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 H 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 G. Carlier
(3)
,
Philippe Moullier
(1, 2, 11)
,
Thomas Voit
(6)
1
Inserm UMR 1089 -
Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques
2 Généthon
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 – U974 SU-INSERM
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 UF - University of Florida [Gainesville]
2 Généthon
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 – U974 SU-INSERM
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 UF - University of Florida [Gainesville]
Caroline Le Guiner
- Fonction : Auteur
- PersonId : 766472
- ORCID : 0000-0002-6904-2300
Thibaut Larcher
- Fonction : Auteur
- PersonId : 735738
- IdHAL : tlarcher
- ORCID : 0000-0002-0396-3190
- IdRef : 076698297
Claire Domenger
- Fonction : Auteur
- PersonId : 1029509
Maud Beuvin
- Fonction : Auteur
- PersonId : 1182877
- IdHAL : maud-beuvin
- ORCID : 0000-0002-5908-761X
Jack-Yves Deschamps
- Fonction : Auteur
- PersonId : 1203334
- ORCID : 0000-0003-3363-7457
Gisele Bonne
- Fonction : Auteur
- PersonId : 183818
- IdHAL : gisele-bonne
- ORCID : 0000-0002-2516-3258
- IdRef : 075894920
Oumeya Adjali
- Fonction : Auteur
- PersonId : 1029485
Résumé
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.