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Innovative gene therapy treatment demonstrated in canine model of DMD

is the most common neuromuscular disease of children (affecting 1 boy in 3500-5000 births). It is caused by a genetic defect in the DMD gene residing on the X chromosome, which results in the absence of the dystrophin protein essential to the proper functioning of muscles.

The treatment being developed by researchers at , Généthon and , is based on the use of an AAV vector (Adeno Associated Virus) carrying a transgene for the skipping of a specific exon which allows functional dystrophin production in the muscle of the patient.

Safety, efficacy and stability of the treatment in dogs

In GRMD (Golden Retriever Muscular Dystrophy) dogs the treatment aimed at skipping exons 6, 7 and 8 of the dystrophin gene. The product was given by loco-regional administration in the forelegs of 18 dogs who were followed for 3.5 months after injection. It was well tolerated by all treated dogs; no immune response against the synthesized dystrophin was observed. Exon skipping resulted in high levels of expression of dystrophin in the treated muscles. The results of this treatment also indicate that, once injected into the muscle tissue a prolonged and stable effect is produced over the observation time of the study and, unlike antisense oligonucleotides already used clinically for exon skipping, it does not need to be re- administered regularly. The synthesis of “new” dystrophin is dependent on the dose of vector injected: the higher the dose, the greater the exon skipping is effective. Muscle strength also increases with dose. 80% of muscle fibers expressed the “new” dystrophin at the highest dose. This is a very encouraging result because a minimum of 40% of dystrophin in muscle fibers is believed to be necessary for the muscle force to be significantly improved.

A phase I/II clinical trial phase

These results open the way for a phase I / II clinical trial by loco-regional administration in the upper limb of non-ambulatory Duchenne muscular dystrophy patients which are amenable to treatment by the specific skipping of exon 53. The regulatory toxicology and biodistribution studies have just ended and the filing of an application with regulatory authorities is planned for 2015.


Atlantic , Genethon and the Institute of Myology are members of the Institute of Biotherapy for Rare Diseases created by the AFM-Telethon. With over 600 experts in Nantes, Paris and Evry it is a unique and potent force for the development of for rare diseases.

This work also received funding under the ADNA (Advanced Diagnostics for New Therapeutic Approaches) program which is dedicated to the development of personalized medicine and supported by the Public Investment Bank.

Publication : Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients

Caroline Le Guiner1,2, Marie Montus2, Laurent Servais3, Yan Cherel4, Virginie Francois1, Jean-Laurent Thibaud5,6, Claire Wary5, Béatrice Matot5, Thibaut Larcher4, Lydie Guigand4, Maeva Dutilleul4, Claire Domenger1, Marine Allais1, Maud Beuvin7, Amélie Moraux8, Johanne Le Duff1, Marie Devaux1, Nicolas Jaulin1, Mickaël Guilbaud1, Virginie Latournerie2, Philippe Veron2, Sylvie Boutin2, Christian Leborgne2, Diana Desgue2, Jack-Yves Deschamps4,9, Sophie Moullec9, Yves Fromes9, Adeline Vulin10, Richard H Smith11, Nicolas Laroudie2, Frédéric Barnay-Toutain2, Christel Rivière2, Stéphanie Bucher2, Thanh-Hoa Le2, Nicolas Delaunay2, Mehdi Gasmi2, Robert M Kotin11, Gisèle Bonne7,12, Oumeya Adjali1, Carole Masurier2, Jean-Yves Hogrel8, Pierre Carlier5, Philippe Moullier1,2,13 and Thomas Voit7

1Atlantic Gene Therapies, INSERM UMR 1089, , CHU de Nantes, Nantes, France; 2Généthon, Evry, France; 3Institut de Myologie, Service of Clinical Trials and Databases, Paris, France; 4Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France; 5Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France; 6UPR de Neurobiologie, Ecole Nationale Vétérinaire d’Alfort, Maisons Alfort, France; 7Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie Paris 6 UPMC-INSERM UMR 974, CNRS FRE 3617, Paris, France; 8Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory, Paris, France; 9Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France; 10Research Institute, Center for Gene Therapy, Nationwide Childrens Hospital, Columbus, Ohio, USA; 11Laboratory of Molecular Virology and Gene Therapy, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, Maryland, USA; 12AP-HP, Groupe Hospitalier Pitié-Salpêtrière,U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France; 13Department of Molecular Genetics and Microbiology,University of Florida, Gainesville, Florida, USA