Journal Article iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer’s Disease

Kondo, Takayuki  ,  Imamura, Keiko  ,  Funayama, Misato  ,  Tsukita, Kayoko  ,  Miyake, Michiyo  ,  Ohta, Akira  ,  Woltjen, Knut  ,  Nakagawa, Masato  ,  Asada, Takashi  ,  Arai, Tetsuaki  ,  Kawakatsu, Shinobu  ,  Izumi, Yuishin  ,  Kaji, Ryuji  ,  Iwata, Nobuhisa  ,  Inoue, Haruhisa

21 ( 8 )  , pp.2304 - 2312 , 2017-11 , Elsevier (Cell Press)
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.

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