Neurotrophic factors (NF) are potent molecules with great promise for treatment of devastating neurodegenerative disorders like Alzheimer´s and Parkinson´s disease. Targeted delivery of NF like NGF or GDNF by means of viral vectors to distinct populations of brain cells may signifi cantly enhance bio-availability and safety of such treatment approaches. However, gene therapy in its current understanding means to introduce e.g. a cDNA coding GDNF into neurons or astrocytes and expressing the factor from that time on continuously, without an option to tune expression levels according to individual patient’s demands or to shut down expression in case of unforeseen side effects. In order to increase effi cacy and safety of gene therapy vectors for treatments of human patients, we here describe the development of a tightly regulatable vector system based on the approved human drug, mifepristone, for applications in the CNS. A two-vector based layout allows modulating levels of the transactivator in order to achieve a very tight off-state while maintaining suffi cient potency for activation of transgene expression. We describe characterization of the vector system in cultured primary brain cells and in the rat striatum and cortex in terms of dependence of vector titres, inducing drug levels, and repeated responsiveness. We believe that such vector system will signifi cantly promote gene therapeutic applications in patients but will also have great impact on basic research applications.
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