Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease

Developments of technologies for delivery of foreign genes to the central n ervous system are opening the field to promising treatments for human neuro degenerative diseases. Gene delivery vectors need to fulfill several criter ia of efficacy and safety before being applied to humans. The ability to dr ive expression of a therapeutic gene in an adequate number of cells, to mai ntain long-term expression, and to allow exogenous control over the transge ne product are essential requirements for clinical application. We describe the use of an adenovirus vector encoding human tyrosine hydroxylase (TH) 1 under the negative control of the tetracycline-sensitive gene regulatory s ystem for direct injection into the dopamine-depleted striatum of a rat mod el of Parkinson's disease. This vector mediated synthesis of TH in numerous striatal cells and transgene expression was observed in a large proportion of them for at least 17 weeks. Furthermore, doxycyline, a tetracycline ana log, allowed efficient and reversible control of transgene expression. Thus , the insertion of a tetracycline-sensitive regulatory cassette into a sing le adenovirus vector provides a promising system for the development of suc cessful and safe therapies for human neurological diseases. Our results als o confirm that future effective gene replacement approaches to Parkinson's disease will have to consider the concomitant transfer of TH and GTP-cycloh ydrolase transgenes because the synthesis of the TH cofactor tetrahydrobiop terin may be crucial for restoration of the dopaminergic deficit.