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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.A.* ; 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. ; Kupatt, C.*

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Nat. Med. 26, 207-214 (2020)

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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 (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs¹, 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 (DMDΔ51-52) 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 DMDΔ52, 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.

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