Forelimb Treatment in a Large Cohort of Dystrophic Dogs Supports Delivery of a Recombinant AAV for Exon Skipping in Duchenne Patients
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Caroline Le Guiner
- Function : Author
- PersonId : 766472
- ORCID : 0000-0002-6904-2300
Thibaut Larcher
- Function : Author
- PersonId : 735738
- IdHAL : tlarcher
- ORCID : 0000-0002-0396-3190
- IdRef : 076698297
Claire Domenger
- Function : Author
- PersonId : 1029509
Maud Beuvin
- Function : Author
- PersonId : 1182877
- IdHAL : maud-beuvin
- ORCID : 0000-0002-5908-761X
Jack-Yves Deschamps
- Function : Author
- PersonId : 1203334
Gisele Bonne
- Function : Author
- PersonId : 183818
- IdHAL : gisele-bonne
- ORCID : 0000-0002-2516-3258
- IdRef : 075894920
Oumeya Adjali
- Function : Author
- PersonId : 1029485
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.