Nature Communications Publishes Preclinical Results Evaluating Antisense Drugs Targeting DNM2 for the Treatment of Centronuclear Myopathy

— Antisense-mediated reduction in DNM2 prevents and rescues myotubular myopathy in mice —

Centronuclear myopathy (CNM) is a rare neuromuscular disease characterized by delayed motor milestones and muscular weakness. Myotubular myopathy, the most severe form of CNM, is a fatal disease that causes profound muscle weakness, feeding difficulty and respiratory distress. Currently, there are no specific treatment options available for patients with myotubular myopathy.

Patients with myotubular myopathy present with an overexpression of dynamin2 (DNM2) protein due to myotubular (MTm1) loss-of-function mutations. Prior research has demonstrated that overexpression of DNM2 results in a CNM phenotype in mice, while decreased levels of DNM2 prevented myotubular myopathy in a mouse model of the disease. Taken together, these findings point to DNM2 as an attractive therapeutic target for the treatment of CNM.

Ionis scientists, in collaboration with researchers at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Illkirch, France, evaluated the effects of reducing DNM2 with DNM2-targeting Generation 2.5 antisense drugs in a mouse model of myotubular myopathy. Generation 2.5 chemistry was designed to increase target affinity, therefore improving potency. This increased potency enables Generation 2.5 antisense drugs to address neuromuscular diseases like CNM by engaging RNA targets in tissues, like skeletal muscle, that are less accessible to antisense drugs. Key findings from the preclinical studies were published in Nature Communications in a paper titled, “Antisense oligonucleotide-mediated DNM2 knockdown prevents and reverts myotubular myopathy in mice.”

In a series of preclinical studies, researchers demonstrated that systemic delivery of DNM2-targeting Generation 2.5 antisense drugs in a mouse model of myotubular myopathy, Mtm1 knockout (Mtm1KO) mice, dose-dependently reduced DNM2 protein levels.  Treatment with DNM2-targeting antisense drugs also extended lifespan and improved whole-body strength when assessed by hanging, grip, string and rotarod tests, compared to untreated mice. Researchers also demonstrated that a reduction in DNM2 levels by approximately 50% was sufficient to achieve disease prevention in the mouse model. Moreover, weekly treatment in post-symptomatic and severely affected Mtm1KO mice rapidly stabilized disease progression and reversed most aspects of the disease phenotype within two weeks of treatment. Taken together, these results demonstrate that weekly systemic delivery of DNM2-targeting antisense drugs in Mtm1KO mice efficiently prevents and reverses myotubular myopathy by rescuing lifespan and restoring muscular force, mass and histology.

These preclinical results validate DNM2 as a therapeutic target for CNM and highlight antisense-mediated reduction of DNM2 as an attractive approach to potentially treat this severe disease in humans. Ionis, in collaboration with Dynacure, is further evaluating DNM2-targeting Generation 2.5 antisense drugs to identify an optimal drug candidate to develop for treatment of patients with severe CNM.


  1. Tasfaout et al., “Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice.” Nature Communications 8, Article number: 15661 (2017), Published online June 7, 2017.