An exciting breakthrough for the treatment of Centronuclear myopathies
In mice with myotubular myopathy (MTM1), also named centronuclear myopathy due to the central position of nuclei, muscle fibers are smaller and unable to produce a normal muscle contraction (left). The decrease in dynamin (DNM2) reverts fiber size to normal and allows the correct positioning of muscle nuclei at the periphery (right).
Feb. 24, 2014
Using an innovative strategy, researchers at the IGBMC managed to cure an animal affected by centronuclear myopathy, also called myotubular myopathy. Through a gene modulation approach, J. Laporte’s team observed an almost total disappearance of clinical signs of this rare disease. In addition to the therapeutic potential they give rise to, these results shed a new light on the mechanisms involved in Centronuclear myopathies. This study is published 24 February 2014 in the Journal of Clinical Investigation.
Myopathies include a wide range of diseases affecting muscle, mostly of genetic origin. Among the most severe forms are the centronuclear myopathies which owe their name to the central position of nuclei in the muscle cells, while they are at the periphery in healthy cells. Nowadays, there is no cure for these rare diseases. The first major sign is an acute muscle weakness that gradually evolves to a complete loss of muscle function.
Several causes can lead to centronuclear myopathies, including myotubularin (MTM1) or dynamin 2 (DNM2) mutations; both are proteins that regulate muscle cell organization. Myotubularin mutations cause the most severe form of the disease, affecting one birth out of 50,000. In this case the disease is called myotubular myopathy, and is associated with an acute muscular weakness from birth as well as a shorter life-expectancy. The mutations responsible for this disease have been identified in 1996 by Jocelyn Laporte and today, his team continues to investigate this pathology. Researchers hypothesized that myotubularin and dynamin 2 proteins are involved in a cellular signaling network that affects muscle function.
The researchers found that in myopathic mice lacking myotubularin, the amount of the dynamin 2 protein is much greater than in healthy mice. This difference may be due to the fact that, in healthy individuals, myotubularin represses the expression or stability of dynamin 2. To test this hypothesis, Jocelyn Laporte’s team at the IGBMC genetically decreased the level of dynamin 2 in myopathic mice lacking myotubularin. Their results are spectacular to say the least. They observed an almost total recovery of all clinical features of the disease, including normal muscle strength and proper localization of nuclei in the majority of muscle cells. Before, animals were dying about two months after birth; they are now reaching the age of 2 years, which is the normal life span for mice.
This study opens new perspectives on the understanding of the molecular mechanisms leading to these myopathies. In addition, the identification of dynamin 2 as a novel therapeutic target for myotubular and centronuclear myopathies raises great hope for a therapeutic application. These very promising results are already subjected to a pre-clinical development program partially funded by the TTO Conectus Alsace. This innovative therapeutic strategy is one of the first examples of "cross- therapy", where the decrease of a gene altered in one myopathy (DNM2) rescues another myopathy resulting from the loss of a different gene (MTM1).