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

• DOI: 10.1016/j.celrep.2017.10.109
• Publication Date: 2017-11-22T14:06:47Z
• Authors: Takayuki Kondo; Keiko Imamura; Misato Funayama; Kayoko Tsukita; Michiyo Miyake; Akira Ohta; Knut Woltjen; Masato Nakagawa; Takashi Asada; Tetsuaki Arai; Shinobu Kawakatsu; Yuishin Izumi; Ryuji Kaji; Nobuhisa Iwata; Haruhisa Inoue
• Keywords: Neurons; 0301 basic medicine; Amyloid beta-Peptides; QH301-705.5; chemical clustering; Induced Pluripotent Stem Cells; Drug Evaluation, Preclinical; patient iPS cells; compound screening; drug repositioning; 3. Good health; Amyloid beta-Protein Precursor; 03 medical and health sciences; in vitro trial; Alzheimer Disease; amyloid β; Humans; Biology (General); Alzheimer’s disease; anti-Aβ cocktail

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.