A team of researchers in France, led by Dr. Ana Buj-Bello (Genethon/Inserm) and teams at the University of Washington and Harvard Medical School in the United States, achieved a new step towards the treatment of myotubular myopathy by gene therapy. The researchers demonstrated the efficacy of administration of a therapeutic vector by a single intravenous injection and identified the dose that restores long-term muscular strength in a large animal model of the disease.
This work, published today in Molecular Therapy, 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 50,000 newborn boys. It is caused by mutations in the MTM1 gene encoding myotubularin, a protein involved in the functioning of muscle cells. The severe form of the disease leads to hypotonia, generalized muscle weakness and death in early infancy due to breathing difficulties. Dogs naturally affected by this myopathy also have a reduced life expectancy. To date, there is no effective treatment for this rare disease.
In the present study, Genethon’s team developed and manufactured an adeno-associated virus (AAV) vector able to deliver a normal copy of the MTM1 gene in the entire musculature. The AAV product was administrated by a simple intravenous injection in ten week-old dogs manifesting the first symptoms of the disease – instead of the locoregional route of administration used in previous studies (Science Translational Medicine, January 2014).
The treatment restored whole-body muscle strength and function, and prolonged the life of affected dogs. Treated dogs were indistinguishable from normal animals 9 months after product injection.
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David L Mack1,2, Karine Poulard3,4, Melissa A Goddard2, Virginie Latournerie3,4, Jessica M Snyder5, Robert W Grange6, Matthew R Elverman2, Jérôme Denard3, Philippe Veron3,4, Laurine Buscara3,4, Christine Le Bec3, Jean-Yves Hogrel7, Annie G Brezovec6, Hui Meng8, Lin Yang9, Fujun Liu9, Michael O’Callaghan10, Nikhil Gopal11, Valerie E. Kelly1, Barbara K Smith12, Jennifer L. Strande13-15, Fulvio Mavilio3,4, Alan H Beggs16, Federico Mingozzi3,4,17, Michael W Lawlor8, Ana Buj-Bello3,4#, and Martin K Childers1,2#
1Department of Rehabilitation Medicine,
2Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, Washington, USA;
3Genethon, Evry, France;
4INSERM, UMR_S951, Evry, France;
5Department of Comparative Medicine, University of Washington, Seattle, Washington, USA;
6Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA;
7Neuromuscular Physiology and Evaluation Lab, Institut de Myologie, Paris, France;
8Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA;
9Department of Biomedical Engineering, University of Florida;
10Audentes Therapeutics, San Francisco, CA, USA;
11Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA;
12Department of Physical Therapy, University of Florida, Gainesville, FL, USA;
13Department of Medicine,
14Department of Cell Biology, Neurobiology and Anatomy,
15Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA;
16The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;
17Institut de Myologie, University Pierre and Marie Curie, Paris, France.