Effects of LRRK2 Inhibitors in Nonhuman Primates

Area of Science:

• Pharmacology
• Toxicology
• Primate Studies

Background:

• Leucine-rich repeat kinase 2 (LRRK2) inhibitors are investigated for therapeutic potential.
• Understanding the toxicological profile of novel LRRK2 inhibitors in preclinical models is crucial.

Purpose of the Study:

• To assess the safety and tolerability of selective, brain-penetrant LRRK2 inhibitors in nonhuman primates.
• To characterize the toxicological effects of these inhibitors on primate lung tissue.

Main Methods:

• Administration of GNE 7915, Compound 25, and MK-1468 to cynomolgus and rhesus monkeys at various doses and durations.
• Histopathological examination of lung tissues, including light and transmission electron microscopy.
• Immunohistochemistry for pro-surfactant C and CD11c.
• Histochemical staining for collagen.

Main Results:

• GNE 7915 showed limited tolerability. Compound 25 and MK-1468 were tolerated for shorter durations.
• Lung findings included type 2 pneumocyte hypertrophy, lamellar body accumulation, intra-alveolar macrophage infiltration, and collagen deposition in alveolar walls.
• These lung changes were associated with Compound 25 and MK-1468 administration.
• Following a 12-week recovery period, lung structural remodeling in MK-1468 treated animals was not reversible.

Conclusions:

• Selective LRRK2 inhibitors can induce significant lung toxicity in nonhuman primates.
• Type 2 pneumocyte alterations and interstitial fibrosis are key pathological findings.
• The observed lung pathology may not be fully reversible, highlighting the need for careful safety evaluations of LRRK2 inhibitors.