2. Academic Validation
  3. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice

Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice

  • Nat Commun. 2017 Jun 7;8:15661. doi: 10.1038/ncomms15661.
Hichem Tasfaout 1 2 3 4,  Suzie Buono 1 2 3 4,  Shuling Guo 5,  Christine Kretz 1 2 3 4,  Nadia Messaddeq 2 3 6,  Sheri Booten 5,  Sarah Greenlee 5,  Brett P Monia 5,  Belinda S Cowling 1 2 3 4,  Jocelyn Laporte 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.
  • 2 INSERM U964, Illkirch 67404, France.
  • 3 CNRS UMR7104, Illkirch 67404, France.
  • 4 FMTS, Strasbourg University, Illkirch 67404, France.
  • 5 Ionis Pharmaceuticals Inc., Carlsbad, California 92010, USA.
  • 6 Service de Microscopie Electronique, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.
PMID: 28589938 DOI: 10.1038/ncomms15661
Abstract

Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 Antisense Oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease.

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