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  • Viral Transfer Technology
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Retargeting of adenoviral vectors to neurons using the HC fragment of tetanus toxin

Gene Therapy volume 7, pages 1584–1592 (2000)Cite this article

Abstract

The HC fragment of tetanus toxin (HC) retains the specific nerve cell binding and transport properties of the holotoxin, but lacks any toxicity. We are investigating the potential for utilising its neurotropism for targeted gene delivery to the central nervous system. Previously we reported the use of HC-polylysine conjugates for selective gene transfer into neuronal cells in vitro. However, as attempts to apply these constructs in vivo were not successful, we have extended these studies to modification of the tropism of adenoviral vectors. Either HC-polylysine conjugates or the Fab fragment of a neutralising anti-knob antibody covalently bound to HC were attached to the virus. Infection of neuronal and non-neuronal cell lines with retargeted virus showed highly increased neuronal cell selectivity, but no significant enhancement of gene delivery into these cells. High concentrations of free HC blocked the infectivity of the retargeted vector efficiently. Intramuscular injection of retargeted virus into mouse tongues resulted in selective gene transfer to the neurons of the hypoglossal nucleus, where no pathological changes were observed. As differentiated neurons do not undergo cell division, appropriate vectors carrying a thymidine kinase gene, which allows selective elimination of dividing cells, may be exploitable for the treatment of tumours of the central nervous system. The demonstrated suitability of the HC fragment of tetanus toxin as targeting moiety for viral vectors also indicates a potential for gene therapy of inherited neurodegenerative diseases such as spinal muscular atrophy.

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Acknowledgements

We would like to express our gratitude to Dr C Shaw, King's College, London, for providing differentiated dorsal root ganglion cells and thank Dr A Pavirani, Transgène (France), for providing the adenoviral vectors used. This work was supported by the March of Dimes Foundation, the British Medical Research Council, National Institutes of Health grants R01 CA68245, R01 CA74242 and R01 HL50255 and a scholarship of the Studienstiftung des deutschen Volkes to CM.

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Authors and Affiliations

  1. Division of Biomedical Sciences, Molecular Genetics Section, Imperial College School of Medicine, London, UK

    H Schneider, C Mühle, A Knight, M Themis, J Carvajal & C Coutelle

  2. Department of Neuropathology, Institute of Neurology, University College, London, UK

    M Groves & F Scaravilli

  3. Gene Therapy Program, University of Alabama at Birmingham, AL, USA

    P N Reynolds & D T Curiel

  4. Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, UK

    N F Fairweather

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Schneider, H., Groves, M., Mühle, C. et al. Retargeting of adenoviral vectors to neurons using the HC fragment of tetanus toxin. Gene Ther 7, 1584–1592 (2000). https://doi.org/10.1038/sj.gt.3301270

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