An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents

M. G. Rots, M. G.L. Elferink, W. M. Gommans, D. Oosterhuis, J. A.C. Schalk, D. T. Curiel, P. Olinga, H. J. Haisma, G. M.M. Groothuis

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27 Scopus citations

Abstract

Background: Inefficiency, aspecificity and toxicity of gene transfer vectors hamper gene therapy from showing its full potential. On this basis significant research currently focuses on developing vectors with improved infection and/or expression profiles. Screening assays with validity to the clinical context to determine improved characteristics of such agents are not readily available since this requires a close relationship to the human situation. We present a clinically relevant tissue slice technology to preclinically test improved vector characteristics. Methods: Slices were prepared from rat, mouse and human liver samples and from tumor tissue. Specificity of gene expression and replication was determined by infecting target and non-target tissue slices with transcriptionally retargeted adenoviruses and oncolytic viruses. Results: Using rat liver slices, we demonstrate efficient knob-mediated adenoviral infectivity. A favorable tumor-on/liver-off profile, resembling in vitro and mouse in vivo data, was shown for a tumor-specific transcriptionally retargeted adenovirus by infecting slices prepared from tumor or liver tissue. Similar liver-off data were found for mouse, rat and human samples (over 3-log lower activity of the tumor-specific promoter compared to cytomegalovirus (CMV)). More importantly, we show that this technology when applied to human livers is a powerful tool to detennine aspecific replication of oncolytic viruses in liver tissue. A2- to 6-log reduction in viral replication was observed for a tumor-specific oncolytic virus compared to the wild-type adenovirus. Conclusions: The precision-cut tissue slice technology is a powerful method to test specificity and efficiency of gene transfer as well as of viral replication using human tissue.

Original languageEnglish
Pages (from-to)35-41
Number of pages7
JournalJournal of Gene Medicine
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2006

Keywords

  • Carcinoma
  • Oncolysis
  • Retargeting
  • Toxicity
  • Virotherapy

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    Rots, M. G., Elferink, M. G. L., Gommans, W. M., Oosterhuis, D., Schalk, J. A. C., Curiel, D. T., Olinga, P., Haisma, H. J., & Groothuis, G. M. M. (2006). An ex vivo human model system to evaluate specificity of replicating and non-replicating gene therapy agents. Journal of Gene Medicine, 8(1), 35-41. https://doi.org/10.1002/jgm.815