Cardiomyocyte-specific modified mRNA of Pkm2 for induction of cardiac regeneration in ischemic heart failure

心肌细胞特异性修饰的 Pkm2 mRNA 用于诱导缺血性心力衰竭的心脏再生

基本信息

批准号：
10161817
负责人：
Lior Zangi
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161817
关键词：
Action Potentials Acute Acute myocardial infarction Address Adult Anisotropy Apoptosis Area Arrhythmia Biological Assay Birth Candidate Disease Gene Cardiac Cardiac Myocytes Cause of Death Cell Proliferation Cells Chronic Cicatrix Clinical Cytosol Data Development Dose Down-Regulation Electrophysiology (science)Embryonic Heart Enzymes Exhibits Functional disorder Gene Delivery Gene Transduction Agent Genes Genetic Transcription HIF1A gene Heart Heart Hypertrophy Heart failure Hypertrophy Hypoxia Impairment In Vitro Incidence Individual Infarction Inflammation Injury Isoenzymes Knock-out Knockout Mice Laboratories Malignant - descriptor Mediating Membrane Potentials Messenger RNA Methods Mitosis Modeling Molecular Morbidity - disease rate Muscle Myocardial Myocardial Ischemia Myocardium Myofibroblast Natural regeneration Nature Neonatal Newts Optics Organism Outcome Pathologic Pentosephosphate Pathway Phase Phylogenetic Analysis Physiologic pulse Population Prevention Process Proliferating Property Proteins Pyruvate Kinase Regenerative capacity Resolution Rest Risk Role Secondary to Signal Pathway Signal Transduction Small Interfering RNA Therapeutic Time Tissue Engineering Treatment Failure Up-Regulation Viral Weight Widow Zebrafish angiogenesis base beta catenin c-myc Genes cardiac regeneration cardiac repair clinical application conditional knockout design differential expression disability fetal functional loss gene delivery system gene therapy genetic analysis healing heart function improved in vivo indium arsenide mortality mouse model multidisciplinary novel prevent regenerative repaired restoration targeted delivery transcription factor

项目摘要

PROJECT SUMMARY Ischemic heart failure (HF) secondary to chronic post myocardial infraction (MI), is a leading cause of death and disability worldwide. The high morbidity and mortality rates in ischemic HF are caused, in large part, by the low regenerative capacity (and therefore repair) of the mammalian adult heart. Several tissue-engineering, cell- and gene-based therapies have been attempted for induction of cardiac regeneration following MI. Since cardiomyocyte (CM) proliferation and cardiac regeneration are highly robust processes in Zebrafish and Newts, efforts to mimic the pro-proliferative mechanisms of these lower phylogenetic organisms in the adult mammalian heart have been attempted using standard gene therapy vectors. Those approaches however, have encountered major challenges that are related to short-term, low, or uncontrolled delivery of the target gene. At best, this has resulted in poor CM proliferation. In other cases, these strategies have led to highly undesirable outcomes, including exacerbation of pathological hypertrophy and inflammation. We have recently shown that modified mRNA (modRNA) delivery is a safe, efficient, transient, non-immunogenic, local, and dose-controlled cardiac gene delivery platform. We have found that the glycolytic enzyme Pyruvate Kinase Muscle Isozyme M2 (Pkm2), which is highly expressed in regenerative fetal and neonatal CMs but not in adult CMs is an effective vehicle for re-awakening cardiac regeneration when delivered at the time of MI. Selective Pkm2 modRNA delivery to distinct cell populations led to a significant increase in their respective rates of proliferation. Proliferation of non-CMs such as myofibroblasts may exacerbate pathological remodeling by impairing diastolic function, disrupting myocardial conduction, and promoting arrhythmias. To circumvent this, we have designed a unique CM-specific modRNA-based approach for improving post-MI cardiac repair and regeneration. This proposal will identify the optimal therapeutic widow for modRNA-mediated delivery of Pkm2 to CMs following the phase of active healing for effective reversal of electro-mechanical dysfunction, will determine the molecular mechanisms by which local and transient delivery of Pkm2 promotes CM proliferation via β-catenin and downstream signaling, and finally determine the altered conduction properties and risk of arrhythmias associated with efficient integration of newly-formed Pkm2-dependent CMs with the host myocardium post MI. The highly translatable nature of our proposed modRNA platform and our integrative, multi-disciplinary experimental plan are ultimately geared towards clinical applicability for ischemic heart failure.

项目概要慢性心肌梗死后继发的缺血性心力衰竭 (HF) 是导致死亡的主要原因缺血性心力衰竭的高发病率和死亡率在很大程度上是由哺乳动物成年心脏的再生能力低（因此修复能力低）。自此以来，人们一直在尝试基于基因的疗法来诱导心肌梗死后的心脏再生。心肌细胞（CM）增殖和心脏再生是斑马鱼和蝾螈中高度稳健的过程，模仿这些较低系统发育生物在成体中的促增殖努力机制然而，哺乳动物心脏一直在尝试使用标准基因治疗载体。遇到了与短期、低水平或不受控制的目标交付相关的重大挑战在最好的情况下，这会导致 CM 增殖不良，而在其他情况下，这些策略会导致高度的 CM 增殖。我们最近发现了不良后果，包括病理性肥大和炎症的恶化。表明修饰的 mRNA (modRNA) 递送是一种安全、高效、瞬时、非免疫原性、局部和我们发现了糖酵解酶丙酮酸激酶。肌肉同工酶 M2 (Pkm2)，在再生胎儿和新生儿 CM 中高表达，但在成人中不表达选择性心肌梗死时递送的 CM 是重新唤醒心脏再生的有效载体。 Pkm2 modRNA 递送到不同的细胞群导致它们各自的比率显着增加肌成纤维细胞等非 CM 的增殖可能会加剧病理重塑。损害舒张功能，扰乱心肌传导，并促进心律失常。我们设计了一种独特的基于 CM 特异性 modRNA 的方法，用于改善 MI 后心脏修复和该提案将确定 modRNA 介导的 Pkm2 递送的最佳治疗寡妇。在积极愈合阶段之后对 CM 进行有效逆转机电功能障碍，将确定 Pkm2 局部和瞬时递送促进 CM 增殖的分子机制通过β-catenin和下游信号传导，最终确定传导特性和风险与新形成的 Pkm2 依赖性 CM 与宿主有效整合相关的心律失常我们提出的 modRNA 平台和我们的综合性的高度可翻译性。多学科实验计划最终面向缺血性心脏的临床适用性失败。