Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by the lack of dystrophin, which maintains muscle membrane integrity. We used an adenine base editor (ABE) to modify splice donor sites of the dystrophin gene, causing skipping of a common DMD deletion mutation of exon 51 (Delta Ex51) in cardiomyocytes derived from human induced pluripotent stem cells, restoring dystrophin expression. Prime editing was also capable of reframing the dystrophin open reading frame in these cardiomyocytes. Intramuscular injection of Delta Ex51 mice with adeno-associated virus serotype-9 encoding ABE components as a split-intein trans-splicing system allowed gene editing and disease correction in vivo. Our findings demonstrate the effectiveness of nucleotide editing for the correction of diverse DMD mutations with minimal modification of the genome, although improved delivery methods will be required before these strategies can be used to sufficiently edit the genome in patients with DMD.

Automated summary

This study demonstrated the use of adenine base editor to restore dystrophin expression in cardiomyocytes affected by Duchenne muscular dystrophy mutation, as well as reframing the dystrophin open reading frame. In vivo experiments with mice showed successful gene editing and disease correction, indicating the potential of nucleotide editing for diverse DMD mutations with minimal genome modification.