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Moretti, A.; Fonteyne, L.; Giesert, F.; Hoppmann, P.; Meier, A. B.; Bozoglu, T.; Baehr, A.; Schneider, C. M.; Sinnecker, D.; Klett, K.; Fröhlich, T.; Rahman, F. Abdel; Haufe, T.; Sun, S.; Jurisch, V.; Kessler, B.; Hinkel, R.; Dirschinger, R.; Martens, E.; Jilek, C.; Graf, A.; Krebs, S.; Santamaria, G.; Kurome, M.; Zakhartchenko, V.; Campbell, B.; Voelse, K.; Wolf, A.; Ziegler, T.; Reichert, S.; Lee, S.; Flenkenthaler, F.; Dorn, T.; Jeremias, I.; Blum, H.; Dendorfer, A.; Schnieke, A.; Krause, S.; Walter, M. C.; Klymiuk, N.; Laugwitz, K. L.; Wolf, E.; Wurst, W. and Kupatt, C. (2020): Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. In: Nature Medicine, Vol. 26, No. 2: pp. 207-214

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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(1), intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. (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 Ca2+ 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.

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