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Corticospinal tract transduction: a comparison of seven adeno-associated viral vector serotypes and a non-integrating lentiviral vector

Gene Therapy volume 19, pages 49–60 (2012)Cite this article

Abstract

The corticospinal tract (CST) is extensively used as a model system for assessing potential therapies to enhance neuronal regeneration and functional recovery following spinal cord injury (SCI). However, efficient transduction of the CST is challenging and remains to be optimised. Recombinant adeno-associated viral (AAV) vectors and integration-deficient lentiviral vectors are promising therapeutic delivery systems for gene therapy to the central nervous system (CNS). In the present study the cellular tropism and transduction efficiency of seven AAV vector serotypes (AAV1, 2, 3, 4, 5, 6, 8) and an integration-deficient lentiviral vector were assessed for their ability to transduce corticospinal neurons (CSNs) following intracortical injection. AAV1 was identified as the optimal serotype for transducing cortical and CSNs with green fluorescent protein (GFP) expression detectable in fibres projecting through the dorsal CST (dCST) of the cervical spinal cord. In contrast, AAV3 and AAV4 demonstrated a low efficacy for transducing CNS cells and AAV8 presented a potential tropism for oligodendrocytes. Furthermore, it was shown that neither AAV nor lentiviral vectors generate a significant microglial response. The identification of AAV1 as the optimal serotype for transducing CSNs should facilitate the design of future gene therapy strategies targeting the CST for the treatment of SCI.

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Acknowledgements

This study was supported by a Research Councils UK Academic Fellowship (LM), the British Pharmacological Society's Integrative Pharmacology Fund (LM), Friends of Guy's Hospital Research Grants (LM and RJY-M), a Biotechnology and Biological Sciences Research Council's Doctoral Training Grant (TH), financial support from the 7th EU Framework Programme (PERSIST project, grant agreement no 222878, to RJY-M) and a grant from Genoma España (RJY-M). We would also like to acknowledge Bas Blits and Erich Ehlert for their help with the production of the AAV vectors.

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  1. Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King′s College London, London, UK

    T H Hutson & L D F Moon

  2. Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    J Verhaagen

  3. School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey, UK

    R J Yáñez-Muñoz

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  1. T H Hutson
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Correspondence to T H Hutson.

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Hutson, T., Verhaagen, J., Yáñez-Muñoz, R. et al. Corticospinal tract transduction: a comparison of seven adeno-associated viral vector serotypes and a non-integrating lentiviral vector. Gene Ther 19, 49–60 (2012). https://doi.org/10.1038/gt.2011.71

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