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Recombinant adeno-associated virus type 2 mediates highly efficient gene transfer in regenerating rat skeletal muscle

Gene Therapy volume 9, pages 1037–1043 (2002)Cite this article

Abstract

The recent identification of genes responsible for several muscle diseases, particularly inherited myopathies, has made gene transfer to pathologic muscle tissue an attractive research field. As early pathologic changes in myopathic muscle involve repeated necrosis-regeneration cycles, leading to the coexistence of myofibers at different stages of maturity, a delivery system for efficient, durable gene therapy of inherited muscle diseases should allow gene transfer into myofibers at any stage of maturity. Experiments with rat skeletal muscles showed that recombinant adeno-associated virus (rAAV) type 2 can be highly efficient and even improve gene transfer in regenerating as compared with mature muscle, provided that vector injection is performed during the myotube growth period of the regenerative process. At this early period of muscle regeneration, young regenerating myotubes strongly express heparan sulfate proteoglycan AAV type 2 receptor. Improvement was associated with a greater number of transduced myofibers in muscle samples and an increase in viral genomic copies in transduced muscle. No significant deleterious effects on muscle phenotype or any evident alterations in the regenerative process were observed in transduced muscles. Unlike other available viral vectors, whose transduction efficiencies are highly maturation-dependent, rAAV type 2-based vectors provide efficient in vivo gene transfer in myofibers at various stages of maturity, making AAV a promising delivery system for pathological muscle tissue.

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Acknowledgements

The authors are grateful to the Vector Core of the University Hospital of Nantes (supported by the Association Française contre les Myopathies (AFM)) for providing AAV CMV nls LacZ vectors. Anti-laminin monoclonal antibody 2E8, developed by E Engvall, was obtained from the Developmental Studies Hybridoma Bank maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA, USA.

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Authors and Affiliations

  1. UMR 703 INRA-Ecole Nationale Vétérinaire de Nantes, Nantes, France

    J Abadie, L Guigand, M Wyers & Y Cherel

  2. Laboratoire de Thérapie Génique, CHU Hotel-DIEU, Nantes, France

    V Blouin

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  1. J Abadie
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  2. V Blouin
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  3. L Guigand
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Abadie, J., Blouin, V., Guigand, L. et al. Recombinant adeno-associated virus type 2 mediates highly efficient gene transfer in regenerating rat skeletal muscle. Gene Ther 9, 1037–1043 (2002). https://doi.org/10.1038/sj.gt.3301773

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