iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β 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 β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.
['Kondo|Takayuki|T|', 'Imamura|Keiko|K|', 'Funayama|Misato|M|', 'Tsukita|Kayoko|K|', 'Miyake|Michiyo|M|', 'Ohta|Akira|A|', 'Woltjen|Knut|K|', 'Nakagawa|Masato|M|', 'Asada|Takashi|T|', 'Arai|Tetsuaki|T|', 'Kawakatsu|Shinobu|S|', 'Izumi|Yuishin|Y|', 'Kaji|Ryuji|R|', 'Iwata|Nobuhisa|N|', 'Inoue|Haruhisa|H|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D004353:Drug Evaluation, Preclinical D006801:Humans D057026:Induced Pluripotent Stem Cells D009474:Neurons
compound screening in vitro trial amyloid β anti-Aβ cocktail Alzheimer’s disease chemical clustering drug repositioning patient iPS cells