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- Title
Retargeting of adenoviral vectors to neurons using the H<sub>C</sub> fragment of tetanus toxin.
- Authors
Schneider, H; Groves, M; Mühle, C; Reynolds, P N; Knight, A; Themis, M; Carvajal, J; Scaravilli, F; Curiel, D T; Fairweather, N F; Coutelle, C
- Abstract
The He fragment of tetanus toxin (He) retains the specific nerve ceil 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 He-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 He-polylysine conjugates or the Fab fragment of a neutralising anti-knob antibody covalently bound to He were attached to the virus. Infection of neuronal and nonneuronal 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 He 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 He 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.
- Subjects
TETANUS toxin; ADENOVIRUSES; GENE therapy
- Publication
Gene Therapy, 2000, Vol 7, Issue 18, p1584
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301270