Single-Swap Base Editing for the Correction of Common Duchenne Muscular Dystrophy Mutations

Duchenne Muscular Dystrophy, DMD, is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein. Here we describe the use of an adenine base editor for single-swap editing of the three most therapeutically relevant exons, DMD exons 45, 51, and 53, that could benefit 30 percent of all DMD patients. Single-swap editing can enable beneficial exon skipping or reframing and restore dystrophin protein production in human induced pluripotent stem cell-derived cardiomyocytes. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate base editing as a potential gene editing therapy for common DMD mutations.