Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the 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 exon 52 ( Δ52), expression...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 29; p. e2301250120 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
18.07.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the
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
exon 52 (
Δ52), expression of an internally shortened dystrophin can be achieved by skipping of
exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated
Δ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD).
Δ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in
Δ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of
Δ51-52 pigs and its absence in
Δ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in
Δ52 vs. wild-type (WT) samples, was normalized in
Δ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in
Δ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in
Δ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of
exon 51 in
Δ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of
Δ51-52 pigs will show if they develop symptoms of the milder BMD. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Thomas Spencer, University of Missouri, Columbia, MO; received January 22, 2023; accepted June 10, 2023 |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.2301250120 |