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Strategies for CNS-directed gene delivery: in vivo gene transfer to the brain using SV40-derived vectors

Gene Therapy volume 14, pages 939–949 (2007)Cite this article

Abstract

Gene transfer to the central nervous system (CNS) has been approached using various vectors. Recombinant SV40-derived vectors (rSV40s) transduce neurons and microglia effectively in vitro, so we tested rSV40s gene transfer to the CNS in vivo, and characterized the distribution, duration and cell types transduced. We used rSV40s carrying Human Immunodeficiency Virus Type 1 Net protein (HIV-1 Nef) with a C-terminal FLAG epitope tag as a marker, and another with Cu/Zn superoxide dismutase (SOD1). Rats were given vectors stereotaxically, either intraparenchymally into the caudate-putamen (CP) or into the lateral ventricle (LV). FLAG expression was studied for 3 months by immunostaining serial brain sections. After intraparenchymal administration, numerous transgene-expressing cells were seen, many as far as 4 mm from the injection site. Transgene expression remained strong throughout the 3-month study period. Coimmunostaining for lineage markers showed that neurons and, more rarely, microglial cells were tranduced, except astrocytes and oligodendroglia. After injection into the LV, high levels of transgene expression were detected throughout the frontal cortex by Western analysis. Systemic mannitol-induced hyperosmolarity further augmented LV transgene delivery. SV40-derived vectors may, thus, be useful for long-term gene expression in the brain, whether locally by intraparenchymal administration or diffusely by intraventricular injection, with or without mannitol.

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Acknowledgements

This work was supported by NIH Grants MH70287, MH69122 and AI48244. We appreciate the encouragements and advice of several colleagues in formulating and executing these studies: Drs Kathy Kopnisky, Roger J Pomerantz and Diane Rausch.

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Authors and Affiliations

  1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    J-P Louboutin, L Agrawal & D S Strayer

  2. Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA

    B A S Reyes & E Van Bockstaele

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  1. J-P Louboutin
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  2. B A S Reyes
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Correspondence to J-P Louboutin.

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Louboutin, JP., Reyes, B., Agrawal, L. et al. Strategies for CNS-directed gene delivery: in vivo gene transfer to the brain using SV40-derived vectors. Gene Ther 14, 939–949 (2007). https://doi.org/10.1038/sj.gt.3302939

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