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A team of French researchers, led by Dr. Anna Buj-Bello (Genethon/Inserm) and teams at the University of Washington and Harvard Medical School in the United States, have demonstrated the efficacy of gene therapy in models of myotubular myopathy, an extremely severe neuromuscular disease in children. Transfer of the MTM1 gene, which is deficient in the disease, corrected the affected muscles in mice and dogs and prolonged the survival of treated animals. This work, published today in Science Translational Medicine, has been achieved thanks to donations from the French Telethon and the support of the Myotubular Trust.
Myotubular myopathy is an X-linked genetic disease affecting 1 in every 50,000 newborn boys. It is caused by mutations in the gene MTM1 encoding myotubularin, a protein involved in the functioning of muscle cells. In its most serious form, it causes hypotonia, generalized muscle weakness and death in the first years of life. There is currently no effective treatment for this severe rare disease.
The study by the French team at Genethon, and the U.S. team at the University of Washington, aimed at evaluating the efficacy of a single intravenous injection of an adeno-associated virus (AAV) expressing myotubularin in the muscles of mice and dogs which carry an MTM1 mutation.
In 2009, the group directed by Dr. Anna Buj-Bello performed the first study of gene therapy on mice with this disease at Genethon. Their success led to the development of a study in dogs which naturally carry this genetic abnormality, in collaboration with U.S. teams from Boston and Seattle. The vectors used for gene therapy have been developed and manufactured at Genethon.
Exceptional results: normalization of muscle strength and respiratory function and prolonged survival
This normalization is the first demonstration of persistent correction by a single injection of AAV intravenously in a large animal model of neuromuscular disease. A single dose of drug-vector permitted the long-term expression of myotubularin in muscles.
For Dr. Anna Buj Bello, principal investigator at Genethon: “These results are the culmination of four years of research and show how gene therapy is effective for this genetic muscle disease. We finally can envision a clinical trial in patients. These are very promising results. ”
For Dr. Martin Childers from University of Washington: « The implications of the pre-clinical findings are extraordinary for inherited muscular diseases. Two of our dogs treated with AAV-mediated gene therapy appear almost normal with little, if any, evidence, even microscopically, of disease caused by XLMTM. »
For Dr. Alan Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital: “Demonstrating that gene therapy is effective in prolonging the lives of these dogs is extremely exciting, providing us with the necessary information to start planning clinical trials in humans.”
Fulvio Mavilio, Chief Scientific Officer Genethon and co-author of the study: “These results have a significant impact on the prospect of developing treatments neuromuscular diseases. They are indeed very promising.”
Frédéric Revah, CEO Genethon: “For the first time, researchers have obtained a systemic therapeutic effect on neuromuscular disease in dogs with a single intravenous injection: the treatment does not act locally but throughout the body. Genethon is proud to have worked with the best teams in the world and our next goal is working on the implementation of a clinical trial in humans. ”
Laurence Tiennot-Herment, President of the AFM-Téléthon and Genethon : “This result achieved by our laboratory Genethon, in association with the best American teams, is a major step forward for families who constantly fight the disease. Our determination to defeat the disease is stronger than ever and, thanks to the support of donors from Téléthon, we move step by step toward new victories.”
The AFM-Telethon in France, Muscular Dystrophy Association in the United States, Myotubular Trust in Britain, Anderson Family Foundation and Joshua Frase Foundation participated in the financing of this study.
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Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy. Martin K Childers1,2, Romain Joubert3, Karine Poulard3, Christelle Moal3, Robert W Grange4, Jonathan A Doering4, Michael W Lawlor5,6, Branden E. Rider5, Thibaud Jamet3, Nathalie Danièle3, Samia Martin3, Christel Rivière3, Thomas Soker6, Caroline Hammer3, Laetitia Van Wittenberghe3, Mandy Lockard7, Xuan Guan7, Melissa Goddard7, Erin Mitchell7, Jane Barber7, J. Koudy Williams7, David L Mack1, Mark E Furth8, Alban Vignaud3, Carole Masurier3, Fulvio Mavilio3, Philippe Moullier3,9,10, Alan H Beggs5, Anna Buj-Bello3 Science Translational medicine