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

作者：Tasfaout Hichem; Buono Suzie; Guo Shuling; Kretz Christine; Messaddeq Nadia; Booten Sheri; Greenlee Sarah; Monia Brett P; Cowling Belinda S; Laporte Jocelyn

来源：Nature Communications, 2017, 8(1): 15661.

DOI：10.1038/ncomms15661

<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>MTM1</jats:italic>) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (<jats:italic>DNM2</jats:italic>) mutations. We previously showed that genetic reduction of DNM2 expression in <jats:italic>Mtm1</jats:italic> knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of <jats:italic>Dnm2</jats:italic> 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.</jats:p>

• 出版日期2017-6-7