Update (Jan. 10, 2013):This story has been updated with additional information about MDA funding of this and related research projects.
Mice missing the muscle protein myotubularin and showing a disorder mimicking human myotubular myopathy (MTM) showed improvements in muscle structure and function after two weeks of treatment with a laboratory-modified form of the missing protein.
The findings may lead to a trial of the protein-based drug, dubbed 3E10Fv-MTM1, or a similar compound, in people with MTM. In addition, the strategy used to modify myotubularin so that it can enter muscle fibers could potentially be used to modify other muscle proteins and treat other muscle diseases.
The investigators published their findings online Jan. 9, 2013, in Human Molecular Genetics. The team included three MDA grantees: Dustin Armstrong at biotechnology company 4s3 Bioscience in Concord, Mass.; Alan Beggs at Boston Children's Hospital; and Christopher Pierson at Nationwide Children's Hospital in Columbus, Ohio.
MDA began supporting Armstrong in April 2010, through MDA Venture Philanthropy, the drug development arm of the Association's translational research program. Beggs has a current MDA research grant to study the molecular genetics of congenital myopathies, and Pierson had a recent MDA research grant to study treatment of MTM in mouse models.
MTM has an X-linked inheritance pattern, affecting males almost exclusively. Babies born with MTM (myotubularin deficiency) have severe weakness of the skeletal muscles, including those involved in respiration. They often require a ventilator to breathe and a feeding tube for nutrition. Current treatment of MTM is largely supportive care.
The myotubularin protein is an enzyme with multiple effects in muscle tissue, including playing a key role in the ability of muscle fibers to contract when they receive a signal from the nervous system.
Developing a myotubularin enzyme that can penetrate muscle fibers has been challenging. In the newly reported experiments, the investigators fused the myotubularin protein molecule to an antibody (immune system protein) known as 3E10Fv, creating the 3E10Fv-MTM1 compound, which can penetrate muscle fibers while allowing the myotubularin enzyme to retain its usual functions.
The strategy of targeting a protein to muscle and enabling it to penetrate the tissue is something that could be applied to many muscle disorders in which a missing or deficient protein is the underlying cause.
The investigators injected the molecule into leg muscles of mice missing myotubularin (myotubularin "knockout" mice) twice a week for two weeks when the animals were 4 and 5 weeks old.
The researchers used intramuscular injections for these proof-of-concept experiments, but they found that the effects of the treatment spread beyond the injected area and into neighboring muscles. (3E10Fv-MTM1 potentially could be developed into an intravenous medication, as are some other enzyme replacement therapies.)
After only two weeks of treatment with a relatively low dose of 3E10Fv-MTM1, the researchers found that, in comparison to mice given salt solution injections, the treated mice:
The investigators note that these pilot experiments were limited by the small amount of experimental drug available to them. As production is scaled up, they hope to conduct studies of long-term treatment and ultimately, if all goes well, to conduct a human trial.
Comparing 3E10Fv-MTM1 to similar enzyme replacement therapies such as Myozyme (an FDA-approved drug used to treat the muscle enzyme deficiency disorder Pompe disease) the researchers say they believe 3E10Fv-MTM1 "represents a viable new approach" to treating MTM.
They add that, given the positive results with short-term therapy, "we believe that a greater degree of functional and pathological improvement will be seen at an optimal dose and with greater duration of treatment."
One concern is that the immune system may reject therapeutic proteins that it views as "foreign," especially with long-term exposure, a problem that has limited treatment efficacy for some Pompe patients. However, researchers say that, so far, immune rejection of myotubularin compounds has not been seen in animal studies.
In addition to funding enzyme replacement research, MDA is also supporting studies of gene transfer (gene therapy) for MTM, through a research grant to Pierson and a translational research grant to Martin Childers at the University of Washington in Seattle. Gene transfer would involve injecting the myotubularin gene, instead of the protein.