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A photosensitising adenovirus for photodynamic therapy

Gene Therapy volume 6, pages 1742–1750 (1999)Cite this article

Abstract

We have developed a new approach to photodynamic therapy based on adenoviral transduction of the rate-limiting enzyme in heme synthesis. Conventional phototherapy uses porphyrin-based chemical photosensitisers, including δ-aminolaevulinic acid (ALA) which is converted to protoporphyrin IX (PpIX) by the enzymes of the heme biosynthetic pathway. The lack of a specific mechanism for targeting chemical photosensitisers and PpIX to tumour cells means that therapeutic irradiation can damage normal tissue and exposure to sunlight following treatment can cause severe burns. The rate limiting enzyme in PpIX synthesis is ALA-synthase (ALA-S). We have developed a new yeast vector system for manipulation of the adeno- virus genome and used it to construct a virus expressing a mutant form of ALA-S lacking the iron response elements which regulate ALA-S translation and the heme regulatory motifs which regulate import of ALA-S into mitochondria. The virus induces a large increase in PpIX expression and confers photosensitivity on cultured cells. Unlike conventional photodynamic therapy, a viral approach makes it possible to restrict photosensitivity by biological rather than purely physical or chemical means. As with HSV thymidine kinase, ALA-S expression is a general mechanism for sensitisation to a therapeutic agent which can easily be adapted to whatever means of gene delivery is most effective.

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Acknowledgements

We thank Drs Ketner, Larionov, Rusconi and Cox for generously supplying plasmids, strains, viruses, cell lines and antibodies. We thank the Fondation Veillon, Swiss National Science Foundation and Swiss Cancer League for financial support.

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Authors and Affiliations

  1. Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland

    J Gagnebin, M Brunori, M Otter & R Iggo

  2. Otorhinolaryngology, University Hospital (CHUV), Lausanne, Switzerland

    J Gagnebin & P Monnier

  3. Pathology Service, University Hospital (CHUV), Lausanne, Switzerland

    L Juillerat-Jeanneret

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  1. J Gagnebin
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  2. M Brunori
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  3. M Otter
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  4. L Juillerat-Jeanneret
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Gagnebin, J., Brunori, M., Otter, M. et al. A photosensitising adenovirus for photodynamic therapy. Gene Ther 6, 1742–1750 (1999). https://doi.org/10.1038/sj.gt.3300992

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