Gene Therapy for Parkinson's Disease: Does Re-expression of HCN2 in GPe Improve Motor Deficits in Rodent PD Model?

Promising Outcomes of Original Grant:
We hypothesized that dopamine depletion in Parkinson’s disease results in downregulation of a specific ion channel, termed HCN2, in neurons of the external segment of the globus pallidus (GPe); we proposed that this loss of HCN2 is sufficient to trigger and perpetuate pathological activity in the synaptic circuit of GPe and subthalamic nucleus (STN), which is largely responsible for motor symptoms in PD. During the first year, we have demonstrated that dopamine depletion in PD pre-clinical model indeed leads to a loss of HCN2 in GPe, and we have developed adeno-associated virus (AAV) vectors for delivery – re-expression – of HCN2 in GPe as a strategy for gene therapy in PD patients.
Objectives for Supplemental Investigation:
Our work in the second year will focus on testing the effect of viral re-expression of HCN2 in a pre-clinical model of Parkinson’ disease caused by injection of a toxin (6-OHDA) in the substantia nigra compacta (SNc); the 6-OHDA injection results in degeneration of dopaminergic SNc neurons, much like in a late stage of PD. This work will directly test our hypothesis that re-expression of HCN2 in GPe neurons can alleviate motor deficits in the PD pre-clinical model. If successful, we will next test this hypothesis in a primate model of PD, which is the best approximation to human PD patient. This work will be done together with our collaborators Dr. James Surmeier (Northwestern University) and Dr. Hitoshi Kita (University of Tennessee) of the Udall Center of Excellence for Parkinson's Disease Research, Northwestern University.
Importance of This Research for the Development of a New PD Therapy:
Gene therapy based on re-expression of HCN2 in GPe, as proposed in our work, is the first therapeutical strategy that aims not only to disrupt the pathological activity but also to restore normal function in the GPe–STN circuit that is largely responsible for motor symptoms in Parkinson’s disease. This means that, if successful, our strategy will allow the GPe–STN circuit to function properly in the absence of dopaminergic innervation. In other words, we may able to “trick” the GPe–STN circuit into “not noticing” the lack of dopaminergic innervation after degeneration of SNc neurons. Such therapy may provide significant motor improvements to even late stage PD patients.