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Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy

Gene Therapy volume 21, pages 673–681 (2014)Cite this article

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Abstract

Suicide gene therapy (SGT) is a promising strategy for treating cancer. In this work, we show that thymidine phosphorylase (TP) deficiency, the underlying genetic defect in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presents an opportunity to apply SGT using capecitabine, a commonly used prodrug that is converted into 5-fluorouracil by TP. Using an immortalised B-lymphoblastoid cell line from a patient with MNGIE, the tumourigenic EL-4 cell line, lentiviral vectors encoding TP and a double knockout (Tymp−/−Upp1−/−) murine model, we found that EL-4 cell-derived TP+ tumours were exquisitely sensitive to capecitabine and generated a significant local bystander effect. In addition, we detected a spontaneous cytolytic immune response in a significant fraction of the animals surviving more than 20 days after termination of the therapy. These data indicate that, in individuals lacking TP expression, TP is a highly specific suicide gene, which can be used to treat tumours that could hypothetically arise in MNGIE patients undergoing gene therapy, as these tumours will likely originate from the gene-modified cells and will be selectively targeted by capecitabine. These observations have important implications for gene therapy for MNGIE.

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Acknowledgements

This work was supported by the Instituto de Salud Carlos III (grant PI12/00322 to RM), and the United Mitochondrial Disease Foundation (postdoctoral grant 12-029 to JT). We thank Alex Rojo and Marta Rosal (VHIR animal facility) for their help with the in vivo experiments. We also thank María José Carreras for providing the capecitabine for the in vivo experiments.

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Author notes

  1. S López-Estévez and G Ferrer: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain

    S López-Estévez, G Ferrer, M J Mansilla, S Casacuberta-Serra, L Martorell & J Barquinero

  2. Mitochondrial Pathology Unit, VHIR/Universitat Autònoma de Barcelona, Barcelona, Spain

    J Torres-Torronteras & R Martí

  3. Biomedical Network Research, Centre on Rare Diseases (CIBERER) ISCIII, Madrid, Spain

    J Torres-Torronteras & R Martí

  4. Department of Neurology, Columbia University, New York, NY, USA

    M Hirano

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  1. S López-Estévez
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  2. G Ferrer
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Correspondence to J Barquinero.

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López-Estévez, S., Ferrer, G., Torres-Torronteras, J. et al. Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy. Gene Ther 21, 673–681 (2014). https://doi.org/10.1038/gt.2014.41

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  • DOI: https://doi.org/10.1038/gt.2014.41

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