Abstract

Gain-of-function mutations in leucine-rich kinase 2 (LRRK2) are associated with increased incidence of Parkinson's disease (PD); thus, pharmacological inhibition of LRRK2 kinase activity is postulated as a disease modifying treatment for PD. Histomorphological changes in lungs of non-human primates (NHP) treated with small molecule LRRK2 kinase inhibitors have brought the safety of this treatment approach into question. While it remains unclear how LRRK2 kinase inhibition affects the lung, continued studies in NHPs prove to be both cost and resource prohibitive. To develop a tractable alternative animal model platform, we dosed male mice in-diet with the potent, highly selective LRRK2 kinase inhibitor MLi-2 and induced histomorphological changes in lung within one week. Oral bolus dosing of MLi-2, at a frequency modeled to provide steady-state exposure equivalent to that achieved with in-diet dosing, induced type II pneumocyte vacuolation, suggesting pulmonary changes require sustained LRRK2 kinase inhibition. Treating mice with MLi-2 in-diet for up to 6 months resulted in type II pneumocyte vacuolation which progressed only modestly over time and was fully reversible following withdrawal of MLi-2. Immunohistochemical analysis of lung revealed a significant increase in pro-surfactant protein C staining within type II pneumocytes. In the present study, we demonstrated the kinetics for onset, progression, and rapid reversibility of chronic LRRK2 kinase inhibitor effects on lung histomorphology in rodents and provide further evidence for the de-risking of safety and tolerability concerns for chronic LRRK2 kinase inhibition in PD.

Significance Statement We have defined a mouse model by which the on-target lung effects of LRRK2 kinase inhibition can be monitored, whereas previous in vivo testing relied solely on non-human primates. Data serves to de-risk long-term treatment with LRRK2 kinase inhibitors, as all lung changes were mild and readily reversible.