A new publication in the journal PNAS further confirms the role of DNM2 reduction in potential treatment for centronuclear myopathies. Previously the team at IGBMC in Strasbourg had established that reducing levels of the protein Dynamin 2 reduces symptoms in the muscle disease caused by mutations in the MTM1 and BIN1 genes. This was a very exciting development as it highlighted a potential common treatment for these conditions. This new publication confirms that the same strategy is effective in reducing centronuclear myopathy disease symptoms caused by the DNM2 gene itself.

PNAS is the journal of the National Academy of Sciences of the USA. You can read the full article here:  Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy, Buono et al 2018 

Lay summary

‘There are several forms of centronuclear myopathies due to mutations in different genes. Dynamin is found everywhere in the body, however mutation in dynamin 2 (DNM2) can cause one form of centronuclear myopathy. We know that dynamin has a very important role in muscles, and it works closely together with other genes mutated in centronuclear myopathies. We are investigating if reducing dynamin is beneficial for centronuclear and myotubular myopathies. We have shown previously that by reducing dynamin we can rescue the symptoms of myotubular myopathy in mice, as well as one type of centronuclear myopathy in mice, due to mutations in amphiphysin (BIN1). In this study we wanted to investigate if reducing dynamin is also beneficial for another form of centronuclear myopathy, due to mutations in dynamin 2 (DNM2), in mice.

Unlike in myotubular myopathy where the loss of myotubularin is the cause of the disease, previous studies suggest that mutations in dynamin 2 may cause the protein to become more active. Mice have been created by the team of Marc Bitoun (Institute of Myology, Paris), which have a dynamin 2 mutation commonly found in patients. These mice have a mild muscle weakness, and altered muscle fiber size. Using these mice we tested if reducing dynamin could improve the myopathy phenotype. We tested two different approaches: a viral approach (adeno-associated virus), and an antisense oligonucleotide approach, to reduce dynamin. Using either approach to reduce dynamin, we found that the distribution of muscle fibers was restored, with mice exhibiting normal fiber size. In addition muscle mass was also restored to wild type levels, and muscle fiber structure was corrected. Importantly reducing dynamin did not seem to have any obvious negative effects in these mice. In mice this is very promising, and we are now working with industrial partners to try and develop an antisense oligonucleotide drug that can be delivered; in the short term to animals in preclinical trials, and in the long term if successful we hope to be able to start clinical trials with patients.’ Dr Belinda Cowling, Head of Research, Dynacure www.dynacure.com