News Release

Gene therapy: Microdystrophin restores muscle strength in Duchenne muscular dystrophy

Peer-Reviewed Publication


Researchers from Genethon, the AFM-Telethon laboratory, Inserm (UMR 1089, Nantes) and the University of London (Royal Holloway) demonstrated the efficacy of an innovative gene therapy in the treatment of Duchenne muscular dystrophy. Indeed, after injecting microdystrophin (a "shortened" version of the dystrophin gene) via a drug vector, the researchers managed to restore muscle strength and stabilise the clinical symptoms in dogs naturally affected by Duchenne muscular dystrophy. A first. This work, published today in Nature Communications, has been achieved thanks to donations from the French Telethon.

Duchenne muscular dystrophy is a rare progressive genetic disorder involving all the muscles of the body, and affects 1 in 5,000 boys. It is the most common neuromuscular disorder in children. It is associated with abnormalities in the DMD gene, which encodes dystrophin, a protein that is essential for proper muscle function. This gene is one of the largest in our genome (2.3 million base pairs, of which over 11,000 are coding). Because of this size, it is technically impossible to insert the entire DNA for dystrophin into a viral vector (or even the 11,000 coding base pairs alone), as is usually done for gene therapy.

To meet this challenge, teams at Genethon developed, in collaboration with a team at Royal Holloway University of London led by Pr. Dickson, and produced, a gene therapy drug combining an AAV-type viral vector with a shortened version of the dystrophin gene (approximately 4,000 base pairs), allowing the production of a functional protein. Dr Le Guiner's team tested this innovative treatment in 12 dogs naturally affected by Duchenne muscular dystrophy. By injecting this microdystrophin intravenously, and hence into the whole body of the dogs, the researchers observed that dystrophin expression returned to a high level, and muscle function was significantly restored, with stabilisation of the clinical symptoms observed for over 2 years following injection of the drug (see video). No immunosuppressive treatment was administered beforehand, and no side-effects were observed.

Some Golden Retrievers develop Duchenne muscular dystrophy naturally. The successful treatment of these dogs, which show the same clinical symptoms as children with this disease, and are of a similar weight, is a decisive step toward developing the same treatment in children. "This preclinical study demonstrates the safety and efficacy of microdystrophin, and makes it possible to consider developing a clinical trial in patients. Indeed, this is the first time that it has been possible to treat the whole body of a large-sized animal with this protein. Moreover, this innovative approach allows treatment of all patients with Duchenne muscular dystrophy, regardless of the genetic mutation responsible," says Caroline Le Guiner, the main author of this study.

"This is tremendously exciting progress towards a gene therapy for DMD. The studies in GRMD dogs have been spectacular and exceeded our expectations. My team has worked for many years to optimise a gene therapy medicine for DMD, and now the quite outstanding work of colleagues in France, in Genethon, in Nantes and in Paris has taken us close to clinical trials in DMD patients. I pay thanks also to the amazing and steadfast support of this research by AFM-Telethon and MDUK (Muscular Dystrophy UK) which has been essential to this achievement." commented George Dickson.

For Frederic Revah, Chief Executive Officer of Genethon: "For the first time, researchers obtained a systemic therapeutic effect on a neuromuscular disease in dogs using microdystrophin, and without immunosuppressive treatment. This highly complex cutting edge technology has been developed as part of an exceptional collaborative effort between Genethon and academic teams from Britain and France. Now our bioproduction experts have the task of producing a sufficient quantity of these new drug vectors, under GMP conditions, for the clinical trial."

"This new evidence of the efficacy of gene therapy in Duchenne muscular dystrophy strengthens the therapeutic arsenal developed (exon skipping, CRISPR Cas-9, pharmacogenetics, etc.), and the first results are there. We need to forge ahead to complete the final phase and transform these scientific advances into drugs for children," emphasises Serge Braun, Scientific Director of AFM-Telethon.


