Abstract
Glial cell-derived neurotrophic factor (GDNF) has been shown to increase the survival of dopaminergic neurones in various deleterious environments. Therefore, it has been suggested that GDNF gene transfer has important potentialities for neuroprotective therapy for Parkinson's disease. However, undesirable effects of GDNF gene delivery such as behavioral alterations in healthy rats and down-regulation of tyrosine hydroxylase at long-term have been described1.Therefore, we have constructed a tightly controlled autoregulatory tetracycline-inducible AAV vector (AAV-ptetbidiON) in which transcription of both the reverse tetracycline transactivator (rtTA) and the transgene are initiated from a bidirectional tetracycline- responsive promoter2. Using a modified AAV-ptetbidiON harbouring the M2 mutant transactivator3 encapsidated into AAV serotype 1 to deliver the human GDNF cDNA, widespread transduction of the striatum has been obtained in the induced state (in the presence of doxycycline). The striatal tissue concentration of GDNF was 75 pg/mg tissue in doxycycline-treated animals whereas it was undistinguishable from the endogenous level (4.5 pg/mg) in untreated animals. Unilateral administration of the AAV1-ptetbidiON-GDNF vector to the striatum of healthy rats resulted in a contralateral rotational behavior in doxycycline-treated but not in untreated animals. In addition, a doxycycline-dependent downregulation of tyrosine hydroxylase in the dopaminergic nerve terminals of the injected side was observed.These data suggest that behavioral and metabolic effects of striatal delivery of GDNF in healthy rats can be tightly controlled by using the autoregulatory rAAV1-ptetbidiON-GDNF vector.1 Georgievska et al. (2004). J. Neurosci. 24, 6437-6445.2 Chtarto et al. (2003). Gene Ther. 10, 86-96.3 Urlinger et al. (2000) Proc Natl Acad Sci U S A. 97:7963-8.The presenter is inventor on a patent describing a vector which is owed by the University.
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