A Permanent Genetic Treatment for Spinal Muscular Atrophy Using Base Editors

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the SMN1 gene that reduce survival motor neuron (SMN) protein expression. Despite progress in the field that has resulted in therapies, there remains no permanent cure for SMA. SMN2 is a paralogous gene that mainly differs from SMN1 by a C•G-to-T•A transition in exon 7, resulting in the skipping of exon 7 in most SMN2 transcripts. Editing of the SMN2 exon 7 mutation should in principle offer a therapeutic strategy to restore SMN protein levels. Here, I will present a base editing approach to precisely edit SMN2 to revert the T•A to C•G mutation. We tested a range of different adenosine base editors (ABEs) and Cas9 variants, resulting in >80% intended editing in patient-derived fibroblasts with concomitant increases in SMN2 exon 7 and SMN protein levels. Delivery of these optimized ABEs via a dual adeno-associated virus approach resulted in precise SMN2 editing in an SMA mouse model. Moreover, we generated and characterized ABEs fused to high-fidelity versions of Cas9 variants which reduced potential off-target editing. These novel technologies may provide a long-lasting cure for SMA with several advantages compared to exogenous gene replacement. 

Learning Objectives:

1. Discuss the genetic basis of a severe neuromuscular disease.

2. Explain how base editors work.

3. List some basic scientific considerations while developing a gene editing therapy.