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

被引：90

作者：

Le Guiner, Caroline ^{[1
,2
]}

Montus, Marie ^{[2
]}

Servais, Laurent ^{[3
]}

Cherel, Yan ^{[4
]}

Francois, Virginie ^{[1
]}

Thibaud, Jean-Laurent ^{[5
,6
,7
,8
]}

Wary, Claire ^{[5
,6
,7
]}

Matot, Beatrice ^{[5
,6
,7
]}

Larcher, Thibaut ^{[4
]}

Guigand, Lydie ^{[4
]}

Dutilleul, Maeva ^{[4
]}

Domenger, Claire ^{[1
]}

Allais, Marine ^{[1
]}

Beuvin, Maud ^{[9
]}

Moraux, Amelie ^{[10
]}

Le Duff, Johanne ^{[1
]}

Devaux, Marie ^{[1
]}

Jaulin, Nicolas ^{[1
]}

Guilbaud, Mickael ^{[1
]}

Latournerie, Virginie ^{[2
]}

Veron, Philippe ^{[2
]}

Boutin, Sylvie ^{[2
]}

Leborgne, Christian ^{[2
]}

Desgue, Diana ^{[2
]}

Deschamps, Jack-Yves ^{[4
,11
]}

Moullec, Sophie ^{[11
]}

Fromes, Yves ^{[11
]}

Vulin, Adeline ^{[12
]}

Smith, Richard H. ^{[13
]}

Laroudie, Nicolas ^{[2
]}

Barnay-Toutain, Frederic ^{[2
]}

Riviere, Christel ^{[2
]}

Bucher, Stephanie ^{[2
]}

Thanh-Hoa Le ^{[2
]}

Delaunay, Nicolas ^{[2
]}

Gasmi, Mehdi ^{[2
]}

Kotin, Robert M. ^{[13
]}

Bonne, Gisele ^{[9
,14
]}

Adjali, Oumeya ^{[1
]}

Masurier, Carole ^{[2
]}

Hogrel, Jean-Yves ^{[10
]}

Carlier, Pierre ^{[5
,6
,7
]}

Moullier, Philippe ^{[1
,2
,15
]}

Voit, Thomas ^{[9
]}

机构：

[1] Univ Nantes, CHU Nantes, INSERM UMR 1089, Atlantic Gene Therapies, Nantes, France

[2] Genethon, Evry, France

[3] Serv Clin Trials & Databases, Inst Myol, Paris, France

[4] ONIRIS, INRA UMR 703, Atlantic Gene Therapies, Nantes, France

[5] Inst Myol, Lab RMN, Paris, France

[6] AIM, Paris, France

[7] CEA, Paris, France

[8] Ecole Natl Vet Alfort, UPR Neurobiol, Maisons Alfort, France

[9] Univ Paris 06, Inst Myol, Grp Hosp Pitie Salpetriere, UPMC INSERM UMR 974,CNRS FRE 3617, Paris, France

[10] Inst Myol, Neuromuscular Physiol & Evaluat Lab, Paris, France

[11] ONIRIS, Ctr Boisbonne, Atlantic Gene Therapies, Nantes, France

[12] Nationwide Childrens Hosp, Ctr Gene Therapy, Res Inst, Columbus, OH USA

[13] NHLBI, Lab Mol Virol & Gene Therapy, NIH, Bethesda, MD 20892 USA

[14] Grp Hosp Pitie Salpetriere, AP HP, UF Cardiogenet & Myogenet, Serv Biochim Metab, F-75634 Paris, France

[15] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA

来源：

MOLECULAR THERAPY | 2014年 / 22卷 / 11期

关键词：

RETRIEVER MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE; GENE-TRANSFER; EXPRESSION; RESTORATION; MODELS; SAFETY; DEFICIENCY; EFFICACY; VECTORS;

D O I：

10.1038/mt.2014.151

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 nnyofibers 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 minimurn 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 nonannbulatory DMD patients.

引用

页码：1923 / 1935

页数：13

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