Novel molecular therapies for CPVT

CPVT 的新型分子疗法

基本信息

批准号：
10450029
负责人：
Vassilios James Bezzerides
金额：
$ 17.02万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-12 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450029
关键词：
Adrenergic Agents Advisory Committees Affect Alanine Arrhythmia Biomedical Engineering Boston Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cardiac Cardiac Myocytes Cardiac conduction system Cardiac development Cardiovascular system Catecholaminergic Polymorphic Ventricular Tachycardia Cells Child Clinical Communities Data Defect Defibrillators Dependovirus Development Disease Disease model Electrophysiology (science)Event Exercise Family Flecainide Foundations Gene Mutation Generations Genes Genome engineering Genotype Heart Heart Arrest Hereditary Disease Human Engineering Inherited International Investigation Lead Life Malignant - descriptor Mediating Mentors Mentorship Modeling Molecular Mus Mutation Myocardial Outcome Pathogenesis Pathogenicity Patients Pediatric Hospitals Pediatric cardiology Peptides Pharmacology Phenotype Phosphorylation Program Development Publishing Recurrence Reporting Research Research Personnel Research Technics Role Ryanodine Ryanodine Receptor Calcium Release Channel Serine Signal Pathway Sodium Sodium Channel Sodium Channel Blockers Stress Structure Syncope System Testing Therapeutic Time Tissue Engineering Tissue Model Tissues Toxic effect Training Training Programs Translational Research Translations Treatment Failure Ventricular Arrhythmia calmodulin-dependent protein kinase II career development chromatin immunoprecipitation clinical application clinical phenotype clinical translation clinically relevant effectiveness testing experience experimental study first-in-human gene therapy genome editing heart rhythm human tissue improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor insight medical schools mouse model novel novel therapeutic intervention novel therapeutics patch clamp prevent professor programs receptor sudden cardiac death targeted delivery therapy development treatment optimization young adult

项目摘要

This proposal describes a five-year training and career development program that will prepare its principle investigator, Dr. Vassilios Bezzerides, to be an independent investigator in the field of channelopathies and inherited arrhythmia disorders. This program will build on Dr. Bezzerides’ existing background in cellular and clinical electrophysiology by providing additional expertise in induced pluripotent stem cells (iPSCs), genome editing, and translational research techniques. The principal mentor for this program will be Dr. William Pu, Professor of Pediatrics and Cardiology at Boston Children’s Hospital and Harvard Medical School. Dr. Pu is an internationally recognized expert in cardiac development and iPSC disease modeling. The enclosed proposal outlines a comprehensive training program with structured mentorship including an advisory committee with expertise in cardiovascular research and bioengineering, formal coursework, and a research plan that will provide rigorous training in disease modeling and novel therapy development. This proposal is focused on the investigation of novel therapeutic strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly malignant inherited arrhythmia disorder characterized by life-threatening ventricular arrhythmias during times of stress or exercise. Current CPVT therapy is inadequate, with both therapy related toxicity and frequent treatment failures. Most CPVT cases are caused by mutations in ryanodine receptor type 2 (RYR2), which encodes the major cardiomyocyte intracellular Ca+2 release channel. Using iPSC-CMs, we developed a novel engineered human myocardial model (“opto-chip”) of CPVT that reproduces key features of this arrhythmia at a tissue level. Our preliminary data demonstrates that inhibition of Ca2+/calmodulin kinase II (CaMKII) blocks the pro-arrhythmic phenotype of CPVT iPSC-CMs. In Aim 1, using pharmacology, genome editing, and engineered tissues, Dr. Bezzerides will determine if CaMKII inhibition is a broadly applicable by evaluating pathogenic CPVT genotypes from each of the four canonical pathogenic regions within the RYR2 gene and determine the degree of inhibition necessary for arrhythmia suppression. In Aim 2, Dr. Bezzerides will further develop CaMKII inhibition as a clinically applicable therapeutic strategy for CPVT. To refine this strategy Dr. Bezzerides will test the effectiveness of target CaMKII in the cells of the cardiac conduction system using clinically relevant outcomes. A positive result would serve as the basis for further study as a step towards a first-in-human trial. In Aim 3, Dr. Bezzerides will use genome editing, patch clamp, and a second generation opto-chip assay to dissect the role of late sodium current blockade in the treatment of CPVT. Although controversial, late sodium current blockade may be the mechanistic basis for flecainide’s efficacy in CPVT. Better understanding of the mechanism may lead to new therapeutic options with greater efficacy and lower toxicity. Together, these studies will advance the understanding of arrhythmogenesis in CPVT, open new avenues for novel therapies, and provide a foundation for an independent research program led by Dr. Bezzerides.

