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

• Published in: Nature communications 2017-06, Vol.8 (1), p.15661-15661, Article 15661
• Main Authors: Tasfaout, Hichem, Buono, Suzie, Guo, Shuling, Kretz, Christine, Messaddeq, Nadia, Booten, Sheri, Greenlee, Sarah, Monia, Brett P., Cowling, Belinda S., Laporte, Jocelyn
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 14/19; 14/28; 38; 631/154/556; 631/61/391/1914; 64/60; 692/617/375/374; 692/698/1671/1668/1973; 82/29; 82/51; 82/58; 82/80; Animals; Disease Models, Animal; Dynamin II - genetics; Dynamin II - metabolism; Female; Genetics; Humanities and Social Sciences; Kidney - metabolism; Life Sciences; Liver - metabolism; Male; Mice; Mice, Knockout; multidisciplinary; Muscle Contraction; Muscle, Skeletal - metabolism; Mutation; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - metabolism; Myopathies, Structural, Congenital - therapy; Neuromuscular diseases; Oligonucleotides, Antisense - genetics; Phenotype; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Proteins; Recombination, Genetic; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15661

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. X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.