Publication: Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Caroline Le Guiner1,2,*, Laurent Servais3, Marie Montus2, Thibaut Larcher4, Bodvael, Fraysse1, Sophie Moullec5, Marine Allais1, Virginie Francois1, Maeva Dutilleul4, Alberto Malerba6, Taeyoung Koo6, Jean-Laurent Thibaut7,8, Beatrice Matot7, Marie Devaux1, Johanne Le Duff1, Jack-Yves Deschamps5, Ines Barthelemy8,9, Stephane Blot8,9, Isabelle Testault10, Karim Wahbi11, Stephane Ederhy12, Samia Martin2, Philippe Veron2, Christophe Georger2, Takis Athanasopoulos6,13,14, Carole Masurier2, Federico Mingozzi2, Pierre Carlier7, Bernard Gjata2, Jean-Yves Hogrel15, Oumeya Adjali1, Fulvio Mavilio2, Thomas Voit16,#,* Philippe Moullier1,17,#,*, George Dickson6,

Nature communications,

Affiliations: 1Atlantic Gene Therapies, INSERM UMR 1089, Universite de Nantes, CHU de Nantes, IRS2, Nantes Biotech, 22, bd Benoni Goullin, 44200 Nantes, France ; 2 Genethon, 1 bis rue de l'Internationale, 91000 Evry, France ; 3 Institute I-Motion, Hopital Armand Trousseau, 26 avenue du Dr A. Netter, 75571 Paris, France ; 4 Atlantic Gene Therapies, INRA UMR 703, ONIRIS, La Chantrerie, BP 40706, 44307 Nantes, France ; 5 Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, La Chantrerie, BP 40706, 44307 Nantes, France ; 6 School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, TW200EX, UK ; 7 Institut de Myologie, Laboratoire RMN, AIM & CEA, 47 bd de l'Hopital, 75013 Paris, France ; 8 Universite Paris-Est, Ecole Nationale Veterinaire d'Alfort, 7 avenue du General de Gaulle, 94704 Maisons-Alfort, France ; 9 INSERM U955-E10 Biology of the NeuroMuscular System, Faculte de medecine, 8 rue du General Sarrail, 94000 Creteil, France ; 10 Centre Hospitalier Veterinaire Atlantia, 22 rue Rene; Viviani, Nantes, France ; 11 Service de cardiologie, AP-HP, Cochin Hospital - Universite Paris Descartes-Sorbonne Paris ; Cite; - Institut de Myologie, Reference Center for Muscle Diseases, 27 rue du Faubourg St Jacques, Paris, France ; 12 Service de cardiologie, hopital Saint-Antoine, AP-HP, 184 rue du Faubourg St Antoine, Paris, France ; 13 Faculty of Science & Engineering, University of Wolverhampton, Wulfruna St, Wolverhampton WV1 1LY, UK ; 14 Current Address: Cell & Gene Therapy Discovery Research (CGTDR), Platform Technology & Sciences (PTS), 5S100(06) GlaxoSmithKline (GSK), Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK 15 Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory, 47 bd de l'Hopital, 75013 Paris, France ; 16 NIHR Biomedical Research Centre, UCL Institute of Child Health / Great Ormond Street, Hospital NHS Trust, London WC1N 3JH, UK

About Genethon

Genethon, located in Evry, France, is a non-profit R&D organisation dedicated to the development of biotherapies for orphan genetic diseases, from research to clinical validation. Genethon is specialized in the discovery and development of gene therapy drugs and has multiple ongoing programs at clinical, preclinical and research stage for neuromuscular, blood, immune system, liver and eye diseases.

Discover Genethon's pipeline:

About AFM-Telethon

The French Muscular Dystrophy Association (AFM) federates patients with neuromuscular diseases and their parents. Thanks mostly to donations from France's annual Telethon (92.7 million euros in 2016), the AFM-Telethon has become a major player in biomedical research for rare diseases in France and worldwide. It currently supports 34 clinical trials for genetic diseases affecting the eye, blood, brain, immune system and neuromuscular system. Thanks to its Genethon research lab, the AFM-Telethon stands out through its unique ability to produce and test its own gene-based medicines.

About Inserm

Founded in 1964, the French National Institute of Health and Medical research (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of National Education, Higher Education and Research and the Ministry of Social Affairs. Inserm is the only French public research institute to focus entirely on human health with nearly 15000 researchers, engineers, technicians, post-doctoral students and more than 300 laboratories. The mission of its scientists is to study all diseases, from the most common to the rarest. Inserm is a member of Aviesan*, the French National Alliance for Life Sciences and Health founded in 2009.

Inserm UMR 1089, the Nantes gene therapy laboratory, conducts translational research programs to develop and evaluate gene therapy products for the treatment of rare genetic diseases (especially for diseases of the neuromuscular system and retina), before proceeding to clinical trials.

  • Other founding members of Aviesan : CEA, CNRS, CHRU, CPU, INRA, INRIA, Inserm, Institut Pasteur, IRD

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