Gene therapy leads to robust improvements in animal model of fatal muscle disease

January 22, 2014
Dr. Martin Childers displays a family tree of dogs carrying and affected by a gene mutation similar to X-linked myotybular myopathy in children. Credit: Clare McLean/University of Washington

Preclinical studies show that gene therapy can improve muscle strength in small- and large-animal models of a fatal congenital pediatric disease known as X-linked myotubular myopathy. The results, appearing in the Jan. 22 issue of Science Translational Medicine, also demonstrate the feasibility of future clinical trials of gene therapy for this devastating disease.

Researchers, based at the University of Washington, Seattle, Washington, Généthon, France, Boston Children's Hospital in Massachusetts, and Virginia Polytechnic Institute and State University (Virginia Tech) in Blacksburg, Virginia, conducted the study. The scientists found that both mice and dogs responded from a single intravascular injection of AAV, produced at Généthon, with robust improvement in , corrected muscle structure at the microscopic level, and prolonged life. No toxic or immune response was observed in the dogs.

These results demonstrate the efficacy of for myotubular myopathy in animal models and pave the way to a clinical trial in patients.

Children born with X-linked myotubular myopathy, which affects about 1 in 50,000 male births, have very weak skeletal muscles, causing them to appear floppy, with severe respiratory difficulties. Survival beyond birth requires intensive support, often including tube feeding and mechanical ventilation, but effective therapy is not available for patients, and most die in childhood.

Alan H. Beggs of Boston Children's Hospital, co-senior author on the paper, has studied the mutated gene, known as MTM1, for many years and previously showed that replacing missing myotubularin protein effectively improved MTM muscles' ability to contract.

Based on seminal work on local and systemic administration in a mouse model of the disease performed by Anna Buj-Bello at Généthon since 2009, Martin K. Childers, a professor of rehabilitation medicine and a regenerative medicine researcher at the University of Washington, worked with the Buj-Bello and Beggs groups.

They tested using an engineered adenovirus vector, created by Généthon. The vector is a vehicle for delivering a replacement MTM1 gene into cells. The researchers used two animal models: mice with an engineered MTM1 mutation and dogs carrying a naturally occurring MTM1 gene mutation. These mutant animals appear very weak with shortened lifespans, similar to patients with myotubular myopathy.

"The implications of the pre-clinical findings are extraordinary for inherited muscular diseases," said Childers, co-senior author on the paper, and co-principal investigator of the study. "Two of our dogs treated with adenovirus gene therapy appear almost normal with little, if any, evidence, even microscopically, of disease caused by XLMTM."

"These results are the culmination of four years of research and show how gene therapy is effective for this genetic muscle disease," said Buj-Bello. "We finally can envision a clinical trial in patients. These are very promising results for future trials in humans. "

Robert W. Grange, Virginia Tech associate professor of human nutrition, foods and exercise, and Virginia Tech graduate student Jon Doering provided expertise to demonstrate the dramatic rescue of muscle function in the treated dogs.

"The functional improvement was truly remarkable," said Grange. "It is both incredibly exciting and humbling to contribute to such a meaningful project – a true highlight of our careers."

Explore further: Enzyme replacement therapy shows promising results in X-linked myotubular myopathy

More information: "Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy," by M.K Childers et al. Science Translational Medicine, 2014.

Related Stories

Recommended for you

Artificial beta cells

December 8, 2016

Researchers led by ETH Professor Martin Fussenegger at the Department of Biosystems Science and Engineering (D-BSSE) in Basel have produced artificial beta cells using a straightforward engineering approach.

Key regulator of bone development identified

December 8, 2016

Loss of a key protein leads to defects in skeletal development including reduced bone density and a shortening of the fingers and toes—a condition known as brachydactyly. The discovery was made by researchers at Penn State ...

Researchers question lifelong immunity to toxoplasmosis

December 8, 2016

Medical students are taught that once infected with Toxoplasma gondii—the "cat parasite"—then you're protected from reinfection for the rest of your life. This dogma should be questioned, argue researchers in an Opinion ...

TET proteins drive early neurogenesis

December 7, 2016

The fate of stem cells is determined by series of choices that sequentially narrow their available options until stem cells' offspring have found their station and purpose in the body. Their decisions are guided in part by ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.