G2019S LRRK2 Kinase Inhibition in Heterozygous Mice Avoids Lung Phenotype Observed with Inhibition of WT LRRK2.

Gain-of-function mutations in the LRRK2 protein elevate kinase activity, and heterozygous or homozygous carriers of mutant LRRK2 have an increased risk of Parkinson's disease (PD), together suggesting that inhibition of mutant LRRK2 kinase activity may be a promising therapeutic target. Conversely, LRRK2 knockout mice and people with homozygous loss-of-function LRRK2 mutations exhibit prominent pathologic changes in lung and kidney, and nonselective inhibition of wild-type and mutant LRRK2 kinase at therapeutic doses causes on-target toxicity in rodent and nonhuman primate models, most prominently in lung. Numerous LRRK2 variants have been described that cause increased phosphorylation of endogenous substrates. The G2019S mutation is the most prevalent, occurring in up to 40% of PD patients in certain populations, with the vast majority being heterozygous. We previously disclosed a series of G2019S LRRK2-selective kinase inhibitors designed to avoid on-target side effects. In this study, we examined the effect of a LRRK2 inhibitor specific for the G2019S variant, STF-3600, in WT, and heterozygous or homozygous G2019S LRRK2 knock-in (KI) mice. This inhibitor did not cause vacuolization in lungs of WT or heterozygous G2019S LRRK2 KI mice but did cause lung toxicity in homozygous G2019S LRRK2 KI mice that was similar to what was observed with the nonselective inhibitor, MLi-2. This study underscores the potential of G2019S LRRK2-selective kinase inhibitors to be safe and effective for heterozygous G2019S LRRK2 PD carriers.