Titre : | Correction of muscle function in myotubular myopathy by AAV-mediated MTM1 replacement |
contenu dans : | |
Auteurs : | Congrès international de myologie 2008 (International Congress of Myology 2008; 26-30 mai 2008; Marseille, France) ; Buj Bello A ; Fougerousse F ; Jamet T ; Durand M ; Kretz C ; Danos O ; Douar AM ; Montus M ; Denèfle P ; Mandel JL |
Type de document : | Article |
Année de publication : | 2008 |
Pages : | p. 445 |
Langues: | Anglais |
Résumé : | Myotubular myopathy (XLMTM) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small non-regenerative myofibres with frequent occurence of internalized nuclei. No specific treatment exists to date. Recombinant adeno-associated virus (rAAV) vectors appear as one of the most promising tools for gene therapy of muscular disorders. We have constructed rAAV vectors expressing myotubularin under either a ubiquitous (CMV) or a muscle-specific (desmin) promoter in order test their therapeutic potential in a faithful XLMTM mouse model. We show that a single intramuscular injection of either of these vectors in symptomatic Mtm1-deficient mice rescues the pathological phenotype. Myotubularin replacement corrects nuclei and mitochondria positioning in myofibres and leads to a strong increase in muscle volume. Importantly, the contractile force of mutant muscle becomes comparable to that of wild-type animals 4 weeks after rAAV transduction. This study provides a proof of principle that viral-mediated Mtm1 gene delivery may be an effective therapeutic approach for patients with myotubular myopathy. |