Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing
Chengzu Long(Southwestern Medical Center), Hui Li(Southwestern Medical Center), Malte Tiburcy(German Centre for Cardiovascular Research), Cristina Rodríguez-Caycedo(Southwestern Medical Center), Viktoriia Kyrychenko(Southwestern Medical Center), Huanyu Zhou(Southwestern Medical Center), Yu Zhang(Southwestern Medical Center), Yi-Li Min(Southwestern Medical Center), John M. Shelton(The University of Texas Southwestern Medical Center), Pradeep P.A. Mammen(Southwestern Medical Center), Norman Y. Liaw(University of Göttingen), Wolfram‐Hubertus Zimmermann(German Centre for Cardiovascular Research), Rhonda Bassel‐Duby(Southwestern Medical Center), Jay W. Schneider(Southwestern Medical Center), Eric N. Olson(Southwestern Medical Center)
Cited by 263Open Access
Abstract
gene and efficiently restored dystrophin protein expression in derivative cardiomyocytes. In three-dimensional engineered heart muscle (EHM), myoediting of DMD mutations restored dystrophin expression and the corresponding mechanical force of contraction. Correcting only a subset of cardiomyocytes (30 to 50%) was sufficient to rescue the mutant EHM phenotype to near-normal control levels. We conclude that abolishing conserved RNA splicing acceptor/donor sites and directing the splicing machinery to skip mutant or out-of-frame exons through myoediting allow correction of the cardiac abnormalities associated with DMD by eliminating the underlying genetic basis of the disease.