Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials
Open Access
- 18 November 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 134 (12), 3547-3559
- https://doi.org/10.1093/brain/awr291
Abstract
Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy.Keywords
Funding Information
- Wellcome Trust
This publication has 55 references indexed in Scilit:
- Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation studyThe Lancet, 2011
- Internal deletion compromises the stability of dystrophinHuman Molecular Genetics, 2011
- SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophyNeurology, 2011
- Exon‐skipped dystrophins for treatment of Duchenne muscular dystrophy: Mass spectrometry mapping of most exons and cooperative domain designs based on single molecule mechanicsCytoskeleton, 2010
- DHPR α1S subunit controls skeletal muscle mass and morphogenesisThe EMBO Journal, 2009
- Analysis of Dystrophin Deletion Mutations Predicts Age of Cardiomyopathy Onset in Becker Muscular DystrophyCirculation: Cardiovascular Genetics, 2009
- Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept studyThe Lancet Neurology, 2009
- Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophyJCI Insight, 2009
- Assessment of the feasibility of exon 45–55 multiexon skipping for duchenne muscular dystrophyBMC Medical Genetics, 2008
- Sarcolemma-localized nNOS is required to maintain activity after mild exerciseNature, 2008