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In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

Gene Therapy volume 19, pages 936–946 (2012)Cite this article

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Abstract

The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

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Acknowledgements

We thank Gennadij Raivich, University College London (UCL) for useful discussion. The UCL-based laboratory and AHB were supported by the Biotechnology and Biological Sciences Research Council. AAR and SNW had also received support from the UK Gauchers Association. The King's College London-based laboratory was supported by the Wellcome Trust (GR079491MA), Batten Disease Family Association and the Batten Disease Support and Research Association.

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Author notes

  1. A A Rahim and A M Wong: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK

    A A Rahim & S N Waddington

  2. Paediatric Storage Disorder Laboratory, MRC Centre for Neurodegeneration, Institute of Psychiatry, Kings College London, London, UK

    A M Wong, S Ahmadi, K Hoefer & J D Cooper

  3. Department of Haematology, University College London, London, UK

    S M K Buckley, D A Hughes & A N Nathwani

  4. BHF Glasgow Cardiovascular Centre, Univeristy of Glasgow, Glasgow, UK

    A H Baker

  5. Molecular Medicine, Thrombosis Research Institute, London, UK

    J H McVey

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  1. A A Rahim
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Correspondence to S N Waddington.

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Rahim, A., Wong, A., Ahmadi, S. et al. In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression. Gene Ther 19, 936–946 (2012). https://doi.org/10.1038/gt.2011.157

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