期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 15, 页码 4225-4237出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv155
关键词
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资金
- Association Francaise contre les Myopathies [14784]
- Muscular Dystrophy Campaign [RA4/858]
- Duchenne Research Fund
- Medical Research Council [G0900887]
- Wellcome Trust
- Medical Research Council (MRC) [U105178803]
- MRC [MC_U105178803, G0900887] Funding Source: UKRI
- Medical Research Council [MC_U105178803] Funding Source: researchfish
Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slowdown or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.
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