iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer's Disease
iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer's Disease
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DOI：
10.1016/j.celrep.2017.10.109
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发表时间：
2017-11-21
期刊：
影响因子：
8.8
通讯作者：
Inoue, Haruhisa
中科院分区：
文献类型：
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作者：
Kondo, Takayuki;Imamura, Keiko;Inoue, Haruhisa
在药物开发过程中，体外研究并不总是能充分预测临床试验中人类特异性药物反应。在这里，我们利用人类 iPSC 衍生神经元的优势来筛选和评估阿尔茨海默病 (AD) 的候选治疗药物，这种神经元具有人类特异性的药物反应性。使用来自 iPSC 的纯度接近 100% 的 AD 患者神经元，我们建立了一种针对淀粉样β肽 (Aβ)（AD 致病分子）的稳健且可重复的检测方法，并筛选了药物化合物库。我们获得了 27 个降低 A 的筛选命中结果，通过基于化学结构的聚类对命中结果进行优先排序，并选择了 6 个主要化合物。接下来，为了最大限度地发挥抗 Aβ 作用，我们选择了溴隐亭、色甘酸和托吡酯的协同组合作为抗 Aβ 鸡尾酒。最后，使用来自家族性和散发性 AD 患者的神经元，我们发现该混合物对患者细胞表现出显着且有效的抗 Aβ 作用。这个基于人类 iPSC 的平台有望用于 AD 药物开发。
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 beta peptide (A beta), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 A beta-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-A beta effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-A beta cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-A beta effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.