Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.

Abstract

Parkinson's disease (PD) poses a major unmet therapeutic challenge, with most drug candidates failing in clinical translation despite promising animal model data. Human induced pluripotent stem cell-derived midbrain organoids recapitulate key PD pathological hallmarks - including dopaminergic neuron loss, α-synuclein aggregation, and neuroinflammation - in a genetically defined, human-specific context. This review summarizes drug screening studies in midbrain organoids across genetic, toxin-based, and α-synuclein preformed fibril models. We highlight therapeutic interventions that rescue PD phenotypes, compare organoid and animal model systems, and discuss the personalized medicine potential of patient-derived organoids. We also critically assess current limitations and outline how artificial intelligence integration and assembloid platforms are advancing organoid-based drug discovery towards regulatory acceptance.