title: Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy.
abstract: We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. We now show that this dystrophin expression was accompanied by an elevated expression of α-sarcoglycan, β-dystroglycan (BDG) and--in relevant cases--neuronal nitric oxide synthase (nNOS) at the sarcolemma, each of which is a component of a different subcomplex of the dystrophin-associated glycoprotein complex (DAPC). As expected, nNOS expression was relocalized to the sarcolemma in Duchenne patients in whom the dystrophin deletion left the nNOS-binding domain (exons 42-45) intact, whereas this did not occur in patients with deletions that involved this domain. Our results indicate that the novel internally deleted and shorter dystrophin induced by skipping exon 51 in patients with amenable deletions, can also restore the dystrophin-associated complex, further suggesting preserved functionality of the newly translated dystrophin.
authors.affiliation: The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: Karen
authors.initials: K
authors.lastname: Anthony
authors.forename: Virginia
authors.initials: V
authors.lastname: Arechavala-Gomeza
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D017398:Alternative Splicing; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D049028:Dystrophin-Associated Protein Complex / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D060172:Morpholinos; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D009841:Oligonucleotides / Q000008:administration & dosage
chemical_list: D016189:Dystrophin; D049028:Dystrophin-Associated Protein Complex; D060172:Morpholinos; D009841:Oligonucleotides; C000611335:eteplirsen
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