Combinatorial therapy as a novel treatment strategy for myotubular myopathy


Candidate therapeutics are urgently needed for myotubular myopathy (MTM), which at present remains without treatment. Several strategies have been proposed, and have shown promising results in animal models of the disease. These include gene replacement therapy, which is entering clinical trial, dynamin-2 knockdown, which is under active investigation, and enzyme replacement therapy.

The Dowling lab has started with the hypothesis that safe medicines that have already been studied in children can be “repurposed” for use in x-linked myotubular myopathy (MTM) In a previous study funded by the Myotubular Trust, we examined the idea of rebalancing the lipids (called phosphoinositides or PIPs) that accumulate in the muscle of MTM patients. We showed that genetic inhibition of a protein called PIK3C2B can completely reverse the disease process of the MTM mouse model, and that chemical inhibition of PIK3C2B with wortmannin (a chemical inhibitor of proteins called PI3 kinases) can also improve the muscle symptoms. Unfortunately, the effect with wortmannin is modest, and in addition the drug has potential toxicities in humans that may make it a poor candidate for clinical translation. We are currently in the process of identifying and developing new inhibitors to PIK3C2B that will provide more substantial benefit and be suitable for bringing to patients.

In the meantime, we have identified two new potential treatments for MTM. The first was uncovered using our zebrafish model of MTM, via a method called high throughput drug screening. With this method, we screened more than 1000 FDA approved drugs for their ability to improve the appearance and swim behavior of the MTM zebrafish. We identified several “hits” from this screen, and in this proposal are focusing on the most exciting and potentially translatable of these hits. The second drug was identified serendipitously during our work on PIK3C2B in MTM. Both new potential therapies are commonly used in children for conditions other than muscle disease. Based on additional data that we have accumulated, we believe that these two drugs act in different ways from each other to improve the MTM disease process, and furthermore act distinctly from rebalancing PIPs. In our study newly funded by the Myotubular Trust, we will examine the ability of these new drugs to improve the phenotypes of the MTM mouse.

The goal of this work is to identify the drug or drugs that best improve the symptoms of MTM, are safest to use in children, and are thus the best suited for potentially treating patients with MTM. Because these drugs have previously been used in children, we feel that the pathway for clinical development and testing of them can be feasibly accomplished in a timely and cost effective manner. Ultimately, we envision these treatments as ones potentially suitable to all MTM patients, both as stand alone therapy or as a compliment to treatments like gene therapy. Furthermore, we believe these therapeutic strategies may be applicable to the broader range of patients with centronuclear and myotubular myopathy.

We are excited to pursue this novel research with the support of the Myotubular Trust. Our work on therapy development for MTM builds from research previously supported by the Myotubular Trust, by the Canadian Institute for Health Research, the Muscular Dystrophy Association, the US National Institutes of Health, the “Will/Cure” Foundation, and the Joshua Frase Foundation.

Dr Dowling and Team