Microphysiology Systems Database Supplement to Tissue Chips for Precision Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia-Supplement

摘要 罕见疾病的治疗试验具有挑战性，特别是涉及儿童和治疗性疾病的试验。 具有潜在生死后果的选择。针对患者的组织芯片方法具有潜在的 证明治疗效果，而不使患者面临与实验治疗或 随机化到控制臂。此外，针对患者的组织芯片方法可能会降低临床试验的风险。 通过阐明各种变化的机制，优化患者选择并通知未来的临床试验。 在患者的治疗反应中的作用。实现这些长期目标需要证明患者- 特定的组织芯片平台可以准确预测个体患者的治疗反应。在这里我们支持- 摆姿势检验组织芯片预测儿茶酚胺能多形性疾病治疗反应的假设 室性心动过速(CPVT)，一种罕见的遗传性心律失常，并收集对设计至关重要的信息 未来的治疗试验。 CPVT是遗传性心律失常中恶性程度最高、治疗难度最大的疾病之一。的一个标志 CPVT是由运动和情绪应激引起的室性心律失常。尽管接受标准护理治疗，但在- 包括β阻滞剂、植入型心脏除颤器(ICD)或外科交感神经去神经术， 估计8年致命性或接近致命性事件的发生率约为15%，死亡发生率约为6%。在过去的十年里，FLE- 卡奈德已被证明是许多慢性静脉曲张患者的有效治疗方法，无论是联合β阻滞剂还是AS。 单一疗法。然而，一些患者对氟卡胺没有反应。无反应和无反应机制 反应的预测因素尚未确定。我们最近报道，CaMKII抑制是一种促进剂- CPVT的ING治疗策略，未来CaMKII抑制的治疗试验可能在#年进行 CPVT。 在这项提案的UG3阶段，我们将招募对氟卡胺有临床反应的患者， 并从这些患者身上培养出IPSCs。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来源的心肌细胞(IPSC-CMS)的心律失常风险。在超高浓缩铀阶段，我们将- 在一个盘子里形成两个“临床试验”：首先，在一个盘子里的“回溯性临床试验”中，我们将比较病人的 已知的氟卡胺对其IPSC-CMS的反应。第二，我们将评估 CPVT抑制有效的基因类型，并决定是否存在有利或不利的相互作用 CaMKII抑制和氟卡胺之间的关系。 总之，这些研究将严格检验个性化疾病模型可以预测指数的假设。 患者的直观治疗反应，并可用于帮助计划未来的临床试验。

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.