Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials

Karen Anthony, Sebahattin Cirak, Silvia Torelli, Giorgio Tasca, Lucy Feng, Virginia Arechavala-Gomeza, Annarita Armaroli, Michela Guglieri, Chiara S. Straathof, Jan J. Verschuuren, Annemieke Aartsma-Rus, Paula Helderman-Van Den Enden, Katherine Bushby, Volker Straub, Caroline Sewry, Alessandra Ferlini, Enzo Ricci, Jennifer E. Morgan, Francesco Muntoni

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)3544-3556
Number of pages13
JournalBrain
DOIs
Publication statusPublished - 2011

Fingerprint

Dystrophin
Duchenne Muscular Dystrophy
Clinical Trials
Exons
Dystrophin-Associated Proteins
Open Reading Frames
Dystroglycans
Phenotype
Nitric Oxide Synthase Type I
Mutation
Antisense Oligonucleotides
Protein Biosynthesis
Genotype

Keywords

  • Becker muscular dystrophy
  • Duchenne muscular dystrophy
  • dystrophin-associated glycoprotein complex
  • nNOS
  • therapy

Cite this

Anthony, Karen ; Cirak, Sebahattin ; Torelli, Silvia ; Tasca, Giorgio ; Feng, Lucy ; Arechavala-Gomeza, Virginia ; Armaroli, Annarita ; Guglieri, Michela ; Straathof, Chiara S. ; Verschuuren, Jan J. ; Aartsma-Rus, Annemieke ; Helderman-Van Den Enden, Paula ; Bushby, Katherine ; Straub, Volker ; Sewry, Caroline ; Ferlini, Alessandra ; Ricci, Enzo ; Morgan, Jennifer E. ; Muntoni, Francesco. / Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials. In: Brain. 2011 ; pp. 3544-3556.
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Anthony, K, Cirak, S, Torelli, S, Tasca, G, Feng, L, Arechavala-Gomeza, V, Armaroli, A, Guglieri, M, Straathof, CS, Verschuuren, JJ, Aartsma-Rus, A, Helderman-Van Den Enden, P, Bushby, K, Straub, V, Sewry, C, Ferlini, A, Ricci, E, Morgan, JE & Muntoni, F 2011, 'Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials', Brain, pp. 3544-3556. https://doi.org/10.1093/brain/awr291

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials. / Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S.; Verschuuren, Jan J.; Aartsma-Rus, Annemieke; Helderman-Van Den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E.; Muntoni, Francesco.

In: Brain, 2011, p. 3544-3556.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials

AU - Anthony, Karen

AU - Cirak, Sebahattin

AU - Torelli, Silvia

AU - Tasca, Giorgio

AU - Feng, Lucy

AU - Arechavala-Gomeza, Virginia

AU - Armaroli, Annarita

AU - Guglieri, Michela

AU - Straathof, Chiara S.

AU - Verschuuren, Jan J.

AU - Aartsma-Rus, Annemieke

AU - Helderman-Van Den Enden, Paula

AU - Bushby, Katherine

AU - Straub, Volker

AU - Sewry, Caroline

AU - Ferlini, Alessandra

AU - Ricci, Enzo

AU - Morgan, Jennifer E.

AU - Muntoni, Francesco

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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KW - Duchenne muscular dystrophy

KW - dystrophin-associated glycoprotein complex

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KW - therapy

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