Gene therapy may offer effective treatments to patients. Delivering genes to cells in the body has the potential of letting the patient’s cells treat themselves. In the case of PD, delivering the gene for glial-cell derived neurotrophic factor (GDNF) into the brain has the potential to protect brain cells in PD patients. However, if this factor is produced for very long periods, it can have side effects. We propose a new way of turning on and off the production of GDNF in the brain.
This novel way will allow turning on the gene when the cells need and turning it off when there is no need for GDNF in the brains of patients. It is thought that when GDNF is fused with a specific compound, it will possible to regulate it using a common antibiotic called trimethoprin.
We propose to evaluate a number of fusion proteins of GDNF in vitro. The versions that are found to be functional and regulated by trimethoprim will be further investigated in pre-clinical models of Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The GDNF fusion protein that is efficacious in vivo is a candidate for further development of a disease-modifying therapy for Parkinson’s disease.
At the success of this project we will know if the trimethoprim regulation of transgenes is a feasible approach for gene therapy to the CNS. Furthermore, we will shed some light on the possibilities of using GDNF in this contex for further development into a clinical therapy.
We have developed lentiviral vectors that can express functional GDNF both in the cell culture dish and in a pre-clinical model brain. 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 wil result in protction of the dopaminergic cells and their function in vivo. This finding is an important step towards development of a new regulatable gene therapy stsyem for tropihci factors to combat Parkinosn’s disease.
Presentations & Publications
“Efficient regulation of GDNF expression in the brain using targeted proteasomal degradation “L Quintino, E Elgstrand-Wettergren, C Isaksson, C Lundberg. Poster abstract at the 2011 Congress of the European Society for Cell and Gene Therapy held in Brigthon, UK October 27th to 31st.