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Hum Mol Genet. 2015 Aug 1;24(15):4225-37. doi: 10.1093/hmg/ddv155. Epub 2015 May 1.

How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse.

Author information

1
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
2
Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
3
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK, GENEPEP SA, Les Coteaux St Roch, 12 Rue du Fer à Cheval, 34430 St Jean de Védas, France and.
4
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
5
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK, Department of Laboratory Medicine, Karolinska Institutet, Hälsov. 7, SE-14186 Huddinge, Sweden.
6
Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK, dwells@rvc.ac.uk.

Abstract

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 slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.

PMID:
25935000
PMCID:
PMC4492390
DOI:
10.1093/hmg/ddv155
[Indexed for MEDLINE]
Free PMC Article

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