2. Academic Validation
  3. Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy

Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy

  • Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11066-11071. doi: 10.1073/pnas.1808170115.
Suzie Buono 1 2 3 4 5,  Jacob A Ross 6,  Hichem Tasfaout 1 2 3 4,  Yotam Levy 6,  Christine Kretz 1 2 3 4,  Leighla Tayefeh 7,  John Matson 7,  Shuling Guo 7,  Pascal Kessler 1 2 3 4,  Brett P Monia 7,  Marc Bitoun 8 9 10,  Julien Ochala 6,  Jocelyn Laporte 11 2 3 4,  Belinda S Cowling 11 2 3 4
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
  • 2 Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France.
  • 3 Centre National de la Recherche Scientifique, UMR7104, Illkirch, 67404, France.
  • 4 Strasbourg University, 67404 Illkirch, France.
  • 5 Dynacure, 67400 Illkirch, France.
  • 6 Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, SE1 1UL London, United Kingdom.
  • 7 Ionis Pharmaceuticals Inc., Carlsbad, CA 92010.
  • 8 UMRS 974, Sorbonne Université, F-75013 Paris, France.
  • 9 INSERM UMRS 974, Institute of Myology, F-75013 Paris, France.
  • 10 Centre of Research in Myology, Institute of Myology, F-75013 Paris, France.
  • 11 Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; jocelyn@igbmc.fr belinda@igbmc.fr.
PMID: 30291191 DOI: 10.1073/pnas.1808170115
Abstract

Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. We have previously shown that reduction of the large GTPase DNM2 in a mouse model of the X-linked form, due to loss of myotubularin Phosphatase MTM1, prevents the development of the skeletal muscle pathophysiology. As DNM2 is mutated in autosomal dominant forms, here we tested whether DNM2 reduction can rescue DNM2-related CNM in a knock-in mouse harboring the p.R465W mutation (Dnm2RW/+) and displaying a mild CNM phenotype similar to patients with the same mutation. A single intramuscular injection of adeno-associated virus-shRNA targeting Dnm2 resulted in reduction in protein levels 5 wk post injection, with a corresponding improvement in muscle mass and fiber size distribution, as well as an improvement in histopathological CNM features. To establish a systemic treatment, weekly i.p. injections of Antisense Oligonucleotides targeting Dnm2 were administered to Dnm2RW/+mice for 5 wk. While muscle mass, histopathology, and muscle ultrastructure were perturbed in Dnm2RW/+mice compared with wild-type mice, these features were indistinguishable from wild-type mice after reducing DNM2. Therefore, DNM2 knockdown via two different strategies can efficiently correct the myopathy due to DNM2 mutations, and it provides a common therapeutic strategy for several forms of centronuclear myopathy. Furthermore, we provide an example of treating a dominant disease by targeting both alleles, suggesting that this strategy may be applied to other dominant diseases.

Keywords

adeno-associated virus; antisense oligonucleotides; congenital myopathy; dynamin 2; myotubular myopathy.

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