> harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five <i>SMN2</i> regulatory regions. Base editing converted <i>SMN2</i> T6>C, restoring SMN protein levels to wild type. Adeno-associated virus serotype 9-mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average life span, which was enhanced by one-time base editor and nusinersen coadministration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.