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Effects of defective herpes simplex vectors expressing neurotrophic factors on the proliferation and differentiation of nervous cells in vivo

Gene Therapy volume 12, pages 559–569 (2005)Cite this article

Abstract

Neurotrophic factors (NTFs) are known to govern the processes involved in central nervous system cell proliferation and differentiation. Thus, they represent very attractive candidates for use in the study and therapy of neurological disorders. We constructed recombinant herpesvirus-based-vectors capable of expressing fibroblast growth factor-2 (FGF-2) and ciliary neurotrophic factor (CNTF) alone or in combinations. In vitro, vectors expressing FGF-2 and CNTF together, but not those expressing either NTF alone, caused proliferation of O-2A progenitors. Furthermore, based on double-labeling experiments performed using markers for neurons (MAP-2), oligodendrocytes (CNPase) and astrocytes (GFAP), most of the new cells were identified as astrocytes, but many expressed neuronal or oligodendrocytic markers. In vivo, vectors have been injected in the rat hippocampus. At 1 month after inoculation, a highly significant increase in BrdU-positive cells was observed in the dentate gyrus of animals injected with the vector expressing FGF-2 and CNTF together, but not in those injected with vectors expressing the single NTFs. Furthermore, double-labeling experiments confirmed in vitro data, that is, most of the new cells identified as astrocytes, some as neurons or oligodendrocytes. These data show the feasibility of the vector approach to induce proliferation and differentiation of neurons and/or oligodendrocytes in vivo.

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Acknowledgements

This work has been supported by grants from Telethon (E.0954), the Italian Ministry for the University and Scientific Research (FISR), the Italian National Institute of Health (Program Stem Cells, CS 126.1) and the Italian Association for Cancer Research (AIRC). We thank Chiara Zerbini, Luca Boccafogli, Gianluca Gardo, Federica Vasquez, Eros Magri, Daniela Nardo and Fernanda Mora for technical assistance.

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Authors and Affiliations

  1. Department of Diagnostic and Experimental Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy

    P Marconi, E Berto, A Bozac, I Volpi, R Argnani & R Manservigi

  2. Neuroscience Center, University of Ferrara, Ferrara, Italy

    P Marconi, S Zucchini, E Berto, A Bozac, B Paradiso, G Bregola, C Grassi, I Volpi, R Argnani, R Manservigi & M Simonato

  3. Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy

    S Zucchini, B Paradiso, G Bregola, C Grassi & M Simonato

  4. Department of Diagnostic and Experimental Medicine, Section of Pathology, University of Ferrara, Ferrara, Italy

    A Marzola

  5. Biotechnology Center, University of Ferrara, Ferrara, Italy

    R Manservigi & M Simonato

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  1. P Marconi
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Marconi, P., Zucchini, S., Berto, E. et al. Effects of defective herpes simplex vectors expressing neurotrophic factors on the proliferation and differentiation of nervous cells in vivo. Gene Ther 12, 559–569 (2005). https://doi.org/10.1038/sj.gt.3302438

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