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Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

Gene Therapy volume 17, pages 1400–1410 (2010)Cite this article

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Abstract

Muscle is an attractive target because it is easily accessible; it also offers a permissive environment for adeno-associated virus (AAV)-mediated gene transfer and has an abundant blood vascular supply providing an efficient transport system for the secretion of proteins. However, gene therapy of dystrophic muscle may be more difficult than that of healthy tissue because of degenerative–regenerative processes, and also because of the inflammatory context. In this study we followed the expression levels of secreted inhibitors of the proinflammatory tumor necrosis factor (TNF) cytokine after intramuscular (i.m.) injection of AAV6 into dystrophic mdx and healthy C57BL/10 mice. We used two chimeric proteins, namely, the human or murine TNF-soluble receptor I fused with the murine heavy immunoglobulin chain. We conducted an AAV6 dose–response study and determined the kinetics of transgene expression. In addition, we followed the antibody response against the transgenes and studied their expression pattern in the muscle. Our results show that transduction efficiency is reduced in dystrophic muscles as compared with healthy ones. Furthermore, we found that the immune response against the secreted protein is stronger in mdx mice. Together, our results underscore that the pathological state of the muscle has to be taken into consideration when designing gene therapy approaches.

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Acknowledgements

We thank Béatrice Marolleau, Angélique Duvallet and Christophe Georger for technical assistance in the histological analyses. This study was conducted with the financial support of the Association Française contre les Myopathies.

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Authors and Affiliations

  1. Genethon, BP60, Evry, France

    G Moulay, C Masurier, D Scherman & A Kichler

  2. Laboratoire de Pharmacologie Chimique et Génétique UMR 8151 CNRS-U1022 INSERM, Université René Descartes, Chimie Paristech, Faculté de Sciences Pharmaceutiques et Biologiques, Paris, France

    P Bigey, D Scherman & A Kichler

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  1. G Moulay
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Correspondence to A Kichler.

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Moulay, G., Masurier, C., Bigey, P. et al. Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer. Gene Ther 17, 1400–1410 (2010). https://doi.org/10.1038/gt.2010.94

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