Targeted genome editing in vivo corrects a Dmd duplication restoring wild-type dystrophin expression

Tandem duplication mutations are increasingly found to be the direct cause of many rare heritable diseases, accounting for up to 10% of cases. Unfortunately, animal models recapitulating such mutations are scarce, limiting our ability to study them and develop genome editing therapies. Here, we describe the generation of a novel duplication mouse model, harboring a multi-exonic tandem duplication in the Dmd gene which recapitulates a human mutation. Duplication correction of this mouse was achieved by implementing a single-guide RNA (sgRNA) CRISPR/Cas9 approach. This strategy precisely removed a duplication mutation in vivo, restored full-length dystrophin expression, and was accompanied by improvements in both histopathological and clinical phenotypes. We conclude that CRISPR/Cas9 represents a powerful tool to accurately model and treat tandem duplication mutations. Our findings will open new avenues of research for exploring the study and therapeutics of duplication disorders.

Automated summary

Tandem duplication mutations are increasingly being recognized as a direct cause of rare heritable diseases, but the lack of suitable animal models has hindered research and therapeutic development. A novel mouse model with a multi-exonic tandem duplication in the Dmd gene was successfully corrected using a CRISPR/Cas9 approach, leading to restoration of full-length dystrophin expression and improvements in histopathological and clinical phenotypes. This study highlights the potential of CRISPR/Cas9 as a powerful tool for accurately modeling and treating tandem duplication mutations.