Telomerase Specific Gene Therapy 31 Rationale

The general aim of most tumor-specific gene therapy is to selectively kill cancer cells while leaving normal cells unharmed by expressing high concentrations of a therapeutic protein only in malignant cells. Transcriptional targeting, in which a therapeutic gene is placed under transcriptional control of a tumor-specific promoter, is a potentially powerful tool to achieve this aim. Unfortunately, most tumor-specific promoters are relatively weak, and their activity is restricted to a small number of tumor types. The cloned telomerase promoters are attractive candidates for use in gene therapy since both promoters are active in the vast majority of cancer cells tested (but not normal cells), although their activities are quite different, with the hTERC promoter usually substantially stronger than hTERT (Abdul-Ghani et al. 2000, Bilsland et al. 2005, Bilsland et al. 2003, Boyd et al. 2004, Dufes et al. 2005, Groot-Wassink et al. 2004, Plumb et al. 2001). Since optimal cellular concentrations of therapeutic protein will differ between transgenes, it is useful that a wide range of expression levels can be achieved in telomerase gene therapy by taking advantage of the basic toolkit of both promoters. Transcriptional activity of the hTERC promoter is usually low in normal cells but substantially upregulated in cancer cells, while the hTERT promoter is essentially off in most normal cells but is turned on at low levels in cancer cells. Most telomerase gene therapy strategies that have been tested can be broadly categorized as cytotoxic gene therapy approaches or oncolytic virotherapy approaches, both of which aim directly to kill cells expressing telomerase while sparing normal counterparts, thereby circumventing the issue of the phenotypic lag (Keith et al. 2004).

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