Alternations in kidney function have been observed in pre-clinical models of LRRK2 that may represent potential safety liabilities of LRRK2 kinase inhibitor therapeutics for the treatment of Parkinson's disease (PD). The impact of these abnormalities on renal function has not been fully investigated. The main objective of this project is to evaluate the functional consequences of altered kidney function with novel safety biomarkers that are more sensitive than traditional clinical parameters (serum creatinine and blood urea nitrogen, chemicals regulated by the kidneys) in LRRK2 pre-clinical models
Pre-clinical models will be monitored across different time points to characterize kidney function. Several renal safety biomarkers will be measured in the urine, including chemical markers of activity and injury, along with standard examination of kidneys, lungs, liver and spleen. Cellular experiments will also be performed and others to be determined based on any microscopic abnormalities.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
The project is aimed at better understanding the potential risks associated with the alterations in kidney function in LRRK2 pre-clinical models. The potential impact is to facilitate the development of safer LRRK2 kinase inhibitors for the treatment of Parkinson's.
We hope to better evaluate functional consequences of the alterations in kidney function observed in LRRK2 pre-clinical models to inform future risk assessment studies with LRRK2 kinase inhibitors. Depending on the results, the project will help de-risk the alterations in kidney function observed in LRRK2 pre-clinical models or will identify renal safety markers to better detect and monitor potential kidney safety liabilities associated with LRRK2 inhibitors.