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

Caroline Le Guiner 1, 2 Marie Montus 2 Laurent Servais 3 Yan Cherel 4 Virginie François 1 Jean-Laurent Thibaud 5, 3 Claire Wary 3 Béatrice Matot 3 Thibaut Larcher 4 Lydie Guigand 4 Maéva Dutilleul 4 Claire Domenger 1 Marine Allais 1 Maud Beuvin 6 Amélie Moraux 3 Johanne Le Duff 1 Marie Devaux 1 Nicolas Jaulin 1 Mickaël Guilbaud 1 Virginie Latournerie 2 Philippe Veron 2 Sylvie Boutin 2 Christian Leborgne 2 Diana Desgue 2 Jack-Yves Deschamps 4, 7 Sophie Moullec 7 Yves Fromes 7 Adeline Vulin 8 Richard Smith 9 Nicolas Laroudie 2 Frédéric Barnay-Toutain 2 Christel Rivière 2 Stéphanie Bucher 2 Thanh-Hoa Le 2 Nicolas Delaunay 2 Mehdi Gasmi 2 Robert Kotin 9 Gisele Bonne 3, 10 Oumeya Adjali 1 Carole Masurier 2 Jean-Yves Hogrel 3 Pierre Carlier 3 Philippe Moullier 1, 2, 11 Thomas Voit 6
1 Inserm UMR 1089 - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques
2 Généthon [Evry]
3 Institut de Myologie
4 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
5 ENVA - École nationale vétérinaire d'Alfort
6 Centre de recherche en myologie
7 Centre de Boisbonne, Atlantic Gene Therapies
8 Nationwide Children's Hospital
9 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
10 CHU Pitié-Salpêtrière [AP-HP]
11 University of Florida [Gainesville]
Abstract : Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of myofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimum threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonambulatory DMD patients.
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https://www.hal.inserm.fr/inserm-02447482
Contributor : Nicolas Jaulin <>
Submitted on : Tuesday, January 21, 2020 - 4:06:13 PM
Last modification on : Monday, November 9, 2020 - 2:52:03 PM

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UMR1089 | INRA | UNAM | CEA | U974 | UNIV-NANTES | SORBONNE-UNIVERSITE | SU-MEDECINE | CNRS | INRAE

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Caroline Le Guiner, Marie Montus, Laurent Servais, Yan Cherel, Virginie François, et al.. Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients. Molecular Therapy, Nature Publishing Group, 2014, 22 (11), pp.1923-1935. ⟨10.1038/mt.2014.151⟩. ⟨inserm-02447482⟩

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