Centronuclear myopathy: towards the development of a therapy
Cross sections of skeletal muscle. On the left, an image showing healthy muscle fibers, in the middle, muscle fibers of an affected myopathic mouse (smaller fibers with nuclei in the center) and on the right muscle of a myopathic mouse treated with ASOs targeting DNM2 (normal fiber diameter and more nuclei at the periphery of the muscle fibers). Of note the ASO control does not specifically target any mouse genes and has no effect on DNM2 expression.
June 7, 2017
After identifying Dynamin 2 as a potential therapeutic target in congenital myopathies, the team of Jocelyn Laporte has managed to specifically modulate the level of this molecule and to cure almost all signs of disease. These results published on the 7th of June 2017 in the journal Nature Communications provide excellent perspectives for therapeutic development.
Centronuclear myopathies (CNM or myotubular myopathies) are rare genetic diseases characterized by a very disabling muscular weakness and early death. There are several genetic causes of CNM, in particular mutations of genes coding for myotubularin (MTM1) or dynamin2 (DNM2), proteins that regulate the organization of muscle fibers. To date, no specific therapy is available to treat CNM.
Three years ago, researchers from Jocelyn Laporte’s team demonstrated in myopathic mice lacking MTM1 that decreasing the level of DNM2 by genetic cross improved the clinical signs of the disease (Cowling et al., 2014). Animals that previously died of the myopathy by 2 months of age, instead survived 2 years, a normal lifetime for mice. This proof-of-concept published in 2014 identified DNM2 as a new therapeutic target, generating a large interest for therapeutic development. This required however that an injectable compound targeting DNM2 could be developed for clinical use.
Hichem Tasfaout, Belinda Cowling and Jocelyn Laporte at the IGBMC have collaborated with Ionis Pharmaceuticals, a world leader in antisense oligonucleotides (ASO) technology. ASOs are synthetic RNA fragments that can bind very specifically to target messenger RNAs to promote their degradation.
These researchers have demonstrated that injections of ASOs targeting DNM2 messenger RNA in myopathic mice effectively reduced the level of DNM2 and restore muscle function, either to prevent development of the disease (injection before onset of symptoms) or to revert the signs of the myopathy (injections in a severely affected animal). Treatment resulted in improved muscle function and increased lifespan, using a chemistry and dose that can be translated to patients.
These very promising results contributed to the creation of the start-up company Dynacure, which aims to transform this approach into clinical trials.