A new paradigm for identifying patients and drugs at risk for QT prolongation

识别有 QT 延长风险的患者和药物的新范例

基本信息

批准号：
9100797
负责人：
DAN M RODEN
金额：
$ 61.45万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9100797
关键词：
1-Phosphatidylinositol 3-Kinase Action Potentials Address Adopted Antibiotics Area Behavior Benefits and Risks Calcium Cardiac Cardiac Myocytes Case Series Cells Clinical Clinical Medicine Clinical Research Collection Computerized Medical Record Data Drug effect disorder Employee Strikes Equilibrium Exposure to Genes Genetic Variation Genomics Guidelines Hour In Vitro Individual International Ion Channel Ions Laboratories Lead Long QT Syndrome Malignant Neoplasms Medical center Methods Modeling Molecular Moxifloxacin Mutation Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphotransferases Plague Positioning Attribute Process Reaction Recording of previous events Resources Risk Role Scanning Scientist Site Sotalol Therapeutic Torsades de Pointes Variant Ventricular Tachycardia Withdrawal Work cohort design dofetilide drug candidate drug development exome sequencing high risk human subject improved individual patient induced pluripotent stem cell kinase inhibitor novel therapeutics patient population phenome research study response transcriptomics

项目摘要

A new paradigm for identifying patients and drugs at risk for QT prolongation The drug-induced long QT syndrome (diLQTS) continues to be a problem for clinicians balancing risk and benefits across multiple therapeutic areas, and for pharmaceutical scientists and regulators evaluating new drug candidates. The prevalent view is that block of a specific ion current, the rapid component of the cardiac delayed rectifier (IKr), encoded by KCNH2 (also known as HERG), is the common mechanism predisposing to diLQTS across drug classes and that patients with mutations in ion channel genes are at especially increased risk. We present here a body of clinical, genomic, and cellular studies that call these assumptions into question. For example, one important and unexplained clinical feature of diLQTS is that not all IKr blocking drugs confer the same risk; the risk with antiarrhythmics such as sotalol or dofetilide can be 1- 3%, while the risk with IKr-blocking antibiotics such as moxifloxacin is much lower, <1/20,000. Moreover, some drugs, notably phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors developed for cancer, prolong QT interval but do not block IKr. We and others have recently shown that prolonged (hours) exposure of cardiomyocytes to high risk drugs such as dofetilide generates striking prolongation of action potentials (the in vitro correlate of the QT interval) and arrhythmogenic afterdepolarizations. Importantly, this effect is IKr- independent, does not occur with low risk drugs, and is rapidly and completely reversed by intracellular perfusion with PIP3, implicating inhibition of PI3K as a critical and heretofore unrecognized mechanism contributing to diLQTS risk across drugs. Further, analyses of large international cohorts (whose collection we have led) show that variants in ion channel genes contribute only modestly to risk. Thus a fundamental issue that this Project will address is the extent to which diLQTS risk is predictable in an individual patient. In Specific Aim 1, we will generate cardiomyocytes from induced pluripotent stem cells obtained from patients with a history of diLQTS and from a large cohort of drug-tolerant controls we have ascertained. We will then compare genomic, electrophysiologic, and transcriptomic profiles at baseline (Specific Aim 2) and after drug challenge (Specific Aim 3; PI3K inhibitors; IKr blockers) in cardiomyocytes from subjects with diLQTS and from drug-tolerant controls. The results of these experiments will not only inform the drug development process but will also lead to new methods to screen individual subjects for diLQTS risk.

识别有 QT 延长风险的患者和药物的新范例药物引起的长 QT 综合征 (diLQTS) 仍然是临床医生平衡风险的一个问题和跨多个治疗领域的益处，以及药物科学家和监管机构的评估新候选药物。普遍的观点是阻止特定离子流，即离子流的快速分量。心脏延迟整流 (IKr)，由 KCNH2（也称为 HERG）编码，是常见机制跨药物类别易出现 diLQTS，并且离子通道基因突变的患者处于特别是增加了风险。我们在此介绍一系列临床、基因组和细胞研究，将这些研究称为假设受到质疑。例如，diLQTS 的一个重要且无法解释的临床特征是：所有 IKr 阻断药物都会带来相同的风险；服用索他洛尔或多非利特等抗心律失常药物的风险可能是 1- 3%，而莫西沙星等 IKr 阻断抗生素的风险要低得多，<1/20,000。此外，一些药物，特别是针对癌症开发的磷脂酰肌醇-4,5-二磷酸 3-激酶 (PI3K) 抑制剂，可延长 QT间期但不阻断IKr。我们和其他人最近表明，长时间（数小时）暴露于心肌细胞对多非利特等高风险药物的作用会导致动作电位显着延长（ QT 间期的体外相关性）和致心律失常后除极。重要的是，这种效应是 IKr- 独立，不会与低风险药物一起发生，并且可以通过细胞内注射快速完全逆转用 PIP3 灌注，表明抑制 PI3K 是一种关键且迄今为止未被认识的机制跨药物导致 diLQTS 风险。此外，对大型国际队列的分析（我们收集了其集合）研究表明，离子通道基因的变异对风险的影响很小。因此一个根本问题该项目将解决的是个体患者 diLQTS 风险的可预测程度。在具体目标1，我们将从患者身上获得的诱导多能干细胞产生心肌细胞具有 diLQTS 病史并从我们已经确定的大量耐药对照中确定。我们随后将比较基线（具体目标 2）和用药后的基因组、电生理学和转录组图谱挑战（具体目标 3；PI3K 抑制剂；IKr 阻滞剂）来自 diLQTS 受试者和来自耐药对照。这些实验的结果不仅将为药物开发过程提供信息，而且还将带来新的方法来筛查个体受试者的 diLQTS 风险。