title: Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients.
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.
authors.affiliation: 1] Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France [2] Généthon, Evry, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Guiner
authors.affiliation: Généthon, Evry, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Montus
authors.affiliation: Institut de Myologie, Service of Clinical Trials and Databases, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Servais
authors.affiliation: Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cherel
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Francois
authors.affiliation: 1] Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France [2] UPR de Neurobiologie, Ecole Nationale Vétérinaire d'Alfort, Maisons Alfort, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Thibaud
authors.affiliation: Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Wary
authors.affiliation: Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Matot
authors.affiliation: Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Larcher
authors.affiliation: Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Guigand
authors.affiliation: Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Dutilleul
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Domenger
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Allais
authors.affiliation: Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie Paris 6 UPMC-INSERM UMR 974, CNRS FRE 3617, Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Beuvin
authors.affiliation: Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Moraux
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Le Duff
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Devaux
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jaulin
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guilbaud
authors.affiliation: Généthon, Evry, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Latournerie
authors.affiliation: Généthon, Evry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Veron
authors.affiliation: Généthon, Evry, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Boutin
authors.affiliation: Généthon, Evry, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Leborgne
authors.affiliation: Généthon, Evry, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Desgue
authors.affiliation: 1] Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France [2] Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France.
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.affiliation: Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Moullec
authors.affiliation: Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fromes
authors.affiliation: Research Institute, Center for Gene Therapy, Nationwide Childrens Hospital, Columbus, Ohio, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vulin
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, Maryland, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Smith
authors.affiliation: Généthon, Evry, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Laroudie
authors.affiliation: Généthon, Evry, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Barnay-Toutain
authors.affiliation: Généthon, Evry, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Rivière
authors.affiliation: Généthon, Evry, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bucher
authors.affiliation: Généthon, Evry, France.
authors.forename: Thanh-Hoa
authors.initials: TH
authors.lastname: Le
authors.affiliation: Généthon, Evry, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delaunay
authors.affiliation: Généthon, Evry, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Gasmi
authors.affiliation: Laboratory of Molecular Virology and Gene Therapy, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, Maryland, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kotin
authors.affiliation: 1] Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie Paris 6 UPMC-INSERM UMR 974, CNRS FRE 3617, Paris, France [2] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.affiliation: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Oumeya
authors.initials: O
authors.lastname: Adjali
authors.affiliation: Généthon, Evry, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Masurier
authors.affiliation: Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Hogrel
authors.affiliation: Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Carlier
authors.affiliation: 1] Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France [2] Généthon, Evry, France [3] Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.affiliation: Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie Paris 6 UPMC-INSERM UMR 974, CNRS FRE 3617, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
mesh_terms: D000818:Animals; D015331:Cohort Studies; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D005552:Forelimb / Q000503:physiopathology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D012342:RNA, Small Nuclear / Q000235:genetics* / Q000378:metabolism
chemical_list: D016189:Dystrophin; D012342:RNA, Small Nuclear; C405487:U7 small nuclear RNA