Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice.

Hichem Tasfaout, Valentina M Lionello, Christine Kretz, Pascale Koebel, Nadia Messaddeq, Deborah Bitz, Jocelyn Laporte, Belinda S Cowling

Molecular therapy : the journal of the American Society of Gene Therapy 2018 Apr 04

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Myotubular myopathy, or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the myotubularin (MTM1) gene cause myotubular myopathy, and no specific curative treatment is available. We previously found that dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, whereas its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice. Here, we propose a novel approach targeting Dnm2 mRNA. We screened and validated in vitro and in vivo several short hairpin RNA (shRNA) sequences that efficiently target Dnm2 mRNA. A single intramuscular injection of AAV-shDnm2 resulted in long-term reduction of DNM2 protein level and restored muscle force, mass, histology, and myofiber ultrastructure and prevented molecular defects linked to the disease. Our results demonstrate a robust DNM2 knockdown and provide an alternative strategy based on reduction of DNM2 to treat myotubular myopathy. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Citation

Hichem Tasfaout, Valentina M Lionello, Christine Kretz, Pascale Koebel, Nadia Messaddeq, Deborah Bitz, Jocelyn Laporte, Belinda S Cowling. Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice. Molecular therapy : the journal of the American Society of Gene Therapy. 2018 Apr 04;26(4):1082-1092