Open AccessTargeted genome editing in vivo corrects a Dmd duplication restoring wild‐type dystrophin expression
Author(s) -
Maino Eleonora,
Wojtal Daria,
Evagelou Sonia L,
Farheen Aiman,
Wong Tatianna W Y,
Lindsay Kyle,
Scott Ori,
Rizvi Samar Z,
Hyatt Elzbieta,
Rok Matthew,
Visuvanathan Shagana,
Chiodo Amanda,
Schneeweiss Michelle,
Ivakine Evgueni A,
Cohn Ronald D
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013228
Subject(s) - sick child , medical genetics , genetics , genome , medicine , library science , biology , pediatrics , computer science , gene
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.