Parkinson’s Disease

A neurodegenerative disease. Major focus of Randy Schekman and Thomas Südhof at Session IV.

ASAP — Aligning Science Across Parkinson’s

• Founded after Schekman’s wife’s death from PD; approached by Sergey Brin’s family office (Brin carries genetic predisposition)
• 150+ lab international network; patient, hands-off, basic-science-first funding
• Design principle: lots of shots on goal — don’t repeat the amyloid mistake from Alzheimer’s with Lewy bodies
• Working >20 known familial PD genes

Key Targets

• LRRK2 — brightest near-term target; >30 biotechs pursuing; Denali’s brain-penetrant kinase inhibitor in Phase 2
• Alpha-synuclein — lower levels or accelerate clearance of aggregated forms
• Montara — brain-only delivery platform (Kevan Shokat, UCSF) including brain-only LRRK2 inhibitor

Animal Model Challenges

• Animal models for PD are a “persistent embarrassment” (Schekman)
• Newer alpha-synuclein knock-in mice are finally recapitulating progression — including hyposmia — but it’s been a long dry spell
• A key example of the translation cliff