title: Effect of selective LRRK2 kinase inhibition on nonhuman primate lung.
abstract: 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: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA. fuji.reina@gene.com watts.ryan@gene.com.
authors: Reina N
authors: RN
authors: Fuji
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Michael
authors: M
authors: Flagella
authors: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Miriam
authors: M
authors: Baca
authors: The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10018, USA.
authors: Marco A S
authors: MA
authors: Baptista
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Jens
authors: J
authors: Brodbeck
authors: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Bryan K
authors: BK
authors: Chan
authors: The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10018, USA.
authors: Brian K
authors: BK
authors: Fiske
authors: Department of Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Lee
authors: L
authors: Honigberg
authors: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Adrian M
authors: AM
authors: Jubb
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Paula
authors: P
authors: Katavolos
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Donna W
authors: DW
authors: Lee
authors: Department of Nonclinical Biostatistics, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Sock-Cheng
authors: SC
authors: Lewin-Koh
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Tori
authors: T
authors: Lin
authors: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Xingrong
authors: X
authors: Liu
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Shannon
authors: S
authors: Liu
authors: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Joseph P
authors: JP
authors: Lyssikatos
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Jennifer
authors: J
authors: O'Mahony
authors: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Mike
authors: M
authors: Reichelt
authors: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Merone
authors: M
authors: Roose-Girma
authors: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Zejuan
authors: Z
authors: Sheng
authors: The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10018, USA.
authors: Todd
authors: T
authors: Sherer
authors: Department of Pharmacodynamic Biomarkers, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Ashley
authors: A
authors: Smith
authors: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Margaret
authors: M
authors: Solon
authors: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Zachary K
authors: ZK
authors: Sweeney
authors: Department of Safety Assessment, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Jacqueline
authors: J
authors: Tarrant
authors: The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10018, USA.
authors: Alison
authors: A
authors: Urkowitz
authors: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Søren
authors: S
authors: Warming
authors: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Murat
authors: M
authors: Yaylaoglu
authors: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Shuo
authors: S
authors: Zhang
authors: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Haitao
authors: H
authors: Zhu
authors: Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
authors: Anthony A
authors: AA
authors: Estrada
authors: Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. fuji.reina@gene.com watts.ryan@gene.com.
authors: Ryan J
authors: RJ
authors: Watts
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008168:Lung / Q000002:abnormalities / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D008252:Macaca fascicularis; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: C577934:(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone; C587728:2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile; D015415:Biomarkers; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases