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Mol Ther. 2014 Nov;22(11):1923-35. doi: 10.1038/mt.2014.151. Epub 2014 Aug 4.

Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients.

Author information

1
1] Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France [2] Généthon, Evry, France.
2
Généthon, Evry, France.
3
Institut de Myologie, Service of Clinical Trials and Databases, Paris, France.
4
Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France.
5
Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
6
1] Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France [2] UPR de Neurobiologie, Ecole Nationale Vétérinaire d'Alfort, Maisons Alfort, France.
7
Institut de Myologie, Laboratoire RMN, AIM & CEA, Paris, France.
8
Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre and Marie Curie Paris 6 UPMC-INSERM UMR 974, CNRS FRE 3617, Paris, France.
9
Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory, Paris, France.
10
1] Atlantic Gene Therapies, INRA UMR 703, ONIRIS, Nantes, France [2] Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France.
11
Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, Nantes, France.
12
Research Institute, Center for Gene Therapy, Nationwide Childrens Hospital, Columbus, Ohio, USA.
13
Laboratory of Molecular Virology and Gene Therapy, National Heart Lung and Blood Institute, National Institute of Health, Bethesda, Maryland, USA.
14
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.
15
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.

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.

PMID:
25200009
PMCID:
PMC4429735
DOI:
10.1038/mt.2014.151
[Indexed for MEDLINE]
Free PMC Article
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