LRRK2

Leucine-rich repeat kinase 2 — the brightest near-term target for Parkinson’s disease. Discussed at Session IV.

Biology

• Dominant alleles cause ~2× kinase hyperactivity
• Over 30 biotechs are pursuing LRRK2 inhibitors

Key Programs

• Denali — brain-penetrant LRRK2 kinase inhibitor, Phase 2 readout expected summer 2026; aims to dial down the kinase hyperactivity
• Montara — brain-only LRRK2 inhibitor (Kevan Shokat’s brain-only delivery platform from UCSF); would dodge LRRK2’s peripheral effects. Südhof is excited about this approach

Clinical Considerations

• A brain-only inhibitor would address the concern about peripheral LRRK2 inhibition effects
• Part of ASAP’s multi-target strategy: lots of shots on goal, not betting on one pathway