该提案描述了一个为期五年的培训和职业发展计划，该计划将制定其原则研究员 Vassilios Bezzerides 博士将成为通道病领域的独立研究员该项目将以 Bezzerides 博士在细胞和遗传性心律失常方面的现有背景为基础。通过提供诱导多能干细胞 (iPSC)、基因组方面的额外专业知识来进行临床电生理学该项目的主要导师是 William Pu 博士，濮博士是波士顿儿童医院和哈佛医学院的儿科和心脏病学教授。所附提案是国际公认的心脏发育和 iPSC 疾病建模专家。概述了一个全面的培训计划和结构化的指导，包括一个咨询委员会心血管研究和生物工程方面的专业知识、正式课程以及研究计划在疾病建模和新疗法开发方面提供严格的培训。儿茶酚胺能多形性室性心动过速（CPVT）新治疗策略的研究，一种高度恶性的遗传性心律失常疾病，其特征是在发病期间出现危及生命的室性心律失常。目前的 CPVT 治疗不足，存在与治疗相关的毒性且频繁。大多数 CPVT 病例是由 2 型兰尼定受体 (RYR2) 突变引起的。使用 iPSC-CM 编码主要的心肌细胞胞内 Ca+2 释放通道。 CPVT 的工程人体心肌模型（“光芯片”）可在一定时间内再现这种心律失常的关键特征我们的初步数据表明，抑制 Ca2+/钙调蛋白激酶 II (CaMKII) 可阻断 CPVT iPSC-CM 的促心律失常表型在目标 1 中，利用药理学、基因组编辑和工程设计。 Bezzerides 博士将通过评估致病性来确定 CaMKII 抑制是否广泛适用 RYR2 基因内四个典型致病区域中每一个的 CPVT 基因型，并确定在目标 2 中，Bezzerides 博士将进一步开发 CaMKII。为了完善这一策略，Bezzerides 博士将测试抑制作为 CPVT 的临床适用治疗策略。使用临床相关的靶标 CaMKII 在心脏传导系统细胞中的有效性积极的结果将作为进一步研究的基础，作为迈向首次人体试验的一步。目标 3，Bezzerides 博士将使用基因组编辑、膜片钳和第二代光芯片检测来剖析晚期钠电流阻断在 CPVT 治疗中的作用，尽管存在争议，但晚期钠电流阻断的作用。目前的封锁可能是氟卡尼在 CPVT 中疗效的机制基础。这些机制可能会带来更有效、更低毒性的新治疗选择。研究将增进对 CPVT 心律失常发生的理解，为新疗法开辟新途径，并为 Bezzerides 博士领导的独立研究项目提供基础。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia.

儿茶酚胺能多形性室性心动过速的基因治疗。

DOI：
10.1016/j.hlc.2023.01.018
发表时间：
2023-04-01
期刊：
Heart, lung & circulation
影响因子：
0
作者：
P. Pérez;R. Hylind;T. Roston;Vassilios J. Bezzerides;D. Abrams
通讯作者：
D. Abrams

Paediatric/congenital cardiology physician scientists-An endangered species.

儿科/先天性心脏病医师科学家-濒临灭绝的物种。

DOI：
发表时间：
2020-10
期刊：
影响因子：
5.5
作者：
Hansmann, Georg;Bezzerides, Vassilios
通讯作者：
Bezzerides, Vassilios

Gene therapy for inherited arrhythmias.

遗传性心律失常的基因治疗。

DOI：
发表时间：
2020
期刊：
影响因子：
10.8
作者：
Bezzerides, Vassilios J;Prondzynski, Maksymilian;Carrier, Lucie;Pu, William T
通讯作者：
Pu, William T

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca2+/Calmodulin-Dependent Kinase II.

通过抑制 Ca2/钙调蛋白依赖性激酶 II 治疗儿茶酚胺能多形性室性心动过速。

DOI：
10.1161/circulationaha.118.038514
发表时间：
2019-07-30
期刊：
Circulation
影响因子：
37.8
作者：
Vassilios J. Bezzerides;Ana Caballero;Suya Wang;Yulan Ai;R. Hylind;Fujian Lu;Danielle A Heims;K. D. Chambers;Donghui Zhang;D. Abrams;W. Pu
通讯作者：
W. Pu