title: Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials.
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.
authors.affiliation: The Dubowitz Neuromuscular Centre, UCL, Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Anthony
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: Virginia
authors.initials: V
authors.lastname: Arechavala-Gomeza
authors.forename: Annarita
authors.initials: A
authors.lastname: Armaroli
authors.forename: Michela
authors.initials: M
authors.lastname: Guglieri
authors.forename: Chiara S
authors.initials: CS
authors.lastname: Straathof
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Verschuuren
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.forename: Paula
authors.initials: P
authors.lastname: Helderman-van den Enden
authors.forename: Katherine
authors.initials: K
authors.lastname: Bushby
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016366:Open Reading Frames; D010641:Phenotype; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D016189:Dystrophin
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