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Transient suppression of hepatocellular replication in the mouse liver following transduction with recombinant adeno-associated virus

Gene Therapy volume 22, pages 917–922 (2015)Cite this article

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Abstract

Recombinant vectors based on adeno-associated virus (AAV) are proving to be powerful tools for genetic manipulation of the liver, for both discovery and therapeutic purposes. The system can be used to deliver transgene cassettes for expression or, alternatively, DNA templates for genome editing via homologous recombination. The replicative state of target cells is known to influence the efficiency of these processes and knowledge of the host–vector interactions involved is required for optimally effective vector deployment. Here we show, for the first time in vivo, that in addition to the known effects of hepatocellular replication on AAV-mediated gene transfer, the vector itself exerts a potent, albeit transient suppressive effect on cell cycle progression that is relieved on a time course that correlates with the known rate of clearance of input single-stranded vector DNA. This finding requires further mechanistic investigation, delineates an excellent model system for such studies and further deepens our insight into the complexity of interactions between AAV vectors and the cell cycle in a clinically promising target tissue.

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Acknowledgements

We thank Margot Latham (The Children’s Hospital at Westmead) for assistance in manuscript preparation. This work was supported by an Australian National Health and Medical Research Council (NHMRC) project grant (1008021). APD was supported by an NHMRC Postgraduate Research Scholarship (477110) and a Children’s Medical Research Institute PhD stipend.

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Authors and Affiliations

  1. Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Westmead, New South Wales, Australia

    A P Dane, S C Cunningham, C Y Kok, G J Logan & I E Alexander

  2. Department of Haematology, University College London Cancer Institute, London, UK

    A P Dane

  3. Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia

    I E Alexander

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  1. A P Dane
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  2. S C Cunningham
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Correspondence to I E Alexander.

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Dane, A., Cunningham, S., Kok, C. et al. Transient suppression of hepatocellular replication in the mouse liver following transduction with recombinant adeno-associated virus. Gene Ther 22, 917–922 (2015). https://doi.org/10.1038/gt.2015.66

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  • DOI: https://doi.org/10.1038/gt.2015.66

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