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Journal of Pharmacology and Experimental Therapeutics

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OtherDrug Discovery and Translational Medicine

Characterization of the onset, progression, and reversibility of morphological changes in mouse lung following pharmacological inhibition of LRRK2 kinase activity

Dianne Bryce, Christopher M Ware, Janice D Woodhouse, Paul J Ciaccio, J Michael Ellis, Laxminarayan G Hegde, Sabu Kuruvilla, Matthew L Maddess, Carrie G Markgraf, Karin M Otte, Frederique M Poulet, Lauren M Timmins, Matthew Kennedy and Matthew J. Fell
Journal of Pharmacology and Experimental Therapeutics January 28, 2021, JPET-AR-2020-000217; DOI: https://doi.org/10.1124/jpet.120.000217
Dianne Bryce
1Discovery Neuroscience, Merck & Co., Inc., United States of America
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  • For correspondence: brycedk1@gmail.com
Christopher M Ware
1Discovery Neuroscience, Merck & Co., Inc., United States of America
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Janice D Woodhouse
2Pharmacology, Merck & Co., Inc., United States of America
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Paul J Ciaccio
3Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., United States of America
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J Michael Ellis
4Discovery Chemistry, Merck & Co., Inc., United States of America
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Laxminarayan G Hegde
2Pharmacology, Merck & Co., Inc., United States of America
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Sabu Kuruvilla
3Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., United States of America
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Matthew L Maddess
4Discovery Chemistry, Merck & Co., Inc., United States of America
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Carrie G Markgraf
3Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., United States of America
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Karin M Otte
5PPDM, Merck & Co., Inc., United States of America
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Frederique M Poulet
3Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., United States of America
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Lauren M Timmins
1Discovery Neuroscience, Merck & Co., Inc., United States of America
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Matthew Kennedy
6Neuroscience, Merck, United States of America
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Matthew J. Fell
7Neuroimmunology, Merck, United States of America
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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.

  • Lung
  • Parkinson's Disease
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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OtherDrug Discovery and Translational Medicine

LRRK2 Kinase Inhibition Affects Mouse Lung

Dianne Bryce, Christopher M Ware, Janice D Woodhouse, Paul J Ciaccio, J Michael Ellis, Laxminarayan G Hegde, Sabu Kuruvilla, Matthew L Maddess, Carrie G Markgraf, Karin M Otte, Frederique M Poulet, Lauren M Timmins, Matthew Kennedy and Matthew J. Fell
Journal of Pharmacology and Experimental Therapeutics January 28, 2021, JPET-AR-2020-000217; DOI: https://doi.org/10.1124/jpet.120.000217

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OtherDrug Discovery and Translational Medicine

LRRK2 Kinase Inhibition Affects Mouse Lung

Dianne Bryce, Christopher M Ware, Janice D Woodhouse, Paul J Ciaccio, J Michael Ellis, Laxminarayan G Hegde, Sabu Kuruvilla, Matthew L Maddess, Carrie G Markgraf, Karin M Otte, Frederique M Poulet, Lauren M Timmins, Matthew Kennedy and Matthew J. Fell
Journal of Pharmacology and Experimental Therapeutics January 28, 2021, JPET-AR-2020-000217; DOI: https://doi.org/10.1124/jpet.120.000217
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