The generation and refinement of new ligand-induced transcription switches is an area of active investigation, but probably none of the available systems is ready for use in humans. Much progress has been made during the last few years to improve performances of tetracycline, rapamycin, RU486, and ecdysone technologies in terms of tightness of regulation and inducibility. It can be predicted that also the most recently described systems will undergo a similar process of optimization. However, while constructing systems that work in cell cultures and animal models is becoming a relatively easy task, the generation of a transcription switch compatible with long-term application in humans is still a very difficult challenge. In a very schematic view, the development of a ligand-induced transcription switch for use in humans is mainly an immuno-logical and a medicinal chemistry/pharmacology task. The activators must not be recognized as nonself, and the ligand must have good oral bioavailability and pharmacokinetic profiles in the absence of toxicity. The need to satisfy both requirements tremendously complicates this particular process and reduces the probability of success.

This is clearly evident if we compare the tetracycline and dimerizer technologies that emerge over the others for their better characterization in living organisms, including nonhuman primates. On one side, there is the tetracycline system that relies on proteins of bacterial origin that may be immunogenic in humans but is induced by a relatively safe drug. On the other side stands the dimerizer-based switch, which has a reduced potential for immunogenicity but is induced by non-immunosuppressive rapamycin analogs that have not yet been characterized for their pharmacological and safety profile.

Despite these difficulties, the future is still bright with promise: the enormous progress in the last years makes us confident that systems fully compatible with use in humans will emerge in a not-too-distant future.

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