Biochemical and clinical variability of Becker muscular dystrophy: Predicting optimal target exons for exon skipping therapy in Duchenne muscular

Karen Anthony, Virginia Arechavala-Gomeza, Valeria Ricotti, Silvia Torelli, Lucy Feng, Giorgio Tasca, Michela Guglieri, Rita Barresi, Annarita Armaroli, Alessandra Ferlini, Kate Bushby, Volker Straub, Enzo Ricci, Caroline Sewry, Jennifer Morgan, Francesco Muntoni

Research output: Contribution to JournalAbstract

Abstract

Exon skipping using antisense oligonucleotides (AONs) is a promising therapy for Duchenne muscular dystrophy (DMD) which aims to genocopy the milder Becker muscular dystrophy (BMD) by restoring the reading frame of an out-of-frame deletion. The less severe phenotype of BMD patients suggests that internally truncated dystrophin retains some functionality. We previously demonstrated that dystrophin and dystrophin-associated protein expression is correlated to clinical severity in BMD patients with in-frame deletions relevant to current exon skipping strategies (exons 51 and 53), and that BMD patients with deletions ending in exon 51 have significantly higher dystrophin levels than those ending in exon 53. We have now studied deletions relevant for skipping exons 44 and 45 which are now being considered for clinical trials. We studied a total of 25 patients; 11 patients had out-of-frame mutations correctable by skipping exons 44 or 45, and 14 patients had in-frame deletions corresponding to the skipping of exon 45. We quantified dystrophin and dystrophin-associated protein expression using immunohistochemistry and total dystrophin mRNA levels using qRT-PCR. DMD patients skippable for exons 44 and 45 had high levels of revertant and trace dystrophin expression (mean: 14% of control) with 6/11 out-of-frame patients presenting with an intermediate phenotype. Corresponding in frame deletions presented with phenotypes ranging from mild to severe BMD, and showed remarkably lower dystrophin levels (∼42% of control) than patients with deletions modelling the skipping of exons 51 or 53 (80% and 56% of control, respectively). Our study provides valuable insights into the stability and/or function of internally truncated dystrophin suggesting that higher levels of the dystrophin produced by skipping exons 44 and 45 are required to achieve the same level of functionality observed with exon 51 and 53 skipping studies.
Original languageEnglish
JournalNeuromuscular Disorders
Publication statusPublished - 2012

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Anthony, K., Arechavala-Gomeza, V., Ricotti, V., Torelli, S., Feng, L., Tasca, G., Guglieri, M., Barresi, R., Armaroli, A., Ferlini, A., Bushby, K., Straub, V., Ricci, E., Sewry, C., Morgan, J., & Muntoni, F. (2012). Biochemical and clinical variability of Becker muscular dystrophy: Predicting optimal target exons for exon skipping therapy in Duchenne muscular. Neuromuscular Disorders.