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Myotubular myopathy 'rescued' in new and innovative pre-clinical studies at IGBMC, France

Press release today, 25th February 2014

Success of an innovative pre-clinical strategy rescuing myotubular myopathy in animals

Using an innovative strategy, researchers at the IGBMC (France) managed to cure animals affected by myotubular myopathy, also called X-linked centronuclear myopathy. Through a gene modulation approach, J. Laporte’s team observed disappearance of clinical signs of this rare disease and a full rescue of lifespan. In addition to the therapeutic potential, these results shed a new light on the mechanisms involved in Centronuclear myopathies.

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 curefor 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 about 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. The mutations responsible for this disease have been identified in 1996 by Jocelyn Laporte and today, his team continues to investigate this pathology.

In collaboration with researchers at the Institute of Myology in Paris, Laporte’s team found that in myopathic mice lacking myotubularin and in patients, the amount of the dynamin 2 protein is higher than expected, suggesting that an increase in dynamin 2 function leads to myotubular myopathy. To test this hypothesis, researchers genetically decreased the level of dynamin 2 in myopathic mice lacking myotubularin. Results are remarkable as they observe an almost total recovery of all clinical features, including normal muscle strength and proper localization of nuclei in the majority of muscle cells. The respiratory function is normalized and treated animals reach a normal lifespan.

This study opens new perspectives on the understanding of the molecular mechanisms leading to these myopathies. 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).

The identification of dynamin 2 as a novel therapeutic target for myotubular/centronuclear myopathies paves the way for further preclinical studies and future clinical trials in patients.

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).

Read the journal article here

On behalf of families, Jocelyn Laporte was recently questioned by us further about this recent research:

Q: How long will it take do you think to understand whether it can be applied to other forms of CNM?

JL: It will take about 6 months from when we begin our next piece of research to have a good idea about whether it can be applied to other forms of CNM and from a mammalian model as a mouse. We are trying to secure funding at the moment to perform these experiments and go further on to the development of the preclinical/clinical approach.

Q: We have read in the publication that DNM2 was reduced post birth in XLMTM mice with something as simple as the licensed drug Tamoxifen - is that correct?

JL: Tamoxifen was a trick to induce the genetic decrease of DNM2 in an animal model which was first genetically modified to respond to Tamoxifen, thus it cannot be used in patients. The conclusion of the experiment however is that reducing DNM2 after the start of the disease appears to be beneficial, and this is indeed what we need to do in patients. Thus we need to validate a novel deliverable approach for patients and they would probably be drugs (without the use of a virus).

Q: What do you see as the next steps and timescales in this research ongoing?

JL: This work is a proof-of-concept and has so far been only experimental work in animals. Now we need to validate a drug that would lead to a similar reduction of DNM2. We aim for the following:

Firstly to validate a deliverable compound, that could be a DNA molecule or chemical compound, which would achieve the same effect on reduction of DNM2, as with the genetic engineering that we did in mice. This should work and is a matter of time, we hope that first results should be available before the end of this year. Then we will have to do further experiments to test for toxicity and route of injection in the animals.

To summarise, we need to validate a drug that achieves similar effects and can be given to patients, testing the same approach in other forms of centronuclear myopathies.

Q: Are there other similar approaches as this, already being used to treat other neuromuscular conditions?

JL: It is a similar methodology as for exon-skipping in Duchenne muscular dystrophy.

Q: Is there a particular reason why you feel that DNM2 is a particularly good drug target?

JL: Dynamin is an enzyme, meaning it is cycling between active and inactive states. The goal is to get a drug that will keep it inactive. This is a much better target than a "structural" protein like dystrophin (the protein responsible for causing Duchenne muscular dystrophy) for example that acts as a linker but has no active/inactive state. Put more simply, we can modulate the activity of DNM2, but we cannot modulate the activity of dystrophin.

Q: How easy will it be for you to find a drug that can target DNM2?

JL: If we are lucky we may find that a drug already on the market for another purpose can do the job. This is called 'drug repurposing'. This is a high risk/high gain project: we may find nothing, but if we do, expedite clinical trials are possible before release of the drug to the community, therefore benefiting patients sooner.

Myotubular Trust would like to thank Dr Jocelyn Laporte for taking the time to answer these questions.

Note: Dr Jocelyn Laporte and colleagues will be at the 2014 Myotubular Trust Family Conference held in London, to help answer any questions. You can pre-register to join us for our Family Conference on 12th July here.