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AAV-Based Approach for Regulatable and Cell Type-Specific Gene Therapy in PD: Restoring Excitability to an Intrinsically Silenced Subpopulation of GP Neurons

Abnormally synchronized activity within the basal ganglia, specifically between the external globus pallidus (GPe) and subthalamic nucleus (STN), is a hallmark of altered network activity in Parkinson's disease. Strikingly, deep brain stimulation of STN, which disrupts the GPe–STN synchronous activity, elevates PD motor symptoms; this provides a direct evidence for pathological significance of the abnormal GPe–STN activity.

We propose to develop gene therapy based on the use of recombinant adeno-associated virus (rAAV) vectors with regulatable gene expression. This therapy will aim to reverse cellular pathology observed in a subpopulation of GP cells in PD animal models, which may underlie the pathological bursting of GP–STN neurons. If successful, this approach may disrupt rhythmic bursting but not normal GPe–STN activity in the PD brain, and hence provide a highly specific Symptoms & Side Effects treatment for even late-stage PD.

Final Outcome

Dr. Osten and his group demonstrated that dopamine depletion in PD pre-clinical models indeed leads to a loss of HCN2 in GPe. The team has developed adeno-associated virus (AAV) vectors for delivery – re-expression – of HCN2 in GPe as a strategy for gene therapy in PD patients. This work led to additional support from MJFF to continue these studies.


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