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  • Inherited Disease
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Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy

Abstract

Introduction of dystrophin by gene transfer into the dystrophic muscles of Duchenne muscular dystrophy (DMD) patients has the possibility of triggering an immune response as many patients will not have been exposed to some (or all) of the epitopes of dystrophin. This could in turn lead to cytotoxic destruction of transfected muscle fibres. We assessed such concerns in the dystrophin-deficient mdx mouse using plasmid DNA as the gene transfer system. This avoids complications associated with the administration of viral proteins. Gene transfer of cDNAs encoding mouse full-length or a truncated minidystrophin did not evoke either a humoral or cytotoxic immune response. Mdx mice may be tolerant due to the presence of rare ‘revertant’ dystrophin-positive fibres in their skeletal muscles. In contrast, gene transfer of human full-length or minidystrophin provoked both humoral and cytotoxic responses leading to destruction of the transfected fibres. These experiments demonstrate the potential risk of deleterious effects following gene therapy in DMD patients and lead us to suggest that patients enrolled in gene therapy trials should ideally have small, preferably point, mutations and evidence of ‘revertant’ dystrophin-positive muscle fibres.

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Acknowledgements

We wish to thank the following: David Baker (UCL, London) for the anti-CD8 antibody; Terry Partridge (MRC CSC, London) for the founding stock of our mdx-nude colony; Jeff Chamberlain (Michigan) for the mouse dystrophin plasmids; Kay Davies and Don Love (Oxford) and George Dickson (Royal Holloway, London) for the human dystrophin cDNAs; Louise Anderson (Newcastle) for the anti-dystrophin monoclonal antibodies; Serge Braun (Transgene, Strasbourg) for the alternative human full-length dystrophin plasmid and Jill McMahon (Gene Targeting Unit) for advice on histology and imaging. This work was funded by the MRC, the Muscular Dystrophy Campaign and the Wellcome Trust.

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Ferrer, A., Wells, K. & Wells, D. Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Gene Ther 7, 1439–1446 (2000). https://doi.org/10.1038/sj.gt.3301259

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