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

Hichem Tasfaout, Suzie Buono, Shuling Guo, Christine Kretz, Nadia Messaddeq, Sheri Booten, Sarah Greenlee, Brett P. Monia, Belinda S. Cowling () and Jocelyn Laporte ()
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Hichem Tasfaout: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Suzie Buono: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Shuling Guo: Ionis Pharmaceuticals Inc.
Christine Kretz: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Nadia Messaddeq: INSERM U964
Sheri Booten: Ionis Pharmaceuticals Inc.
Sarah Greenlee: Ionis Pharmaceuticals Inc.
Brett P. Monia: Ionis Pharmaceuticals Inc.
Belinda S. Cowling: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Jocelyn Laporte: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15661

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