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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：
10038088
负责人：
KEVIN KIT PARKER
金额：
$ 87.57万
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：
2020-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038088
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 Effectiveness 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 Placebos 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 effective therapy genome editing improved individual patient individualized medicine induced pluripotent stem cell inhibitor/antagonist 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

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.

总结