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: Drug Development; Amyloid (mycology)

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