iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid ß Combination for Alzheimer's Disease.

In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer's disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid ß peptide (Aß), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aß-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aß effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aß cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aß effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.