1. Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy
- Author
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Moretti, A., Fonteyne, L., Giesert, F., Hoppmann, P., Meier, A. B., Bozoglu, T., and Baehr, A.
- Subjects
Cytokines -- Health aspects ,Duchenne muscular dystrophy -- Care and treatment ,Gene therapy -- Patient outcomes ,Membrane proteins -- Health aspects ,Biological sciences ,Health - Abstract
Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMD[DELTA]52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMD[DELTA]52 pigs.sup.1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. .sup.2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMD[DELTA]51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMD[DELTA]52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca.sup.2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease. CRISPR-Cas9-mediated gene editing restores dystrophin expression in both pig and human induced pluripotent stem cell models of Duchenne muscular dystrophy, with beneficial effects on skeletal muscle and cardiac function., Author(s): A. Moretti [sup.1] , L. Fonteyne [sup.2] , F. Giesert [sup.3] , P. Hoppmann [sup.1] , A. B. Meier [sup.1] , T. Bozoglu [sup.1] , A. Baehr [sup.1] , [...]
- Published
- 2020
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