Consortium Led Evaluation of Integrated Human-Relevant Approaches to Identify Drug Induced Cardiovascular Liabilities

联盟牵头对识别药物引起的心血管疾病的人类相关综合方法进行评估

• 批准号: 9905886
• 负责人: Jennifer B Pierson
• 金额: $ 50万
• 依托单位: HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905886
• 关键词: Consortium; Led; Evaluation; Integrated; Human

Title: Consortium Led Evaluation of Integrated Human-Relevant Approaches to Identify Drug Induced Cardiovascular Liabilities FOA Title and Number: Validating Human Stem Cell Cardiomyocyte Technology for Better Predictive Assessment of Drug-Induced Cardiac Toxicity (U01 Clinical Trial Not Allowed), RFA- FD-19-002 Proposed project start date: September 30, 2019 Proposed end date: September 30, 2022 Project Summary/Abstract: Cardiovascular drug-induced toxicity remains a major cause of drug attrition in both preclinical and clinical phases of drug development (Laverty et al., 2011). This is likely due to gaps in the traditional preclinical models used to assess cardiotoxicities. Additionally, many of the traditional methods are deployed in later stages of drug development causing costly late stage attrition. Advancements in both in vitro technology platforms and human stem cell-derived cardiomyocytes (hSC-CMs) offer an opportunity to improve the current preclinical testing paradigm by using mechanistically-relevant assays earlier in the drug development process. A paradigm shift like this will require appropriate confidence in the assay platforms, cells and underlying mechanisms associated with the cardiotoxicities, as well as gathering expertise to conduct evaluation and validation, a complex task. These efforts are best suited to a collaborative effort between multiple stakeholders including individual scientists and organizations. This proposal includes an effort to first define cellular mechanisms of cardiovascular toxicity, followed by a process to test and build confidence in the in vitro methods capable of predicting said toxicities. The objective of this proposed research aligns well with the FDA’s area of interest, “1. Modernize Toxicology to Enhance Product Safety.” Skilled scientific coordination and management is a requirement for the efficient design and execution of multi-site collaborative science. This is particularly essential for the studies proposed here that are intended to provide direct value to applied drug development and drug safety via engagement of public and private sector scientists. This multi-sector and multi- disciplinary expertise will allow the proposed program to effectively define core cardiovascular liabilities and build consensus on the utility of novel in vitro assays that provide insights into these liabilities. The organizational experience, in addition to a broad scientific membership, gives HESI the credibility needed to conduct unbiased science and give the drug development community confidence in these new assays. HESI is the right organization to tackle these challenges and address the cardiovascular safety issues from a novel and twenty-first century science perspective.

标题：由财团牵头的综合人类相关药物识别方法的评价 诱发的心血管责任 FOA标题和编号：验证人类干细胞心肌细胞技术是否更好 药物心脏毒性的预测性评估(不允许U01临床试验)，RFA- FD-19-002 项目开工日期：2019年9月30日 建议结束日期：2022年9月30日 项目摘要/摘要： 心血管药物引起的毒性仍然是临床前和临床前药物磨损的主要原因 以及药物开发的临床阶段(Laverty等人，2011年)。这可能是由于 传统的临床前模型用于评估心脏毒性。此外，许多传统的 方法被部署在药物开发的后期阶段，导致代价高昂的后期自然减员。 体外技术平台和人类干细胞来源的研究进展 心肌细胞(HSC-CMS)为改善目前的临床前检测提供了机会 在药物开发过程的早期使用与机械相关的分析方法。一个 像这样的范式转变需要对分析平台、细胞和 与心脏毒性相关的潜在机制，以及收集专业知识以 进行评估和验证，这是一项复杂的任务。 这些努力最适合于多个利益相关者之间的协作努力，包括 个别科学家和组织。这项提案包括首先定义蜂窝 心血管毒性的机制，随后是一个测试和建立信心的过程 能够预测所述毒性的体外方法。这项拟议研究的目的是 与FDA感兴趣的领域很好地结合在一起，“1.使毒理学现代化以增强产品 安全问题。“ 熟练的科学协调和管理是高效设计和管理的要求 执行多站点协作科学。这对于研究来说尤其重要。 旨在为应用药物开发和药物提供直接价值的建议 通过公共和私营部门科学家的参与确保安全。这是一个多部门、多领域的 学科专业知识将使拟议的计划能够有效地定义核心心血管 责任，并就新型体外检测的实用性达成共识，这些检测提供了对 这些债务。组织经验，除了广泛的科学成员外， 给予赫西所需的可信度，以进行公正的科学并给予药物开发 社区对这些新化验的信心。HESI是解决这些问题的合适组织 挑战和解决新世纪的心血管安全问题 科学视角。