Centronuclear myopathies

At Dynacure, our goal is to advance a disease-modifying therapy for patients suffering from Centronuclear Myopathies (CNM),a rare group of genetic muscular disorders ranging from mild to severely affected, with symptoms manifesting from birth to late adulthood, and with variable inheritance ranging from X-linked recessive (XLCNM), autosomal dominant (ADCNM), and autosomal recessive (ARCNM).

Muscle weakness can affect ambulation to the point of requiring wheelchair use, respiratory muscle weakness often needs ventilatory assistance, and difficulty swallowing may lead to a requirement for a gastrostomy to ensure adequate nutrition.

Centronuclear Myopathies are rare and affect between 4,000 and 5, 000 patients in the EU, US, Japan and Australia.

Dynacure believes that antisense technology is the optimal mechanism of action to treat CNM, given the proven ability of potent antisense medicines to modulate difficult to drug biologic targets in other rare diseases. It has been demonstrated that Dyn101 downregulates the expression of dynamin 2, which leads to the prevention and reversion of the disease in a relevant mouse model.

CNMs are genetically widely heterogeneous, and three classical forms of CNM have been characterized:

  • X-linked CNM (XLCNM; OMIM 310400), due to mutations in the phosphoinositides phosphatase myotubularin (MTM1) (Laporte et al., 1996);
  • Autosomal recessive CNM (ARCNM, OMIM 255200), caused by mutations in the membrane remodeling protein amphiphysin 2 (BIN1) (Bohm et al., 2014);
  • Autosomal dominant CNM (ADCNM, OMIM 160150), due to mutations in dynamin 2 (DNM2) (Bitoun et al., 2005).

Mutations in other genes have also been indicated in Centronuclear myopathies, including titin (TTN, Ceyan-Birsoy et al, 2013) and Ryanodine receptor (RYR1, Bevilacqua et al 2001, Wilmshurst et al 2010).

The relationship between the CNM implicated genes in muscle is not well understood yet.

  • However, Jocelyn Laporte and Belinda Cowling, co-founders of Dynacure, demonstrated that the protein dynamin 2 is overexpressed in X-linked CNM.
  • They have also demonstrated that overexpression of dynamin 2 in wild-type mice induces a CNM-like phenotype (Cowling et al., 2011).
  • Subsequently, it was also shown that a 50% reduction of dynamin 2 by creating a genetic cross leads to mice without mtm1 that do not have the disease – i.e the phenotype has been prevented in a relevant x-linked cnm mouse model (Cowling et al. 2014).

The next step is to develop a translated approach that can be used to regulate dynamin 2 in patients.