Study Rationale:
Levodopa and other available treatments for Parkinson’s disease (PD) are initially effective but have unpredictable therapeutic effects and induce serious adverse side effects in more advanced stages of the disease. We have established novel experimental drug candidates that act by increasing activity of a neurotransmitter receptor called mGlu4 and that have potential to improve motor symptoms in both early and advanced stages of the disease. It is important to test these novel drug candidates in large parkinsonian models before advancing to testing in PD patients.
Hypothesis:
We hypothesize that mGlu4 activators reverse motor symptoms and enhance therapeutic effects of levodopa in parkinsonian models.
Study Design:
We will assess motor symptoms using a clinical rating scale that is adapted from the scale used to assess disability in PD patients. After establishing disability of models that have not been treated, we will administer mGlu4 activators and reassess motor disability. After completion of studies to evaluate effects of mGlu4 activators alone, we will co-administer mGlu4 activators with low doses of levodopa to determine whether coadministration provides a greater benefit than could be achieved with either drug alone.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If these and future clinical studies support our hypothesis, mGlu4 positive allosteric modulators (PAMs) could provide a fundamental advance in treatment of PD and allow sustained reversal of motor disability without levodopa-related adverse effects.
Next Steps for Development:
After completion of these studies, the next step will be to perform extensive pre-clinical and early clinical toxicity studies to support advancing an mGlu4 activator drug candidate into testing in PD patients.
Final Outcome
The goals of this grant application were to validate the activity of an mGlu4 PAM in a pre-clinical model. Our results demonstrate that a single dose of an mGlu4 PAM, when given in combination with a low dose of L-DOPA, induces beneficial effects on activity, parkinsonian score, bradykinesia, and ON time, without worsening of dyskinesia. Importantly, these studies also validated an acute motor effect of an mGlu4 PAM when administered with L-DOPA, suggesting that motor function will serve as what is known as a “biomarker” to demonstrate that we have potentiated mGlu4 activity in the brains of people with PD, a critical experimental need for a clinical trial. Overall, the results from this study have validated mGlu4 PAM activity in a non-rodent model of PD, provided rational for the use of an important biomarker, and paved the way for future clinical studies to assess the activity of mGlu4 PAMs in PD patients.