Study Rationale: Levodopa, currently the best treatment for the symptoms of Parkinson’s disease (PD), eventually leads to the development of uncontrollable involuntary movements, called dyskinesia. In addition, the benefits conferred by levodopa diminish over time, leading to motor fluctuations that require more frequent or higher doses of levodopa. After years of treatment, it is therefore difficult to adequately address the symptoms of PD without exacerbating dyskinesia. Many people with advanced PD also experience psychotic manifestations such as hallucinations, which further complicate disease management. In previous experiments, we discovered that modulation of a brain chemical called glycine could alleviate dyskinesia and psychosis, while also improving the symptoms of PD. Here, we propose to conduct further studies to validate our novel therapeutic strategy and bring drugs that boost the brain’s glycine levels one step closer to testing in the clinic.
Hypothesis: Using the gold standard experimental model of PD, we will show that increasing the actions of glycine in the brain alleviates disease symptoms, reduces levodopa-induced dyskinesia and lessens psychotic manifestations.
Study Design: The drug bitopertin, which enhances the actions of glycine in the brain, has been administered to people in clinical studies for conditions other than PD. In these studies, the drug was well tolerated and did not elicit adverse events. In this study, we will use an experimental model of PD to gather data that will make it possible to assess the efficacy of bitopertin in clinical trials in people with PD. Specifically, we will determine the concentrations of bitopertin in the blood following its administration. We will then investigate the effects of bitopertin on PD symptoms, psychosis and the severity of dyskinesia induced by levodopa. Lastly, we will take the first steps toward synthesizing novel forms of bitopertin that show improved pharmacokinetic properties in the body.
Impact on Diagnosis/Treatment of Parkinson’s disease: Treating advanced PD remains challenging: Most people experience dyskinesia and motor fluctuations, while psychotic features are also common. Our project has the potential to provide the first treatment that can alleviate all of these issues, which would significantly increase the quality of life for people with PD.
Next Steps for Development: Once we have completed the studies proposed here, we intend to instigate a clinical trial with bitopertin in people with PD. We will also pursue the characterization of novel forms of bitopertin.