Animal Studies Bode Well for MTM Gene Therapy

Researchers funded in part by MDA found that a single blood-vessel injection of myotubularin genes markedly improved muscle abnormalities and survival in mice and dogs

Martin Childers, an MDA research grantee at the University of Washington in Seattle with a diagram of the inheritance pattern of MTM in his dog colony. Photo by Clare McLean, UW Medicine.
Article Highlights:
  • MDA grantee Martin Childers at the University of Washington in Seattle and colleagues injected genes for the myotubularin protein encased in AAV8 viral shells into blood vessels in mice and dogs deficient in myotubularin.
  • They found the gene therapy markedly improved muscle structure and function, including respiratory function and prolonged survival in the animals.
  • The results bode well for gene therapy of human myotubular myopathy.
by Margaret Wahl on January 22, 2014 - 12:03pm

Update (Feb. 3, 2014): The video from the University of Washington has been edited, and the link has been updated to reflect this.

Update (Jan. 27, 2014): MDA also supported Alan Beggs at Harvard University on this study. We regret not including this information intially.

Update (Jan. 22, 2014): This story has been updated to provide a link to a summary of the journal paper on MTM gene therapy in animal models.


Transferring genes for the myotubularin protein into myotubularin-deficient mice and dogs with a disorder resembling human myotubular myopathy (MTM) had marked benefits for the animals, paving the way for gene-based therapy of human MTM, MDA-supported researchers have found.

MDA research grantee Martin Childers, a professor of rehabilitation medicine at the University of Washington in Seattle, and colleagues, reported the findings Jan. 22, 2014, in Science Translational Medicine. To learn more about the findings, please view this video.

In 2011, Childers (who was then at Wake Forest University) received a three-year grant from MDA's translational research program to study gene therapy of MTM.

"MDA is thrilled by these results," said Jane Larkindale, MDA's vice president of research. "Although demonstrating an effect in an animal model is not definitive proof that a potential therapy will work in human patients, this strong an effect in a larger animal gives us a lot of confidence that this may work. MDA tries to invest in early-stage projects to help investigators gather the critical data to see if a project can turn into an effective therapy, and this project demonstrates how effective this can be. We will be watching this potential therapy with interest as it moves forward in development."

Martin Childers commented, "Our hope is that, because of the success of the therapy used here in animals, that testing in humans with MTM will occur soon." He also said, "This is a seminal finding in the field."

Correction of muscle abnormalities in mice and dogs 

Childers and colleagues initially studied mice genetically engineered not to produce the myotubularin protein. These mice have a disease that resembles human MTM, with profound abnormalities in the structure and function of their skeletal muscles.

Myotubularin genes encased in the shells of type 8 adeno-associated viruses (AAV8 "vectors") were injected into a tail vein in these mice at the onset of disease symptoms or at a later stage of the disease. In both circumstances, muscle abnormalities were corrected, and survival was prolonged.

Childers' group then studied male Labrador retriever dogs with a mutation in the myotubularin gene. These dogs have a disorder that closely resembles that of patients with these types of mutations and normally do not survive beyond 4 months of age. (The myotubularin gene is on the X chromosome. As with other X chromosome-linked disorders, abnormalities in the myotubularin gene affect males almost exclusively.)

The muscles from affected male dogs have reduced synthesis and altered location of the myotubularin protein.

When the investigators injected myotubularin genes inside AAV8 vectors into a blood vessel in three 9-week-old dogs with myotubularin deficiency, they found the therapy was well tolerated, rescued skeletal muscle abnormalities and respiratory function, and prolonged survival for more than a year.

They were pleasantly surprised to find that muscle structure and function was not only restored in areas near the injection but also in muscles distant from it, although not as thoroughly. Notably, the respiratory muscles, particularly the diaphragm, were reached by the therapeutic genes, and their function was normalized in the treated dogs.

In both the mice and dogs, muscle abnormalities were corrected for the duration of the studies — six months in the mice and a year in the dogs — following only a single injection of the therapeutic genes. Of note, there were no unwanted immune responses to the therapy.

Results bode well for gene therapy of human MTM

"Our results demonstrate that intravenous AAV8-mediated gene therapy leads to long-term systemic correction of X-linked myotubular myopathy in small and large animal models at doses compatible with clinical application," the researchers write in their Jan. 22 paper, "and pave the way to a clinical trial of gene therapy for myotubular myopathy."

Protein-based MTM therapy also being studied

In addition to supporting Childers to develop gene-based therapy of MTM, MDA is funding development of MTM therapy based on delivering the myotubularin protein, via a 2013 translational research grant to Valerion Therapeutics in Concord, Mass.

MTM genetic testing available

A study to identify or confirm MTM-causing mutations in the myotubularin gene is open to U.S. and Canadian residents who are at least 1 month old and are suspected of having MTM. Genetic testing will be performed on a sample of saliva and then, if necessary, on a blood sample.

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