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Cell Rep. 2017 Nov 21;21(8):2304-2312. doi: 10.1016/j.celrep.2017.10.109.

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

Author information

1
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Drug-Discovery Cellular Basis Development Team, RIKEN BioResource Center, Kyoto 606-8507, Japan.
2
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
3
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
4
Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
5
Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Fukushima 969-3492, Japan.
6
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
7
Department of Genome-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan; Unit for Dementia Research and Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
8
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Drug-Discovery Cellular Basis Development Team, RIKEN BioResource Center, Kyoto 606-8507, Japan. Electronic address: haruhisa@cira.kyoto-u.ac.jp.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; amyloid β; anti-Aβ cocktail; chemical clustering; compound screening; drug repositioning; in vitro trial; patient iPS cells

PMID:
29166618
DOI:
10.1016/j.celrep.2017.10.109
[Indexed for MEDLINE]
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