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Gene therapy of experimental brain tumors using neural progenitor cells

Abstract

Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis1. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they may travel along the white matter, like neoplastic cells, and engraft stably into the brain2,3. Retrovirus-mediated transfer of the gene for interleukin-4 is an effective treatment for rat brain glioblastomas4. Here, we transferred the gene for interleukin-4 into C57BL6J mouse primary neural progenitor cells and injected those cells into established syngeneic brain glioblastomas. This led to the survival of most tumor-bearing mice. We obtained similar results by implanting immortalized neural progenitor cells derived from Sprague-Dawley rats into C6 glioblastomas. We also documented by magnetic resonance imaging the progressive disappearance of large tumors, and detected 5-bromodeoxyuridine-labeled progenitor cells several weeks after the injection. These findings support a new approach for gene therapy of brain tumors, based on the grafting of neural stem cells producing therapeutic molecules.

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Figure 1: Effects of neural progenitor cells releasing IL-4 on the growth of experimental malignant gliomas.
Figure 2: MRI coronal sections of the brains of two rats with C6 tumors injected with neural progenitor cells releasing IL-4.
Figure 3: Histology of rat brains inoculated with C6 and ST14A.IL-4.3 cells labeled by BrdU.

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Acknowledgements

We thank the technicians of the Department of Neuroradiology (S. Benvenga, L. Caposio and M. Cova) for MRI studies and D. Bonsignorio for help with in vivo experiments with C57BL6 mice. GL261 cells were provided by G. Safrany (National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary). This work was supported by a grant from the Italian Minister of Health to G.F. and by the Italian Association for Cancer Research (AIRC) to E.C. SB was supported by a fellowship from AIRC. L.M. was supported by a grant from IRCCS Policlinico S. Matteo.

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Correspondence to Gaetano Finocchiaro.

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Benedetti, S., Pirola, B., Pollo, B. et al. Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6, 447–450 (2000). https://doi.org/10.1038/74710

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