PuSH - Publication Server of Helmholtz Zentrum München: Systemic deletion of <em>DMD</em> exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking <em>DMD</em> exon 52.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

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)

Publ. Version/Full Text

DOI

PMC

	Open Access Gold (Paid Option)

Abstract
Metrics
Extra information

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.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords 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

Journal Proceedings of the National Academy of Sciences of the United States of America

Quellenangaben Volume: 120, Issue: 29, Article Number: e2301250120

Publisher National Academy of Sciences

Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)

Grants European Research Council (ERC)
ForTragGmbH fur Forschungstransfer der EKFS
Deutsche Forschungsgemeinschaft
European Research Council
European Union
Else Kroner-Fresenius-Stiftung (EKFS)
Bayerische Forschungsstiftung