Mechanistic description
LRRK2 G2019S mutations cause autosomal dominant PD through hyperactivation that impairs vesicular trafficking via Rab GTPase phosphorylation. Multiple Phase 1 programs (DNL151, BIIB094) have demonstrated target engagement (>90% Rab10 dephosphorylation) with manageable safety profiles. Lung toxicity (lamellar body accumulation) represents a dose-limiting concern requiring intermittent dosing strategies. The biomarker (Rab10 phosphorylation) enables patient selection and response monitoring.
Evidence for (3)
LRRK2 G2019S is most common PD-causing mutation
LRRK2 inhibitors rescue lysosomal defects in patient-derived neurons
Phase 1 trials of DNL151/BIIB094 completed with target engagement
Evidence against (2)
LRRK2 inhibitors cause lamellar body accumulation in NHP lungs
LRRK2 G2019S carriers have 30-70% lifetime PD risk - incomplete penetrance