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Stirm, M.* ; Shashikadze, B.* ; Blutke, A.* ; Kemter, E.* ; Lange, A.* ; Stöckl, J.B.* ; Jaudas, F.* ; Laane, L.* ; Kurome, M.* ; Keßler, B.* ; Zakhartchenko, V.* ; Bähr, A.* ; Klymiuk, N.* ; Nagashima, H.* ; Walter, M.* ; Wurst, W. ; Kupatt, C.* ; Fröhlich, T.* ; Wolf, E.*

Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52.

Proc. Natl. Acad. Sci. U.S.A. 120:e2301250120 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of DMD exon 52 (DMDΔ52), expression of an internally shortened dystrophin can be achieved by skipping of DMD exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated DMDΔ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). DMDΔ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in DMDΔ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of DMDΔ51-52 pigs and its absence in DMDΔ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in DMDΔ52 vs. wild-type (WT) samples, was normalized in DMDΔ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in DMDΔ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in DMDΔ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of DMD exon 51 in DMDΔ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of DMDΔ51-52 pigs will show if they develop symptoms of the milder BMD.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Becker Muscular Dystrophy ; Duchenne Muscular Dystrophy ; Exon Skipping ; Pathology ; Pig Model; Skipping Therapy; Mouse Model; Muscle; Quantification; Expression; Database
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 120, Heft: 29, Seiten: , Artikelnummer: e2301250120 Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
Förderungen European Research Council (ERC)
ForTragGmbH fur Forschungstransfer der EKFS
Deutsche Forschungsgemeinschaft
European Research Council
European Union
Else Kroner-Fresenius-Stiftung (EKFS)
Bayerische Forschungsstiftung