hiPSC Cardiomyocyte HTS Electrophysiology System for Detecting Drug Induced Fatal Cardiac Arrhythmias

用于检测药物引起的致命性心律失常的 hiPSC 心肌细胞 HTS 电生理学系统

• 批准号: 9906226
• 负责人: TODD Joseph HERRON
• 金额: $ 58.69万
• 依托单位: CARTOX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906226
• 关键词: Action Potentials; Address; Adoption; Arrhythmia; Biological Assay; Blinded; Calcium; Cardiac; Cardiac Myocytes; Cardiotoxicity; Categories; Cells; Collaborations; Data; Development; Dyes; Electrophysiology (science); Extracellular Matrix; Feasibility Studies; Funding; Human; Imaging Device; In Vitro; Laboratories; Measurement; Methods; Optics; Pharmaceutical Preparations; Phase; Phenotype; Reader; Reagent; Risk; Safety; Scientist; Sensitivity and Specificity; Services; Shipping; Small Business Innovation Research Grant; Source; Speed; Surrogate Markers; System; Technology; Testing; Torsades de Pointes; Toxic effect; Validation; Visualization; Work; base; cost effective; drug development; drug discovery; experimental study; high throughput screening; human stem cells; imaging system; improved; in vivo; induced pluripotent stem cell; instrument; matrigel; miniaturize; monolayer; multi-electrode arrays; new technology; novel; phase 1 study; phase 2 study; pre-clinical; preclinical toxicity; ranolazine; screening; stem cells; voltage

CARTOX SBIR Proposal Abstract CARTOX will use SBIR funds to develop a reliable, cost-effective high throughput electrophysiology screening assay system for assessing the impact of compounds on human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) function. The new technology will address the growing need for a human cardiac system assay to accurately and precisely determine the cardiac safety liability of any drug in development. Phase I studies established the feasibility of CARTOX’s proprietary 96 well plates that promote the maturation of hiPSC-CMs for high throughput screening assays to accurately determine proarrhythmia effects of compounds used for validation of the Comprehensive In Vitro ProArrhythmia Assay (CiPA). CARTOX’s assay relies on the use of voltage and calcium sensitive dyes and offer many advantages over currently utilized multi electrode array assays. Phase II studies will further miniaturize the assay to 1) utilize 384-well format plates, and 2) create a machine for automated electrophysiology assays using hiPSC-CM monolayers and voltage or calcium sensitive dyes, and 3) develop a novel human stem cell derived extracellular matrix for use in the MATURA96 assay. Expected products from this SBIR proposal include a) 384 and 96-well plates of functionally mature hiPSC-CM monolayers, b) an optical mapping system that includes a plate reader, high speed camera and multi-parameter quantification applications, and c) consumables including multi well plates containing novel human stem cell derived ECM and reagents, media.

CARTOX SBIR 提案摘要 CARTOX 将利用 SBIR 资金开发可靠、经济高效的高通量电生理学筛查 用于评估化合物对人诱导多能干细胞衍生的影响的测定系统 心肌细胞（hiPSC-CM）功能新技术将满足人类心脏日益增长的需求。 系统可以准确地分析和确定任何正在开发的药物的心脏安全责任。 I 期研究确立了 CARTOX 专有 96 孔板促进成熟的可行性 hiPSC-CM 用于高通量筛选分析，以准确确定促心律失常效应 用于验证综合体外促心律失常测定 (CiPA) 测定的化合物。 依赖于电压和钙敏感染料的使用，与目前使用的多重染料相比具有许多优点 II 期研究将进一步使测定小型化，以 1) 使用 384 孔板， 2) 使用 hiPSC-CM 单层和电压或电压创建自动电生理学检测机器 钙敏感染料，3) 开发一种新型人类干细胞衍生的细胞外基质，用于 该 SBIR 提案的预期产品包括 a) 384 和 96 孔板 功能成熟的 hiPSC-CM 单层，b) 光学绘图系统，包括读板器、高 测速相机和多参数定量应用，以及 c) 耗材，包括多孔板 含有新型人类干细胞衍生的ECM和试剂、培养基。

项目成果

Human perinatal stem cell derived extracellular matrix enables rapid maturation of hiPSC-CM structural and functional phenotypes.

• DOI: 10.1038/s41598-020-76052-y
• 发表时间: 2020-11-04
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Block T;Creech J;da Rocha AM;Marinkovic M;Ponce-Balbuena D;Jiménez-Vázquez EN;Griffey S;Herron TJ
• 通讯作者: Herron TJ

A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins.

• DOI: 10.1038/s41598-021-96217-7
• 发表时间: 2021-08-16
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Aguayo-Ortiz R;Creech J;Jiménez-Vázquez EN;Guerrero-Serna G;Wang N;da Rocha AM;Herron TJ;Espinoza-Fonseca LM
• 通讯作者: Espinoza-Fonseca LM

hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen.

• DOI: 10.1038/s41598-017-13590-y
• 发表时间: 2017-10-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: da Rocha AM;Campbell K;Mironov S;Jiang J;Mundada L;Guerrero-Serna G;Jalife J;Herron TJ
• 通讯作者: Herron TJ