Human Disease-Specific Induced Pluripotent Stem Cells For Preclinical Drug Testing and Drug Discovery

用于临床前药物测试和药物发现的人类疾病特异性诱导多能干细胞

• 批准号: 10384967
• 负责人: Lynne A Bui
• 金额: $ 172.84万
• 依托单位: KHLORIS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384967
• 关键词: Address; African American population; Area; Arrhythmia; Asian population; Biological Assay; Biological Sciences; Calcium; Calcium Channel; Cardiac; Cardiotoxicity; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Caucasians; Cell Line; Cell Nucleus; Cell Survival; Cells; Chemicals; Cisapride; Clarithromycin; Clinic; Clinical Trials; Collaborations; Collection; Communities; Data; Development; Dexrazoxane; Dilated Cardiomyopathy; Disease; Dose; Doxorubicin; Drug Exposure; Drug Industry; Drug Screening; Drug toxicity; Dyes; Ethnic Origin; Ethnic group; Exposure to; Failure; Familial Hypertrophic Cardiomyopathy; Female; Fiber; Gender; Genetic; Genetic Predisposition to Disease; Heart Abnormalities; Heart Diseases; Hispanic Populations; Hour; Hypertrophic Cardiomyopathy; Hypertrophy; Individual; Industrialization; Inherited; Institutes; Label; Laboratories; Libraries; Long QT Syndrome; Medical; Metabolic; Metoprolol; Mexiletine; Morbidity - disease rate; Muscle Cells; Nifedipine; Pathologic; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Population; Population Heterogeneity; Predisposition; Process; Protocols documentation; Research Project Grants; Rights; Risk; Risk Factors; Safety; Services; Small Business Innovation Research Grant; Sotalol; Stress; Structural defect; Tamoxifen; Technology; Testing; Time; Toxicity Tests; Translating; Universities; Verapamil; Withdrawal; Woman; Work; base; cardioprotection; chronotropic; cohort; cost; dofetilide; drug candidate; drug development; drug discovery; drug market; drug testing; electric impedance; ethnic diversity; gender diversity; high risk; human disease; in vitro Model; induced pluripotent stem cell; innovation; male; member; men; mortality; novel therapeutics; patient population; pre-clinical; predictive modeling; protective effect; racial diversity; ranolazine; resazurin; response; screening; sex; tool

ABSTRACT Drug-induced adverse cardiac effects are a leading cause of drug attrition during pharmaceutical development. In recent years, the withdrawal of several cardiac and non-cardiac drugs from the market due to unpredicted cardiotoxicity has imposed a multibillion-dollar burden on the pharmaceutical industry. As a result, FDA now mandates that all new drugs be tested for cardiotoxicity before entering clinical trials. However, there is still a lack of appropriate safety screening platforms that can accurately predict the proarrhythmic liability of new chemical entities; in particular there are no validated commercial platforms that address the diverse patient population with regard to sex, ethnicity or genetic susceptibility to drug-induced cardiotoxicity. The company is developing a select subset of fifty cell lines from healthy subjects as well as from patients with common hereditary cardiac disorders such as familial hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and long QT syndrome (LQTS), to predict individual and group differences in drug susceptibility to cardiotoxicity. As female sex is an independent risk factor for drug-induced cardiac arrhythmias and women comprise more than 50% of the population, a major focus of this research project will be to quantify the extent gender factors in drug-induced proarrhythmia. Each cell line will be validated functional and pharmacologically. This panel of cell lines will be unique in terms of its breadth and detailed (anonymized) patient and genetic data for each line. While some competing companies cell one or two lines, they do not perform services and do not include the detailed patient and genetic data available to Khloris. Khloris Biosciences is a start-up company based in the Bay Area. Khloris was co-founded by Dr. Joseph Wu (Stanford University) and has worldwide exclusive rights to the world’s largest collection of patient-derived iPSC-CMs developed in his laboratory as well as the anonymized genetic and pathological characterization of each line. The purpose of the current SBIR application is to greatly expand the current offering of Khloris to include a large and diverse collection of validated cell lines comprising male AND female derived disease-specific iPSC- CMs from patients with common hereditary cardiac disorders and genetic backgrounds. We aim to develop and validate this tool as a surrogate in vitro model for prediction of cardiac drug toxicity in patient groups at high risk for drug-induced arrhythmia. Khloris believes this platform will revolutionize drug discovery and development by reassigning the thresholds for cardiotoxicity, thereby reducing the possibility of mistakenly eliminating promising candidates, expediting the advancement of worthy drugs to clinic and discovering new cardiovascular drugs.

摘要 药物引起的不良心脏作用是药物治疗期间药物消耗的主要原因。 发展近年来，几种心脏和非心脏药物从市场上撤出， 不可预测的心脏毒性给制药业带来了数十亿美元的负担。因此，在本发明中， FDA现在要求所有新药在进入临床试验之前进行心脏毒性测试。但 仍然缺乏适当的安全筛查平台，可以准确预测 新的化学实体;特别是没有经过验证的商业平台， 患者人群的性别、种族或对药物诱导的心脏毒性的遗传易感性。 该公司正在从健康受试者和患者中开发一个50种细胞系的精选子集 常见的遗传性心脏病，如家族性肥厚型心肌病（HCM），扩张型心肌病， 心肌病（DCM）和长QT综合征（LQTS），以预测药物治疗的个体和组间差异。 对心脏毒性的敏感性。由于女性是药物性心律失常的独立危险因素 妇女占人口的50%以上，这项研究项目的一个主要重点将是量化 性别因素在药物诱发心律失常中的作用程度。将对每种细胞系进行功能验证， - 是的这组细胞系在广度和详细程度（匿名）方面都是独一无二的 每一行的患者和基因数据。虽然一些竞争公司的细胞一个或两个线，他们不 这些信息不包括Khloris可获得的详细患者和基因数据。 Khloris Biosciences是一家位于湾区的初创公司。Khloris由Joseph博士共同创立 吴（斯坦福大学），并拥有全球独家权利，世界上最大的收集患者源性 在他的实验室中开发的iPSC-CM，以及 每一行。 目前SBIR申请的目的是大大扩展Khloris目前的产品， - 包含雄性和雌性来源的疾病特异性iPSC的大量且多样化的经验证的细胞系集合， 来自具有常见遗传性心脏病和遗传背景的患者的CM。我们致力于发展和 验证该工具作为预测高风险患者组心脏药物毒性的替代体外模型 药物引起的心律失常Khloris认为，这个平台将通过以下方式彻底改变药物发现和开发： 重新分配心脏毒性的阈值，从而减少错误地排除有希望的 候选人，加快有价值的药物的临床进展和发现新的心血管药物。