Promising Outcomes of Original Grant:
Our goal is to develop novel therapeutic molecules that promote normal dopamine neurotransmission in the brain affected by PD. We hypothesize that these molecules will augment the beneficial actions of low-dose levodopa therapy and reduce adverse dyskinesias. To this end, we tested a small-molecule inhibitor of the brain-enriched phosphodiesterase-1 (PDE1) for its ability to reverse akinesia and attenuate motor dyskinesias in a rodent model of PD. PD models treated with a PDE1 inhibitor displayed better spontaneous motor activity in the presence of levodopa and significantly fewer dyskinetic behaviors.
Objectives for Supplemental Investigation:
A critical step in translating our observation of rodents into a viable human pharmacotherapy for PD is confirmation in a non-human primate. The current project will evaluate the utility of this therapeutic approach in higher animals, by testing the motor benefits of a PDE1 inhibitor in non-human primates. In the proposed studies we will first perform a pharmacokinetic study in non-human primate models intended to establish optimal dosing conditions for our PDE1 inhibitor in primates. Motor dyskinesias will be elicited in MPTP-treated models by chronic levodopa administration. Models will then be treated with levodopa in the absence or presence of a PDE1 inhibitor in order to determine if PDE1 inhibition attenuates the expression of motor dyskinesias evoked by levodopa, without compromising normal movement. These experiments will test whether, analogous to our rodent studies, pharmacological inhibition of PDE1 effectively reduces the expression of motor side effects associated with chronic levodopa treatment in primates.
Importance of This Research for the Development of a New PD Therapy:
The appearance of motor dyskinesias represents a major, debilitating side effect of chronic levodopa treatment and a significant challenge for the long-term management of PD. To date, no pharmacological therapies have yet been approved for the maintenance of motor dyskinesias. PDE1 inhibition represents a novel pharmacological approach to promote the positive motor effects of levodopa, while reducing the expression of dyskinesias. If successful in primates, this therapy will be poised to continue preclinical development and enter human clinical evaluation as an anti-dyskinetic medication in PD.
Intra-Cellular Therapies Inc has initiated studies to test the motor effects of novel PDE-1 inhibitors in non-human primate models of Parkinson’s disease. We have confirmed that two potent and selective PDE-1 inhibitors are orally bioavailable in adult female macaques. These compounds are currently being studied with regard to their effects on dyskinesia (chorea and dystonia) and on Parkinson’s disability in female MPTP-lesioned macaques displaying stable dyskinesia after chronic treatment with L-DOPA.