Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Plurip

使用人类 Plurip 代谢组学鉴定心脏毒性生物标志物

• 批准号: 8253185
• 负责人: ROBERT E BURRIER
• 金额: $ 14.67万
• 依托单位: STEMINA BIOMARKER DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253185
• 关键词: Adverse drug effect; Adverse effects; Biological Assay; Biological Markers; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cause of Death; Cell Density; Cells; Centers for Disease Control and Prevention (U.S.); Data; Detection; Development; Dose; Drug Industry; Embryo; FDA approved; Future; Generations; Goals; Healthcare; Hip region structure; Human; In Vitro; International; Machine Learning; Marketing; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methods; Modeling; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pluripotent Stem Cells; Public Health; Reporting; Risk; Safety; Screening procedure; Services; Statistical Methods; Stem cells; System; Techniques; Technology; Testing; Toxic effect; Toxicology; Training; United States; Withdrawal; base; blind; cell type; cost; density; detector; drug candidate; drug development; drug market; human embryonic stem cell; improved; in vitro Assay; in vivo; induced pluripotent stem cell; innovation; liquid chromatography mass spectrometry; metabolomics; novel strategies; pre-clinical; prevent; response; small molecule; stem; therapeutic development; tool; validation studies

DESCRIPTION (provided by applicant): Cardiotoxicity, as a result of adverse drug effects, is a serious problem that has yet to be effectively screened prior to patient exposure. Cardiac safety is one of the leading causes of compound attrition in the pharmaceutical industry and withdrawal of FDA-approved drugs from the market. The purpose of this proposal is to alleviate the financial burden of compound attrition due to cardiotoxicity, but more importantly, to improve public health through the development of an in vitro assay to predict a drug's ability to induce cardiotoxicity. Stemina Biomarker Discovery ("Stemina") proposes to do so through the use of metabolomics on treated cardiomyocytes derived from human embryonic stem (hES) and human induced pluripotent stem (hiPS) cells. These technologies will be used to discover human endogenous small molecule biomarkers which predict cardiotoxicity, with an emphasis on cardiomyopathy. The use of metabolomics to measure small molecules secreted by human cardiomyocytes in response to drugs is a novel approach and may pave the way for a new generation of more accurate predictive toxicology screens. Stemina has already used such a paradigm to develop predictive methods to assess development toxicology in stem cells. Stemina's long-term goal is to fully develop this humanized, high throughput cardiotoxicity screen so that it would be a valuable tool to pharmaceutical and biotech companies during preclinical development of therapeutics. In order to achieve this long term goal, Stemina is first proposing to establish an experimental platform for each cardiomyocyte culture system (Aim 1). In Aim 2, we will use these systems to develop a dose response curve for each of the 24 compounds (16 cardiotoxic and 10 non-cardiotoxic) as a training set to establish a predictive metabolomic model. These dose response curves will be used to determine 3 concentrations for drug treatment to be utilized in Aim 3. Stemina will then establish a specific metabolic signature of candidate human biomarkers of drug-induced cardiotoxicity (Aim 3). To do so, human pluripotent stem (hPS) cell-derived cardiomyocytes will be treated with well-established known inducers and non-inducers of cardiotoxiciy. The spent medium from treated cells will be analyzed with mass spectrometry in order to study the secreted metabolites, or secretome, of these cells. Small molecules whose abundances vary dependent upon whether cells were treated with an inducer or non-inducer of cardiotoxicity will serve as candidate biomarkers of cardiotoxicity. In future studies, these candidate biomarkers will be validated through the use of specialized mass spectrometry techniques. Lastly, the ability of these biomarkers to adequately predict cardiotoxicity will be tested through the use of a blind study. Completion of these aims will encourage further discussions with partnering companies in order to develop a kit that can detect the validated biomarkers of cardiotoxicity. Stemina will then utilize this kit to market a service to predict whether or not a compound will induce cardiotoxicity that will serve pharmaceutical companies in pre-clinical screening trials. Such a service will provide the first humanized screening assay for cardiotoxicity based on cardiomyocyte metabolism and will likely improve public health. PUBLIC HEALTH RELEVANCE: Adverse effects of drugs to patients are the fourth leading cause of death in the United States; one such an adverse effect is drug-induced cardiotoxicity, illustrating a need for a better predictive assay for cardiotoxicity. Stemina Biomarker Discovery proposes to develop biomarkers of cardiotoxicity that would drive a service model to predict the cardiotoxicity-potential of drug candidates in order to prevent cardiotoxicity in patients. Such a product will greatly improve public health.

描述(由申请人提供)：由于药物不良反应导致的心脏毒性是一个严重的问题，在患者接触之前尚未进行有效的筛查。心脏安全是制药业化合物损耗和FDA批准的药物退出市场的主要原因之一。这项建议的目的是减轻由于心脏毒性造成的化合物磨损的经济负担，但更重要的是，通过开发一种体外试验来预测药物诱导心脏毒性的能力来改善公众健康。Stemina Biomarker Discovery(“Stemina”)建议通过对来自人类胚胎干细胞(HES)和人类诱导多能干细胞(HIPS)的心肌细胞进行代谢组学处理来实现这一点。这些技术将被用于发现预测心脏毒性的人类内源性小分子生物标记物，重点是心肌病。利用代谢组学来测量人类心肌细胞对药物的反应所分泌的小分子是一种新的方法，可能为新一代更准确的预测毒理学筛查铺平道路。Stemina已经使用这样的范例来开发预测方法来评估干细胞的发育毒理学。Stemina的长期目标是全面开发这种人性化、高通量的心脏毒性筛查，使其在治疗药物的临床前开发期间成为制药和生物技术公司的宝贵工具。为了实现这一长期目标，Stemina首先提出为每个心肌细胞培养系统建立一个实验平台(目标1)。在目标2中，我们将使用这些系统来开发24种化合物(16种心脏毒性和10种非心脏毒性)中每一种的剂量反应曲线作为训练集，以建立预测代谢组模型。这些剂量反应曲线将被用来确定用于AIM 3的药物治疗的3个浓度。然后，Stemina将建立药物引起的心脏毒性的候选人类生物标记物的特定代谢特征(AIM 3)。为此，人类多能干细胞(HPS)来源的心肌细胞将被公认的心脏毒性诱导剂和非诱导剂治疗。处理过的细胞的废液将用质谱仪进行分析，以研究这些细胞的分泌代谢物或分泌组。小分子的丰度变化取决于细胞是用心脏毒性诱导剂还是非诱导剂处理，它们将作为心脏毒性的候选生物标记物。在未来的研究中，这些候选生物标志物将通过使用专门的质谱学技术进行验证。最后，这些生物标志物充分预测心脏毒性的能力将通过盲法研究进行测试。完成这些目标将鼓励与合作公司进行进一步讨论，以开发一种可以检测心脏毒性的有效生物标记物的试剂盒。然后，Stemina将利用这一试剂盒来营销一项服务，以预测一种化合物是否会引起心脏毒性，这将为制药公司在临床前筛查试验中提供服务。这项服务将提供第一个基于心肌细胞新陈代谢的心脏毒性人性化筛查试验，并可能改善公众健康。 公共卫生相关性：在美国，药物对患者的不良反应是第四大致死原因；其中一种不良反应是药物引起的心脏毒性，这说明需要一种更好的心脏毒性预测方法。Stemina Biomarker Discovery建议开发心脏毒性的生物标记物，该生物标记物将驱动一种服务模型来预测候选药物的心脏毒性潜力，以预防患者的心脏毒性。这样的产品将极大地改善公众健康。