Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy

Sebahattin Cirak, Lucy Feng, Karen Anthony, Virginia Arechavala-Gomeza, Silvia Torelli, Caroline Sewry, Jennifer E. Morgan, Francesco Muntoni

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)462-467
Number of pages6
JournalMolecular Therapy
DOIs
Publication statusPublished - 2012

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Dystrophin
Duchenne Muscular Dystrophy
Exons
Glycoproteins
Nitric Oxide Synthase Type I
Sarcolemma
Therapeutics
Sarcoglycans
Dystroglycans
Morpholinos
Intramuscular Injections
Oligonucleotides
Open Reading Frames

Cite this

Cirak, Sebahattin ; Feng, Lucy ; Anthony, Karen ; Arechavala-Gomeza, Virginia ; Torelli, Silvia ; Sewry, Caroline ; Morgan, Jennifer E. ; Muntoni, Francesco. / Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy. In: Molecular Therapy. 2012 ; pp. 462-467.
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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.",
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Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy. / Cirak, Sebahattin; Feng, Lucy; Anthony, Karen; Arechavala-Gomeza, Virginia; Torelli, Silvia; Sewry, Caroline; Morgan, Jennifer E.; Muntoni, Francesco.

In: Molecular Therapy, 2012, p. 462-467.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in duchenne muscular dystrophy

AU - Cirak, Sebahattin

AU - Feng, Lucy

AU - Anthony, Karen

AU - Arechavala-Gomeza, Virginia

AU - Torelli, Silvia

AU - Sewry, Caroline

AU - Morgan, Jennifer E.

AU - Muntoni, Francesco

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