Dopamine receptors are internalized into the cells once stimulated by their agonist in physiological conditions. The applicants have recently shown that, in the context of levodopa-induced dyskinesias, the debilitating motoric manifestation that limit the use of the best drug ever developed for Parkinson's disease, dopamine receptors are not enough internalized in response to the levodopa administration as too many remain at the membrane surface, i.e. being still available for continuing stimulation. We further demonstrated that such impairment of trafficking was caused by a relative decrease in the protein machinery responsible for the physiological internalization.
We here propose using a gene therapy strategy to increase the expression of the lacking protein machinery by overexpressing one member, the G protein-coupled receptor kinase 6 (GRK6) in the basal ganglia of dyskinetic non-human primates, hoping to abolish the dyskinesia severity. If successful, our strategy could be either further developed or could interest the pharmaceutical industry for developing small molecules aimed at promoting the expression or activity of GRK6.
Final Outcome
The researchers successfully demonstrated that abnormal involuntary movements and dyskinesia are lessened by overexpression of GRK6 in pre-clinical models. Conversely, silencing GRK6 with microRNAs made dyskinesia worse. Remarkably, GRK6 suppresses dyskinesia in pre-clinical models without compromising the antiparkinsonian effects of levodopa; it also prolongs the beneficial effects of lower doses. These results offer hope of achieving the elusive goal of controlling both dyskinsia and motor fluctuations in Parkinson’s disease.
As a result of the seed funding from MJFF, the team has now received follow-on funding from the National Institutes of Health to extendits studies to include in vivo experiments demonstrating the functional role of GRK6 and other GRK isoforms in levodopa-induced dyskinesia.