Tissue chips for precision treatment of catecholaminergic polymorphic ventricular tachycardia

总结 罕见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。 有可能导致生死的选择患者特异性组织芯片方法有可能 在不使患者暴露于实验性治疗相关风险的情况下证明治疗疗效，或 此外，患者特异性组织芯片方法可以降低临床试验的风险。 通过优化患者选择，并通过阐明各种瓦里的基础机制，为未来的临床试验提供信息， 患者的治疗反应。实现这些长期目标需要证明患者- 特定的组织芯片平台准确地预测个体患者的治疗反应。在这里，我们亲- 提出了一个假设，即组织芯片预测治疗反应的儿茶酚胺能多态性 室性心动过速（CPVT），一种罕见的遗传性心律失常，并收集信息的设计关键 未来的治疗试验 CPVT是遗传性心律失常中恶性程度最高、治疗最困难的一种。的标志 CPVT是由运动和情绪应激引起的室性心律失常。尽管有标准治疗，在- 包括β受体阻滞剂、植入式心脏起搏器（ICD）或外科交感神经心脏去神经术， 估计8年致死或接近致死事件发生率约为15%，死亡发生率约为6%。在过去的十年里， 已证明卡尼是许多CPVT患者的有效治疗方法，无论是与β受体阻滞剂联合使用，还是作为 单一疗法。然而，有些患者对氟卡尼没有反应。无反应机制和 反应的预测因素尚未确定。我们最近报道，CaMKII抑制是一个承诺- CPVT的治疗策略，以及未来的CaMKII抑制治疗试验可能会在 CPVT。 在该提案的UG 3阶段，我们将招募已知对氟卡尼有临床反应的患者， 并从这些患者身上产生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衍生的心肌细胞（iPSC-CM）的心律失常风险。在UH 3阶段，我们将- 在一个培养皿中形成两个“临床试验”：首先，在一个培养皿中的“回顾性临床试验”中，我们将比较患者的 已知的氟卡尼响应于其iPSC-CM的响应。其次，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 钙调素激酶Ⅱ抑制和氟卡尼之间的关系。 这些研究将严格检验个性化疾病模型可以预测个体化疾病的假设。 患者的治疗反应，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.