Inhibition of the kinase activity of leucine-rich repeat kinase 2 (LRRK2) is under investigation as a possible treatment for Parkinson's disease. However, there is no clinical validation as yet, and the safety implications of targeting LRRK2 kinase activity are not well understood. We evaluated the potential safety risks by comparing human and mouse LRRK2 mRNA tissue expression, by analyzing a Lrrk2 knockout mouse model, and by testing selective brain-penetrating LRRK2 kinase inhibitors in multiple species. LRRK2 mRNA tissue expression was comparable between species. Phenotypic analysis of Lrrk2 knockout mice revealed morphologic changes in lungs and kidneys, similar to those reported previously. However, in preclinical toxicity assessments in rodents, no pulmonary or renal changes were induced by two distinct LRRK2 kinase inhibitors. Both of these kinase inhibitors induced abnormal cytoplasmic accumulation of secretory lysosome-related organelles known as lamellar bodies in type II pneumocytes of the lung in nonhuman primates, but no lysosomal abnormality was observed in the kidney. The pulmonary change resembled the phenotype of Lrrk2 knockout mice, suggesting that this was LRRK2-mediated rather than a nonspecific or off-target effect. A biomarker of lysosomal dysregulation, di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP), was also decreased in the urine of Lrrk2 knockout mice and nonhuman primates treated with LRRK2 kinase inhibitors. Our results suggest a role for LRRK2 in regulating lysosome-related lamellar bodies and that pulmonary toxicity may be a critical safety liability for LRRK2 kinase inhibitors in patients.
Authors: Reina N. Fuji, Michael Flagella, Miriam Baca, Marco A. S. Baptista, Jens Brodbeck, Bryan K. Chan, Brian K. Fiske, Lee Honigberg, Adrian M. Jubb, Paula Katavolos, Donna W. Lee, Sock-Cheng Lewin-Koh, Tori Lin, Xingrong Liu, Shannon Liu, Joseph P. Lyssikatos, Jennifer O'Mahony, Mike Reichelt, Merone Roose-Girma, Zejuan Sheng, Todd Sherer, Ashley Smith, Margaret Solon, Zachary K. Sweeney, Jacqueline Tarrant, Alison Urkowitz, Søren Warming, Murat Yaylaoglu, Shuo Zhang, Haitao Zhu, Anthony A. Estrada, Ryan J. Watts