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

Kim Blakeley UW Medicine

Preclinical studies show that gene therapy can improve muscle strength in small- and large-animal models of a fatal congenital childhood disease know as X-linked myotubular myopathy.

The findings, appearing as the cover story in the January 22, 2014 issue of Science Translational Medicine, also demonstrate the feasibility of future clinical trials of gene therapy for this devastating disease.

Watch a video by Brian Donohue on this study.

Researchers at the University of Washington, Généthon in France, Boston Children’s Hospital, and Virginia Polytechnic Institute and State University in Blacksburg, Va., conducted the study.

The study was 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. The UW’s Martin K. Childers, working with Buj-Bello and Beggs groups, tested gene therapy using an engineered adenovirus vector, created by Généthon. The vector carries a replacement MTM1 gene.

They 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 scientists found that both mice and dogs responded to a single intravascular injection of an adenovirus vector engineered for gene replacement therapy, produced at Généthon. The treated animals had robust improvement in muscle strength, 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 gene replacement therapy 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. They also have 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.

“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 with Buj-Bello and Beggs. “Two of our dogs treated with AAV gene therapy appear almost normal with little, if any, evidence, even microscopically, of disease caused by XLMTM.” Childers is a UW professor of rehabilitation medicine and a regenerative medicine researcher.

“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.”

The study was funded by the Association Francaise contre les Myopathies, the Muscular Dystrophy Association, Myotubular Trust, Genopole d’Evry, INSERM, Region d’Alsace, the Anderson Family Foundation, the Joshua Frase Foundation, Where There’s a Will There’s a Cure Foundation, and the Peter Khuri Fund for Myopathy Research. National Institute of Health grants P50 N5040828, R01 AR044345, R21 AR 064503, AR 0659750 and Ro1 HL115001 also funded the work.