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Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

Gene Therapy volume 11, pages 884–893 (2004)Cite this article

Abstract

One of the possible therapies for Duchenne muscular dystrophy (DMD) is the introduction of a functional copy of the dystrophin gene into the patient. For this approach to be effective, therapeutic levels and long-term expression of the protein need to be achieved. However, immune responses to the newly expressed dystrophin have been predicted, particularly in DMD patients who express no dystrophin or only very truncated versions. In a previous study, we demonstrated a strong humoral and cytotoxic immune response to human dystrophin in the mdx mouse. However, the mdx mouse was tolerant to murine dystrophin, possibly due to the endogenous expression of dystrophin in revertant fibres or the other nonmuscle dystrophin isoforms. In the present study, we delivered human and murine dystrophin plasmids by electrotransfer after hyaluronidase pretreatment to increase gene transfer efficiencies. Tolerance to murine dystrophin was still seen with this improved gene delivery. Tolerance to exogenous recombinant full-length human dystrophin was seen in mdx transgenic lines expressing internally deleted versions of human dystrophin. These results suggest that the presence of revertant fibres may prevent the development of serious immune responses in patients undergoing dystrophin gene therapy.

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Acknowledgements

This work has been funded by grants from the Muscular Dystrophy Campaign of Great Britain and Northern Ireland, the Muscular Dystrophy Association of America, the Association Francaise contre les Myopathies and the United Kingdom Medical Research Council.

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Author notes

  1. H Foster

    Present address: Center for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Surrey, TW20 0EX, UK

Authors and Affiliations

  1. Department of Neuromuscular Diseases, Division of Neuroscience and Psychological Medicine, Gene Targeting Unit, Imperial College London, Charing Cross Hospital, London, UK

    A Ferrer, H Foster, K E Wells & D J Wells

  2. Center for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Surrey, UK

    G Dickson

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  1. A Ferrer
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Ferrer, A., Foster, H., Wells, K. et al. Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins. Gene Ther 11, 884–893 (2004). https://doi.org/10.1038/sj.gt.3302242

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