Adeno-Associated Virus Vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne Muscular Dystrophy (DMD)
In: American Society of Gene & Cell Therapy 19th Annual Meeting ; 19. Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy ; https://hal.archives-ouvertes.fr/hal-01602361 ; 19. Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy, May 2016, Washington, DC, United States. ⟨10.1016/S1525-0016(16)33312-3⟩ ; https://archives-publications.inrae.fr/388922.pdf, 2016
Konferenz
Zugriff:
Duchenne Muscular Dystrophy (DMD) is a X-linked inherited muscle-wasting disease primarily affecting young boys with a prevalence of 1:5,000. The disease is caused by loss-of-function mutations in the gene encoding for the Dystrophin protein and is characterized by systemic, progressive, irreversible and severe loss of muscle function. Among vector systems that allow efficient in vivo gene transfer, recombinant Adeno-Associated Virus vectors (rAAV) hold great promise and allow very efficient transduction of skeletal and cardiac muscles. However, full-length dystrophin cDNA exceeds the packaging capacity for a single rAAV gene-delivery cassette. Therefore, truncated versions namely micro-dystrophins have been designed and optimized to contain few clinically important regions of the dystrophin protein. We have tested a rAAV2/8 vector encoding a sequence optimised canine micro-dystrophin transgene, driven by a muscle-synthetic Spc512 promoter (rAAV2/8-Spc512-µDys) in a total of 12 Golden Retriever Muscular Dystrophy (GRMD) dogs, the canine model of DMD. Isolated limb perfusion studies using a single administration of vector induced high levels of micro-dystrophin expression in the treated limb (up to 90% dystrophin positive fibres) with significant normalisation of histological, NMR imaging and spectroscopy parameters and muscle strength, without deleterious immune responses. Similarly, single-dose intravascular delivery of the same rAAV2/8-Spc512-µDys, in absence of immunosuppression, led to long-term transduction of distant muscle groups and extended lifespan (up to 2 years). Profound improvement of multiple clinical features was observed, including gait and respiratory parameters and no toxicity or deleterious humoral and/or cell-mediated immune responses were observed. This study demonstrates the safety and long term efficacy of rAAV2/8-Spc5.12-µDys gene therapy in a relevant large-animal models of DMD and paves the way towards human clinical gene therapy using systemic peripheral vein administration of vector, ...
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Adeno-Associated Virus Vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne Muscular Dystrophy (DMD)
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Autor/in / Beteiligte Person: | Le Guiner, Caroline ; Servais, Laurent ; Montus, Marie ; Larcher, Thibaut ; Fraysse, Bodvael ; Moullec, Sophie ; Koo, Taeyoung ; Malerba, Alberto ; Le Bec, Christine ; Hebben, Matthias ; Masurier, Carole ; Mingozzi, Federico ; Adjali, Oumeya ; Carlier, Pierre ; Hogrel, Jean-Yves ; Gjata, Bernard ; Cherel, Yan ; Athanasopoulos, Takis ; Mavilio, Fulvio ; Voit, Thomas ; Moullier, Philippe ; Dickson, George ; Généthon ; Service of Clinical Trials and Databases ; Institut de Myologie ; Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher) ; Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS) ; UMR 1089, Atlantic Gene Therapies ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Centre de Boisbonne, Atlantic Gene Therapies ; Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS) ; Holloway, Royal ; University of London ; Laboratoire RMN, Institut de Myologie ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA) ; Neuromuscular Physiology and Evaluation Laboratory ; University of Wolverhampton ; UCL Institute of Child Health |
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Zeitschrift: | American Society of Gene & Cell Therapy 19th Annual Meeting ; 19. Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy ; https://hal.archives-ouvertes.fr/hal-01602361 ; 19. Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy, May 2016, Washington, DC, United States. ⟨10.1016/S1525-0016(16)33312-3⟩ ; https://archives-publications.inrae.fr/388922.pdf, 2016 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2016 |
Medientyp: | Konferenz |
DOI: | 10.1016/S1525-0016(16)33312-3 |
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