Regulation of therapeutic transgene expression can increase the safety of gene therapy interventions， especially when targeting critical organs such as the brain. Although several gene expression systems have been described， none of the current systems has the required safety profile for clinical applications. Our group has previously adapted a system for novel gene regulation based on the destabilizing domain degron technology to successfully regulate glial cell-line derived neurotrophic factor in the brain (GDNF-F-DD). In the present study， we used GDNF-F-DD as a proof-of-principle molecule to fully characterize DD regulation in the brain. Our results indicate that DD could be regulated in a dose-dependent manner. In addition， GDNF-F-DD could also be induced repeatedly， without loss of activity or efficacy . Finally， DD regulation was able to be sustained for 24?weeks without loss of expression or any overt toxicity. The present study shows that DD has great potential to regulate gene expression in the brain.