While inhibitors of LRRK2 activity are currently in clinical trials for the treatment of Parkinson’s disease, the minimum requirement of target engagement to significantly modify disease progression has yet to be determined. This study will examine multiple levels of target engagement in a model of Parkinson’s to determine the threshold of LRRK2 inhibition required to achieve efficacy.
A minimum percentage of LRRK2 inhibition is required to demonstrate efficacy in a Parkinson’s model.
We have shown that LRRK2 inhibition using the Pfizer tool compound PFE360 is protective in an alpha-synuclein-based model of Parkinson’s. We will first determine the percent inhibition of LRRK2 activity associated with this effect and whether it was safe with respect to lung and kidney pathology (previously linked to LRRK2 inhibition). Next, we will determine multiple doses of PFE360 that produce differing levels of LRRK2 inhibition and furthermore employ these doses in a study to establish the threshold of inhibition required to show efficacy against alpha-synuclein-driven neurodegeneration.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
With this information drug development programs will be able to better define doses to be used in both pre-clinical and clinical studies.
Next Steps for Development:
The clinical applications of the results of this study are to better understand minimum LRRK2 inhibition required in order to modify the disease process and within dosing limits that are considered safe.