Regulated GDNF Gene Therapy: A Novel Regulatory System Based on Protein Degradation

Promising Outcomes of Original Grant:
We have developed lentiviral vectors that can express functional GDNF both in the cell culture dish and in the brain of pre-clinical models. These vectors can be regulated by the common antibiotic trimethoprim, which has been used in humans for decades and have few side effects. By giving trimethoprim to the cell culture media or to the drinking water of the models we can induce expression of the trophic factor GDNF. This resulted in protection of the dopaminergic cells and their function in vivo. This finding is an important step towards development of a new regulatable gene therapy system for trophic factors to combat Parkinson’s disease.

Objectives for Supplemental Investigation:
To take this project further we will now determine the dose-response curve for DD-regulated GDNF in vivo. This will give us insight into the possibility of the system for dosing the gene therapy.

Moreover, we will determine if the DD regulation of GDNF is stable by ascertain how long does the GDNF therapeutic effect last, investigate the ON and OFF kinetics of the DD-GDNF system. Last, but not least, we will investigate if there are any indications of toxicity of the DD-system in vivo.

Importance of This Research for the Development of a New PD Therapy: 
The overriding goal of this approach is to develop a safe therapy for Parkinson’s disease using regulated and GDNF expression in the brain. The proposed project aims to further characterizing if the DD system can be safely used to regulate GDNF expression in vivo. We want to evaluate if GDNF regulation by the DD system is dose dependent, if the regulation is DD stable and if the DD system is toxic. The outcome of this project will be very useful in the guidance for taking DD-regulation of transgene to a clinically useful therapy for Parkinson’s disease.