Журнал генетических синдромов и генной терапии
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Gene Switches for Deliberate Regulation of Transgene Expression: Recent Advances in System Development and Uses

Nuria Vilaboa, Frank Boellmann and Richard Voellmy

It will be desirable in genetic therapies to exert temporal and/or spatial control over the expression of therapeutic genes. Temporal regulation may be achieved by placing the gene of interest under the control of one of several wellknown gene switches. These gene switches comprise at least two elements, i.e., a ligand-dependent transactivator (or transinhibitor) and a transactivator responsive promoter that is functionally linked to the gene of interest. The systems respond to doxycycline, insect steroid hormones, steroid hormone antagonists, rapalogs, or various nonnatural ligands. Deliberate spatial regulation may be attained by the use of promoters that are activated by physical forces which can be directed to an area in need of therapy. Best known are heat shock promoters and radiationinduced promoters. More complex gene switches are capable of both spatially and temporally regulating genes of interest. The present article reviews improvements and further refinements of the latter gene switches as well as exemplifies uses of these gene switches in research and experimental therapy. It further reports on more recently developed gene switches, including complex systems involving multiple transactivators (or transinhibitors) and/or regulating gene product functionality at the transcriptional, posttranscriptional and/or activity level.