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Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

Gene Therapy volume 19, pages 182–188 (2012)Cite this article

Abstract

Insertional mutagenesis following gene therapy with gammaretroviral vectors can cause the development of lymphoproliferation in children with X-linked severe combined immunodeficiency. In experimental studies, recombinant adeno-associated virus (rAAV) vectors have also been reported to increase susceptibility to carcinogenesis. The possibility of vector-induced transformation in quiescent ocular cells is probably significantly lower than in mitotically active cells, but given the increasing number of clinical applications of rAAV and lentiviral vectors for ocular disease, a specific assessment of their oncogenic potential in the eye is important. In this study, we investigated the effect of rAAV2/2 and integrating HIV-1 vectors upon the incidence of ocular neoplasia in p53 tumour-suppressor gene-knockout (p53−/−) mice, which are highly susceptible to intraocular malignant transformation. Subretinal injections of high titre rAAV2/2 or integrating HIV-1 vectors induced no tumours in p53−/− or p53+/− animals, nor significantly affected their natural longevity. We conclude that any insertional events arising from subretinal delivery of these vectors appear insufficient to cause intraocular malignancy, even in highly susceptible animals. These findings support the continued development of these vectors for ocular applications.

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Acknowledgements

We wish to thank Emma West for confocal microscopy. We also thank Dr Alan Clarke of the University of Cardiff, Wales for the supplying the p53-deficient mice used in this study. JWBB and RRA are supported by the National Institute for Health Research Biomedical Research Centre for Ophthalmology. We also wish to thank the Special Trustees of Moorfields Eye Hospital.

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Author notes

  1. K S Balaggan and Y Duran: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Institute of Ophthalmology, London, UK

    K S Balaggan, Y Duran, A Georgiadis, S E Barker, P K Buch, A MacNeil, S Robbie, J W B Bainbridge, A J Smith & R R Ali

  2. Department of Vitreoretinal Surgery, Moorfields Eye Hospital, London, UK

    K S Balaggan & J W B Bainbridge

  3. Department of Pathology, Institute of Ophthalmology, London, UK

    C Thaung

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  1. K S Balaggan
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Correspondence to K S Balaggan.

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Balaggan, K., Duran, Y., Georgiadis, A. et al. Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice. Gene Ther 19, 182–188 (2012). https://doi.org/10.1038/gt.2011.194

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