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-based therapies. Here, we describe the generation of the Dup18-30 mouse model, harbouring 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. This dataset includes the deep amplicon sequencing analysis performed to detect single-sgRNA/Cas9 off-target and on-target effects in the Dup18-30 mice after treatment.Funding provided by: Duchenne Research FundCrossref Funder Registry ID: http://dx.doi.org/10.13039/100009358Funding provided by: Jesse's Journey*Crossref Funder Registry ID: Award Number: Funding provided by: Duchenne UK*Crossref Funder Registry ID: Award Number: Funding provided by: Jesse's JourneyCrossref Funder Registry ID: Funding provided by: Duchenne UKCrossref Funder Registry ID