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Cited by 246Virus-based gene therapy researchMuscle Physiology and DisordersNeurogenetic and Muscular Disorders Research

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

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Le Guiner, Caroline, Servais, Laurent, Montus, Marie, Larcher, Thibaut, Fraysse, Bodvaël, Moullec, Sophie, Allais, Marine, François, Virginie +27 more·2017·Nature Communications
DOI 10.1038/ncomms16105PMC PMC5537486
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Abstract

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV–microdystrophin gene therapy in DMD patients.

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Authors
Le Guiner, C., Servais, L., Montus, M., Larcher, T., Fraysse, B., Moullec, S., Allais, M., François, V., Dutilleul, M., Malerba, A., Koo, T., Thibaut, J.-L., Matot, B., Devaux, M., Le Duff, J., Deschamps, J.-Y., Barthelemy, I., Blot, S., Testault, I., Wahbi, K., Ederhy, S., Martin, S., Veron, P., Georger, C., Athanasopoulos, T., Masurier, C., Mingozzi, F., Carlier, P., Gjata, B., Hogrel, J.-Y., Adjali, O., Mavilio, F., Voit, T., Moullier, P., & Dickson, G.
Affiliations
  • Hôpital Armand-Trousseau (FR)
  • Genethon (France) (FR)
  • Oniris (FR)
  • Inserm (FR)
  • University of London (GB)
  • École Nationale Vétérinaire d'Alfort (FR)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Sorbonne Paris Cité (FR)
  • University of Wolverhampton (GB)
  • Institut de Myologie (FR)
Corresponding author
Moullier, Philippe
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-07-25
Volume
8
Issue
1
Pages
16105-16105
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms16105
PMC
PMC5537486
OpenAlex
W2736939674
Cited by
246
References
2
Citations by year
2026: 13 · 2025: 25 · 2024: 14 · 2023: 29 · 2022: 26 · 2021: 37 · 2020: 31 · 2019: 41 · 2018: 26 · 2017: 4
FWCI
18.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • ORBi (University of Liège) (submittedVersion, other-oa)
Funders
  • Muscular Dystrophy UK
  • Agence Nationale de la Recherche (ANR-14-CE15-0015)
  • Institut National de la Santé et de la Recherche Médicale
  • Institut National de la Recherche Agronomique
  • Université de Nantes
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
Duchenne muscular dystrophy, microdystrophin, gene therapy, recombinant adeno-associated virus, canine model, golden retriever muscular dystrophy, dystrophin expression, long-term safety, large animal model
MeSH terms
Dependovirus, Animals, Disease Models, Animal, Dogs, Genetic Vectors, Male, Muscular Dystrophy, Animal, Genetic Therapy, Dystrophin, Gene Transfer Techniques, Muscle, Skeletal, Transgenes, Muscular Dystrophy, Duchenne, Administration, Intravenous

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