LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits
Marco A S Baptista1, Kalpana Merchant2, Ted Barrett3
1The Michael J. Fox Foundation for Parkinson's Research, Grand Central Station, P.O. Box 4777, New York, NY 10001, USA. mbaptista@michaeljfox.org.
Abstract:
The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson's disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was ~50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.
Insights
Concerns regarding LRRK2 inhibitor lung toxicity in Parkinson's disease (PD) research were investigated. The study found mild, reversible lung effects in macaques, suggesting these are on-target and do not impair pulmonary function, supporting clinical trials.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common genetic cause of Parkinson's disease (PD).
- Development of LRRK2 inhibitors for PD is ongoing, but preclinical studies raised safety concerns due to lung histopathology in nonhuman primates.
- It remains unclear if these lung effects are on-target, reversible, or associated with pulmonary deficits.
Purpose of the Study:
- To investigate if observed lung effects from LRRK2 inhibitors in macaques are on-target pharmacology.
- To determine the reversibility of these lung effects after drug withdrawal.
- To assess if LRRK2 inhibitor treatment leads to pulmonary function deficits.
Main Methods:
- A 2-week repeat-dose toxicology study in macaques using three LRRK2 inhibitors: GNE-7915, MLi-2, and PFE-360.
- Histopathological examination of lung tissues.
- Evaluation of lung function in subsets of animals after drug withdrawal.
- Assessment of LRRK2 inhibition in brain tissue.
Main Results:
- All tested LRRK2 inhibitors induced mild cytoplasmic vacuolation of type II lung pneumocytes, suggesting on-target pharmacology.
- Lung histopathological changes were minimal or absent at doses achieving significant LRRK2 inhibition in the brain.
- The observed lung effects were reversible upon cessation of drug administration.
- Lung function tests revealed no pulmonary deficits despite histological changes.
Conclusions:
- The lung effects observed in nonhuman primates treated with LRRK2 inhibitors are likely on-target and reversible.
- These histological changes do not appear to cause functional pulmonary deficits.
- The findings suggest that LRRK2 inhibitors should not be precluded from clinical testing for Parkinson's disease based on these preclinical lung observations.
