Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy

Nelson CE, Wu Y, Gemberling MP, et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nature medicine 2019;25:427-432

Nelson_2019_Nat Med. Mar;25(3);427-432

Crisp-Cas9 genome editing in a mouse model for DMD (mdx). It shows that the results are persistent and that immune responses can be avoided by starting the treatment immediately after birth (which will not be possible in patients). Furthermore, several safety issues are observed, like modifying effects in other parts of the genome, which could potentially be dangerous.


Duchenne muscular dystrophy (DMD) is a monogenic disorder and a candidate for therapeutic genome editing. There have been several recent reports of genome editing in preclinical models of Duchenne muscular dystrophy(1-6), however, the long-term persistence and safety of these genome editing approaches have not been addressed. Here we show that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of Duchenne muscular dystrophy for 1 year after a single intravenous administration of an adeno-associated virus that encodes CRISPR (AAV-CRISPR). We also show that AAV-CRISPR is immunogenic when administered to adult mice(7); however, humoral and cellular immune responses can be avoided by treating neonatal mice. Additionally, we describe unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. This study shows the potential of AAV-CRISPR for permanent genome corrections and highlights aspects of host response and alternative genome editing outcomes that require further study.

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