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Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

Gene Therapy volume 11, pages 1675–1684 (2004)Cite this article

Abstract

Malignant glioma is a fatal human cancer in which surgery, chemo- and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 × 107 to 1 × 109 plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFα expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 × 109 PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.

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Acknowledgements

We thank Mellanie Osborn and Anna Jones for animal handling and technical assistance during surgery and MRI evaluations. This research is supported by NGVL 1U42RR1657901 and NIH 1P01NS40923-01A1.

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Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    D Wolfe, A Trichel, A Ozuer, N DeLuca, M Murphey-Corb & JC Glorioso

  2. Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    A Niranjan, E Kanal & D Kondziolka

  3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    C Wiley & D Krisky

  4. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J Goss

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Wolfe, D., Niranjan, A., Trichel, A. et al. Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates. Gene Ther 11, 1675–1684 (2004). https://doi.org/10.1038/sj.gt.3302336

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