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

基本信息

批准号：
10701063
负责人：
KEVIN KIT PARKER
金额：
$ 83.34万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10701063
关键词：
Accounting Adrenergic beta-Antagonists 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 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 cardiac implant clinical risk clinical trial in a dish clinical trial on a chip clinically relevant design differentiation protocol dominant genetic mutation effective therapy effectiveness study efficacy evaluation genome editing improved individual patient individualized medicine induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes information gathering inhibitor microphysiology system out-of-hospital cardiac arrest partial response patient response precision medicine predicting response programs prospective randomized placebo controlled trial recruit response standard of care synergism therapeutic development therapeutic target treatment response trial design

项目摘要

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.

概括罕见疾病的治疗试验具有挑战性，特别是那些涉及儿童和治疗的试验选择具有潜在生命或死亡后果的患者特异性组织芯片方法具有潜在的可能性。证明治疗效果而不使患者面临与实验治疗相关的风险或此外，针对患者的组织芯片方法可能会降低临床试验的风险。通过阐明各种潜在机制，优化患者选择并为未来的临床试验提供信息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。检验组织芯片预测儿茶酚胺能多态性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，并收集对于设计的关键信息未来的治疗试验。 CPVT 是遗传性心律失常中最恶性且最难治疗的一种。 CPVT 是由运动和情绪压力引起的室性心律失常，尽管进行了标准护理治疗，但仍然存在。包括β受体阻滞剂、植入式心脏除颤器（ICD）或手术心脏去交感神经术估计 8 年致命或接近致命事件发生率约为 15%，在过去十年中，死亡发生率约为 6%。卡尼德已被证明对于许多 CPVT 患者来说是有效的治疗方法，无论是与 β 受体阻滞剂联合使用还是单独使用然而，一些患者对氟卡尼没有反应。我们最近报道称 CaMKII 抑制是一种有前途的预测因子。 CPVT 的治疗策略，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临床反应已知的患者，并从这些患者身上生成 iPSC 同时，我们将优化组织芯片平台来评估 ar-。在 UH3 阶段，我们将使用患者特异性 iPSC 衍生心肌细胞 (iPSC-CM) 来降低心律失常风险。在一个培养皿中形成两个“临床试验”：首先，在一个培养皿中进行“回顾性临床试验”，我们会比较患者的其次，我们将评估氟卡尼对其 iPSC-CM 反应的谱。 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 CaMKII 抑制和氟卡尼之间的关系。这些研究将共同严格检验个性化疾病模型可以预测个体的假设。可视化患者的治疗反应，可用于帮助规划未来的临床试验。