Tissue chips for precision treatment of catecholaminergic polymorphic ventricular tachycardia

组织芯片精准治疗儿茶酚胺能多形性室性心动过速

• 批准号: 10515796
• 负责人: KEVIN KIT PARKER
• 金额: $ 85.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515796
• 关键词: Accounting; Arrhythmia; Bioreactors; Boston; Calmodulin; Cardiac; Cardiac Myocytes; Case Series; Catecholaminergic Polymorphic Ventricular Tachycardia; Cells; Cessation of life; Child; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials Design; Cryopreservation; Data; Defibrillators; Denervation; Disease model; Emotional Stress; Event; Exercise; Exhibits; Flecainide; Future; Genes; Genetic; Genotype; Goals; Human; In Vitro; Individual; Inherited; Investigational Therapies; Life; Malignant - descriptor; Modeling; Modification; Monitor; Mutation; Operative Surgical Procedures; Patient Recruitments; Patient Selection; Patients; Pediatric Hospitals; Phase; Phosphotransferases; Placebo Control; Precision therapeutics; Prediction of Response to Therapy; Prevalence; Protocols documentation; Randomized; Rare Diseases; Regimen; Reporting; Risk; Ryanodine Receptor Calcium Release Channel; Testing; Therapeutic; Therapeutic Trials; Time; Tissue Engineering; Tissue Microarray; Tissue Model; Treatment Efficacy; Variant; Ventricular; Ventricular Arrhythmia; arm; base; clinical risk; clinically relevant; design; differentiation protocol; effective therapy; effectiveness study; genome editing; improved; individual patient; individualized medicine; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; inhibitor; microphysiology system; out-of-hospital cardiac arrest; partial response; patient response; precision medicine; predicting response; prospective; randomized trial; recruit; response; standard of care; therapeutic development; therapeutic target; treatment response; trial design

SUMMARY Therapeutic trials in rare diseases are challenging, particularly those that involve children and therapeutic choices with potentially life or death consequences. Patient-specific tissue-chip approaches have the potential to demonstrate therapeutic efficacy without exposing patients to risks associated with experimental therapy or randomization to the control arm. Moreover, patient-specific tissue-chip approaches may de-risk clinical trials by optimizing patient selection and inform future clinical trials by elucidating mechanisms that underlie the vari- ation in patients' therapeutic responses. Achieving these long range goals requires demonstration that patient- specific tissue-chip platforms accurately predict the therapeutic responses of individual patients. Here we pro- pose to test the hypothesis that tissue-chips predict therapeutic responses in catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia and to gather information critical for the design of future therapeutic trials. CPVT is among the most malignant and difficult to treat of the inherited cardiac arrhythmias. A hallmark of CPVT is ventricular arrhythmia induced by exercise and emotional stress. Despite standard-of-care therapy, in- cluding β-blockers, implantable cardiac defibrillators (ICDs), or surgical sympathetic cardiac denervation, the estimated 8 year fatal or near-fatal event rate is ~15%, with death occurring in ~6%. Over the past decade, fle- cainide has proven to be effective therapy for many CPVT patients, either in combination with β-blocker or as monotherapy. However, some patients do not respond to flecainide. Mechanisms of non-responsiveness and predictors of response have not been identified. We have recently reported that CaMKII inhibition is a promis- ing therapeutic strategy for CPVT, and future therapeutic trials of CaMKII inhibition will likely be performed in CPVT. In the UG3 phase of this proposal, we will recruit patients whose clinical response to flecainide is known, and generate iPSCs from these patients. At the same time, we will optimize tissue chip platforms to assess ar- rhythmia risk using patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). In the UH3 phase, we will per- form two "clinical trials" in a dish: First, in a "retrospective clinical trial" in a dish, we will compare patients' known flecainide responses to the responses of their iPSC-CMs. Second, we will assess the spectrum of genotypes where CPVT inhibition is effective, and determine if there are favorable or unfavorable interactions between CaMKII inhibition and flecainide. Together these studies will rigorously test the hypothesis that personalized disease models can predict indi- vidual patient therapeutic responses and can be used to help plan future clinical trials.

概括 稀有疾病的治疗试验受到挑战，尤其是涉及儿童和治疗的治疗试验 具有潜在生死后果的选择。患者特定的组织芯片方法具有潜力 在不暴露患者实验疗法或 随机将控制臂化。此外，患者特异性组织芯片方法可能会脱离临床试验 通过优化患者的选择并通过阐明构成不同的机制来为未来的临床试验提供信息 患者治疗反应的ation。实现这些远距离目标需要证明患者 - 特定的组织芯片平台可以准确预测个别患者的治疗反应。在这里我们亲 姿势测试组织芯片预测儿茶酚胺能多态性治疗反应的假设 心室心动过速（CPVT），这是一种罕见的遗传心律不齐，并收集对设计至关重要的信息 未来的治疗试验。 CPVT是遗传性心律不齐的最恶性和难以治疗的人之一。一个标志 CPVT是运动和情绪压力引起的心室心律失常。尽管是护理标准的疗法，但 甲壳β-甲甲基β-植入式心脏除颤器（ICD）或手术交感神经去座， 估计致命的8年或近乎致命的事件率为约15％，死亡发生约为6％。在过去的十年中，飞翔 事实证明，Cainide对许多CPVT患者是有效的治疗 单一疗法。但是，有些患者对氟卡尼没有反应。无反应和 尚未确定响应的预测指标。我们最近报告说，CAMKII抑制是一种承诺 - CPVT治疗策略以及CAMKII抑制的未来治疗试验可能会在 CPVT。 在该提案的UG3阶段，我们将招募对氟卡尼的临床反应的患者 并从这些患者中产生IPSC。同时，我们将优化组织芯片平台以评估AR- 使用患者特异性IPSC衍生的心肌细胞（IPSC-CMS）的节律风险。在UH3阶段，我们将 菜肴中的两个“临床试验”：首先，在菜肴中的“回顾性临床试验”中，我们将比较患者' 已知的氟卡尼对其IPSC-CM的反应的反应。第二，我们将评估 CPVT抑制有效的基因型，并确定是否存在有利或不利的相互作用 在CAMKII抑制和氟卡因之间。 这些研究将共同​​严格检验以下假设，即个性化疾病模型可以预测 视觉患者的治疗反应，可用于帮助计划未来的临床试验。