A Leucine-Rich Repeat Kinase 2 (LRRK2) Pathway Biomarker Characterization Study in Patients with Parkinson's Disease with and without LRRK2 Mutations and Healthy Controls.

Increased leucine-rich repeat kinase 2 (LRRK2) kinase activity is an established risk factor for Parkinson's disease (PD), and several LRRK2-kinase inhibitors are in clinical development as potential novel disease modifying therapeutics. This biomarker characterization study explored within- and between-subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of Ser935 on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, PBMCs, neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase 1/2 pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (n=6), idiopathic PD patients (n=6) and healthy matched control subjects (n=10) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over two days. Within-subject variability (geometric CV, %) of these biomarkers was lowest in whole blood and neutrophils (range: 12.64 to 51.32%) and considerably higher in PBMCs (range: 34.81 to 273.88%). Between-subject variability displayed a similar pattern with relatively lower variability in neutrophils (range: 61.30 to 66.26%) and whole blood (range: 44.94 to 123.11%), and considerably higher variability in PBMCs (range: 189.60 to 415.19%). Group level differences were observed with elevated mean pRab10 levels in neutrophils and a reduced mean pS935/tLRRK2 ratio in PBMCs in PD LRRK2-mutation carriers compared to healthy controls. These findings suggest that the evaluated biomarkers and assays could be used to verify pharmacological mechanisms of action and help explore the dose-response of LRRK2-inhibitors in early phase clinical studies. In addition, comparable α-synuclein aggregation in CSF was observed in LRRK2-mutation carriers compared to idiopathic PD patients.