High-throughput profiling of compound abuse liabilities and identification of addiction-related drug targets using an iPSC-enabled platform

项目总结/摘要 美国阿片类药物成瘾危机的规模清楚地证明了迫切需要突破，以评估 复合滥用倾向，并能够发现新的镇痛剂与最小的滥用潜力。我们 假设改变成瘾相关生理学可以在共培养的hiPSC衍生的神经元中建模 和星形胶质细胞，并通过分析基因表达改变和相关的表型读数来检测。 我们的建议解决了严重缺乏生理相关的工具，能够分析相关的 通过执行特定目标来支持人类神经系统成瘾的分子变化， 包括：（1）产生一组具有稳定的细胞增殖的HiPSC衍生的神经元和星形胶质细胞。 谱系特异性荧光报告基因;（2）执行基于表型的机器学习试点 预测性滥用倾向筛查;以及（3）表型分析和基因表达分析的组合， 表征与化合物暴露相关的分子和细胞变化。成功完成 我们的项目将带来两个重大进展：（1）一个重要的新技术框架，以评估滥用的可能性 候选疗法的早期开发过程和（2）创新的，可扩展的体外试验平台 这使得能够发现靶点和相关的候选治疗剂以减轻成瘾表型。这些 创新将使凯恩生物科学公司能够启动药物发现计划， 通过帮助遏制美国阿片类药物危机的增长并降低死亡率和经济负担而受益 与此次国家紧急状态有关。

Project Summary/Abstract The scale of the US opioid addiction crisis clearly evidences the critical need for breakthroughs to assess compound abuse liabilities and to enable discovery of new analgesics with minimal abuse potential. We hypothesize that altered addiction-associated physiology can be modeled in co-cultured hiPSC-derived neuronal and astrocyte cells and detected by profiling gene expression alterations and associated phenotypic readouts. Our proposal addresses the significant lack of physiologically-relevant tools capable of profiling relevant molecular changes that underpin addiction in the human nervous system by executing Specific Aims that encompass: (1) generation of a panel of multicolor hiPSC-derived neuronal and astrocyte cells with stable lineage specific fluorescent reporters; (2) execution of a phenotype-based pilot machine learning-enabled predictive abuse liability screen; and (3) combination of phenotypic profiling and gene expression analysis to characterize the molecular and cellular changes associated with compound exposure. Successful completion of our project will deliver 2 significant advances: (1) an important new technical framework to assess abuse potential of candidate therapeutics early in the development process and (2) an innovative, scalable in vitro assay platform that enables discovery of targets and associated candidate therapeutics to mitigate addiction phenotypes. These innovations will position Cairn Biosciences to initiate drug discovery programs that will bring significant societal benefit by helping to stem the growth of the US opioid crisis and reduce the mortality rates and economic burden associated with this National Emergency.