IngentaConnect Conditional expression of a suicide gene by the telomere reverse ...

Authors: Painter, Richard G.¹; Lanson, Nicholas A.¹; Jin, Zhengmin¹; Park, Frank; Wang, Guoshun

Source: Cancer Science, Volume 96, Number 9, September 2005 , pp. 607-613(7)

Abstract:

Integration of a therapeutic gene into the host cell genome permits stable expression of the gene product in the target cells and its progeny. However, non-directional integration of any given gene can pose the risk of activating tumor genes or silencing tumor suppressor genes. Therefore, including a safety-control element into integrating vector systems is an important advance towards safer human gene therapy. Here, we report on a gene expression cassette that can be potentially exploited in integrating vector systems to eliminate post-therapeutic tumorigenesis. The Herpes simplex virus thymidine kinase (hsvTK) gene under the transcriptional control of the human telomere reverse transcriptase promoter (hTERTp) was incorporated into a self-inactivating HIV-based lentiviral vector. The hTERT promoter is silent in normal somatic cells and re-activated in tumor cells. Therefore, normal gene-corrected cells should not express hsvTK from the promoter. However, if some gene-corrected cells subsequently become tumorigenic and the hTERT promoter is re-activated, application of ganciclovir (GCV), a clinically used antiviral drug, will achieve selective deletion of the cancerous cells. Our experimental data indicated that the hTERTp-hsvTK cassette in the lentiviral vector was sufficient to differentiate between tumor cells and normal cells, thus eradicating tumor cells selectively in vitro and in vivo. These results proved the principle of using the element in integrating vectors for safer gene delivery. (Cancer Sci 2005; 96: 607 –613)

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Conditional expression of a suicide gene by the telomere reverse transcriptase promoter for potential post-therapeutic deletion of tumorigenesis