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.