MDA’s translational research program has announced it is funding research into a potential treatment for the inherited muscle disorder X-linked myotubular myopathy (MTM).
The grant of $369,365 grant to Wake Forest University professor Martin Childers will fund a three-year study of myotubularin gene transfer in mice and dogs that have an MTM-like disease.
In preliminary studies in MTM mice, myotubularin gene transfer appeared to restore strength to severely weakened muscles. Researchers now want to test the treatment in dogs, whose body size and muscle physiology more closely resemble that of humans.
"MDA is pleased to support research to determine the potential of gene therapy to treat myotubular myopathy," said MDA Vice President for Research Sanjay Bidichandani. "This important work should give us the information we need to determine the feasibility of gene transfer therapy for human MTM."
The study is a collaboration between the Wake Forest School of Medicine in Winston-Salem, N.C., and the French nonprofit research laboratory Généthon. It is being jointly funded by MDA and the Association Française Contre les Myopathies (AFM), the French neuromuscular disease group. The AFM is a major player in biomedical research into rare diseases in France and worldwide, currently funding 36 clinical trials and the Généthon research lab.
"We are very pleased to be working with Dr. Childers' group at Wake Forest," said Frédéric Revah, chief executive at Généthon. "The great match between his group's skills and those at Généthon will enable us to accelerate the development of a gene therapy for myotubular myopathy."
Also working with Childers on this project are Alan Beggs at Children's Hospital Boston and Harvard Medical School; Rainer Storb and Zejing Wang at the Fred Hutchinson Cancer Center in Seattle; and Robert Grange at Virginia Polytechnic Institute in Blacksburg, Va.
Researchers intend to administer the treatment using an adeno-associated virus (AAV) vector. AAV vectors are gene-delivery vehicles in which the genes for the virus are removed and the desired gene (in this case, for myotubularin) inserted. The AAV vector used in this treatment is AAV8.
Using AAV8, researchers plan to inject myotubularin genes into a blood vessel that goes to a hind leg in dogs bred to have an MTM-like disease. The researchers will be delivering the genes to the whole limb, via an intravenous infusion. This is a delivery method that is being considered for use in human gene therapy.
At the same time, researchers plan to treat the dogs with a short-term course of immunosuppressive drugs in order to lessen the dog’s potential immune response to either the viral vector or to the myotubularin protein made from the new genes.
The grant will be disbursed over a three-year period as various milestones are met. Milestones include testing the therapy again in MTM mice, testing it in MTM dogs, and doing strength testing on the treated animals.
If the gene transfer is safe and works to restore muscle strength in the dogs, researchers plan to move forward as quickly as possible with applications to test the drug in human clinical trials.
In addition, if the immunosuppressive drugs used in the dogs appear to improve the outcome of the gene transfer, such drugs may be tested in MTM patients undergoing this type of experimental treatment.