Objective/Rationale:
Levodopa-induced dyskinesias (LID) affect the majority of patients with advanced Parkinson’s disease, compounding their disability. Therefore, drugs that prevent or limit LID are critically needed to improve patients’ quality of life. Increased understanding of the mechanisms underlying LID suggests that one key component is dysregulation of endogenous opiates and their receptors, leading to disturbed neuronal networks and impaired control of motor function. The goal of this project is to perform pre-clinical studies to test the anti-LID efficacy and safety of a drug that has desirable activities at opioid receptors.
Project Description:
The study will test the efficacy of an opiate receptor-modulating drug with a unique combination of receptor subtype selectivities in a well-established pre-clinical model of Parkinson’s disease and LID. The impact of the drug on the severity and duration of dyskinesias, as well as the anti-parkinsonian effects of levodopa will be determined using standard rating scales. Both acute administration and long-term maintenance treatment paradigms will be employed, and pharmacokinetic/pharmacodynamic correlations will be established. In addition to efficacy, the safety of the compound will be evaluated to ensure its viable use in the clinic. At the conclusion of the study, molecular and biochemical studies will be performed to gain further insight into the mechanisms of LID and the anti-LID effects of the drug.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project aims to develop a new medication for LID, whose medical needs are currently not addressed effectively. Studies demonstrating a favorable efficacy and safety profile for this drug will have a clear impact on moving this line of therapy forward for testing in patients with Parkinson’s disease in a controlled clinical trial. Having an effective and safe anti-dyskinetic drug as an adjunct to levodopa can allow patients with Parkinson’s disease to experience the full antiparkinsonian effects of levodopa without the induction of uncomfortable involuntary movements.
Anticipated Outcome:
The objective of this research is to test the ability of a specific opiate receptor-modulating drug to safely and effectively repress LID without blocking the beneficial anti-parkinsonian effects of the dopamine precursor. On successful completion of these studies, we will understand the dosing and efficacy of the drug, enabling its advancement to clinical trials in patients.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Final Outcome
The objective of this project was to determine the efficacy and safety of a novel agent in reducing levodopa-induced dyskinesia (LID) in a pre-clinical model of Parkinson’s disease (PD). The drug is currently used clinically for another indication but its pharmacological mechanisms of action indicated that it may be repurposed to help adjust motor responses to levodopa and reduce the occurrence of disabling dyskinesias. The drug was tested in six parkinsonian pre-clinical models exhibiting stable LID. Marked reduction of LID in a dose-dependent manner without decrement in the antiparkinsonian action of levodopa was observed. In addition, these effects on LID were sustained following chronic administration in a course of 4-week daily treatment. At efficacious doses the drug, combined with levodopa, was well tolerated and did not cause sedation or other adverse effects. In conclusion, this compound is a safe and effective anti-LID agent, and these results in pre-clinical models support the advancement to clinical testing.