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

Author

Listed:
  • Caroline Le Guiner

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
    Généthon)

  • Laurent Servais

    (Institute I-Motion, Hôpital Armand Trousseau)

  • Marie Montus

    (Généthon)

  • Thibaut Larcher

    (Atlantic Gene Therapies)

  • Bodvaël Fraysse

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Sophie Moullec

    (Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, La Chantrerie)

  • Marine Allais

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Virginie François

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Maeva Dutilleul

    (Atlantic Gene Therapies)

  • Alberto Malerba

    (School of Biological Sciences, Royal Holloway, University of London)

  • Taeyoung Koo

    (School of Biological Sciences, Royal Holloway, University of London)

  • Jean-Laurent Thibaut

    (Institut de Myologie, Laboratoire RMN, AIM & CEA
    Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort)

  • Béatrice Matot

    (Institut de Myologie, Laboratoire RMN, AIM & CEA)

  • Marie Devaux

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Johanne Le Duff

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Jack-Yves Deschamps

    (Atlantic Gene Therapies, Centre de Boisbonne, ONIRIS, La Chantrerie)

  • Inès Barthelemy

    (Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort
    INSERM U955-E10 Biology of the NeuroMuscular System, Faculté de médecine)

  • Stéphane Blot

    (Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort
    INSERM U955-E10 Biology of the NeuroMuscular System, Faculté de médecine)

  • Isabelle Testault

    (Centre Hospitalier Vétérinaire Atlantia)

  • Karim Wahbi

    (Service de cardiologie, AP-HP, Cochin Hospital–Université Paris Descartes-Sorbonne Paris Cité–Institut de Myologie, Reference Center for Muscle Diseases)

  • Stéphane Ederhy

    (Service de cardiologie, hôpital Saint-Antoine, AP-HP)

  • Samia Martin

    (Généthon)

  • Philippe Veron

    (Généthon)

  • Christophe Georger

    (Généthon)

  • Takis Athanasopoulos

    (School of Biological Sciences, Royal Holloway, University of London
    Faculty of Science and Engineering, University of Wolverhampton
    Present address: Cell & Gene Therapy Discovery Research (CGTDR), Platform Technology & Sciences (PTS), 5S100(06) GlaxoSmithKline (GSK), Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK)

  • Carole Masurier

    (Généthon)

  • Federico Mingozzi

    (Généthon)

  • Pierre Carlier

    (Institut de Myologie, Laboratoire RMN, AIM & CEA)

  • Bernard Gjata

    (Généthon)

  • Jean-Yves Hogrel

    (Institut de Myologie, Neuromuscular Physiology and Evaluation Laboratory)

  • Oumeya Adjali

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech)

  • Fulvio Mavilio

    (Généthon)

  • Thomas Voit

    (NIHR Biomedical Research Centre, UCL Institute of Child Health/Great Ormond Street Hospital NHS Trust)

  • Philippe Moullier

    (Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, IRS2 Nantes Biotech
    University of Florida)

  • George Dickson

    (School of Biological Sciences, Royal Holloway, University of London)

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.

Suggested Citation

  • Caroline Le Guiner & Laurent Servais & Marie Montus & Thibaut Larcher & Bodvaël Fraysse & Sophie Moullec & Marine Allais & Virginie François & Maeva Dutilleul & Alberto Malerba & Taeyoung Koo & Jean-L, 2017. "Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16105
    DOI: 10.1038/ncomms16105
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    Cited by:

    1. Trevor J. Gonzalez & Katherine E. Simon & Leo O. Blondel & Marco M. Fanous & Angela L. Roger & Maribel Santiago Maysonet & Garth W. Devlin & Timothy J. Smith & Daniel K. Oh & L. Patrick Havlik & Ruth , 2022. "Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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