Characterization of the Onset, Progression, and Reversibility of Morphological Changes in Mouse Lung after Pharmacological Inhibition of Leucine-Rich Kinase 2 Kinase Activity

Gain-of-function mutations in leucine-rich kinase 2 (LRRK2) are associated with increased incidence of Parkinson disease (PD); thus, pharmacological inhibition LRRK2 activity is postulated as a disease-modifying treatment PD. Histomorphological changes lungs nonhuman primates (NHPs) treated small-molecule inhibitors have brought the safety this approach into question. Although it remains unclear how affects lung, continued studies NHPs prove to be both cost- and resource-prohibitive. To develop tractable alternative animal model platform, we dosed male mice in-diet potent, highly selective inhibitor MLi-2 induced histomorphological lung within 1 week. Oral bolus dosing at frequency modeled provide steady-state exposure equivalent that achieved type II pneumocyte vacuolation, suggesting pulmonary require sustained inhibition. Treating for up 6 months resulted vacuolation progressed only modestly over time was fully reversible after withdrawal MLi-2. Immunohistochemical analysis revealed significant increase prosurfactant protein C staining pneumocytes. In present study, demonstrated kinetics onset, progression, rapid reversibility chronic effects on histomorphology rodents further evidence derisking tolerability concerns SIGNIFICANCE STATEMENT We defined mouse by which on-target can monitored, whereas previous vivo testing relied solely primates. Data serve derisk long-term inhibitors, all were mild readily reversible.