MicroRNA Inhibition for Cardiac Regeneration in Ischemia

MicroRNA 抑制促进缺血心脏再生

基本信息

批准号：
9407663
负责人：
Bhawanjit K Brar
金额：
$ 24.08万
依托单位：
JAAN BIOTHERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-17 至 2019-03-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407663
关键词：
Acute Acute myocardial infarction Adult Adverse effects Age American Amputation Animal Model Anterior Descending Coronary Artery Arterial Fatty Streak Biological Response Modifier Therapy Blood Tests Blood flow Businesses California Capsid Cardiac Cardiac Catheterization Procedures Cardiac Myocytes Cause of Death Cessation of life Cicatrix Clinical Clinical Research Congestive Heart Failure Coronary Cytokinesis Dependovirus Deterioration Development Dimensions Direct Costs Disease Doctor of Medicine Doctor of Philosophy Down-Regulation Drug or chemical Tissue Distribution Effectiveness Electrophysiology (science)Facilities and Administrative Costs Failure Formulation Functional disorder Future Heart Heart failure Histologic Histopathology Human Imagery Industrialization Industry Infarction Injection of therapeutic agent Injury Institutes Intravenous Investigational New Drug Application Investigational Therapies Ischemia Laboratories Left Left Ventricular Dysfunction Legal patent Ligation Mammals Medical Metabolic Methods MicroRNAs Modeling Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Outcome Patient-Focused Outcomes Patients Perfusion Pharmacology Phase II Clinical Trials Physiology Population Prevalence Probability Procedures Process Proteins Recurrence Regenerative response Reperfusion Therapy Research Research Design Residual state Safety Seaweed Site Survivors Technology Thrombus Time Tissues Toxicology Translating Tropism Universities Viral Virus Woman Zebrafish base cardiac regeneration clinical application clinical development clinically relevant design efficacy testing experience functional improvement healing heart function human disease improved in vivo inhibitor/antagonist innovation intravenous administration medical schools mortality mouse model muscle regeneration novel therapeutics outcome forecast percutaneous coronary intervention phase 1 study pleiotropism preclinical study professor restoration standard of care translational scientist

项目摘要

PROJECT SUMMARY Ischemic heart disease (IHD) is the single largest cause of death worldwide. A heart attack or myocardial infarction (MI) results from limitation of coronary blood flow to the heart, causing ischemia and irreversible death of cardiomyocytes. The ultimate size of an infarct correlates with the degree of deterioration of heart function, compromise of contractile reserve, and the likelihood of mortality from heart failure (HF). Prompt restoration of arterial perfusion with thrombolytic and antiplatelet therapy during percutaneous coronary interventions has led to a decline in acute mortality from MI. However, the prevalence of HF among survivors has been augmented, because irreversible cardiomyocyte death results in residual ischemia and myocardial scarring causing left ventricular dysfunction. The failure of human adult cardiomyocytes to regenerate themselves endogenously, and couple successfully with surviving myocardium following an infarction, constitutes a major clinical problem. This is compounded by the lack of adjunctive treatments, pharmacologic or cellular, that can be administered in conjunction with reperfusion to successfully stimulate regeneration of heart muscle. Promotion of endogenous cardiomyocyte regeneration in the ischemic-infarcted heart, with concomitant reduction of scar size, would offer a powerful new treatment of this devastating disease and its adverse pathophysiologic consequences. Inhibition of a specific combination of four microRNAs (miR-99, miR-100, let-7a and let-7c) is a critical regulator of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. The sequences and target proteins of these four microRNAs (miRs) are conserved in humans. In vivo, adeno-associated virus (AAV) delivery of inhibitors of these miRs into the hearts of mice with a permanent MI increases cardiomyocyte regeneration which was confirmed by the expression of proliferation and cytokinesis markers, scar tissue regression and heart functional improvement. JAAN Biotherapeutics L.L.C. has developed an optimized, single virus formulation, JBT-miR2 that simultaneously expresses inhibitors to miR-99/100 and let-7a/c. Use of this AAV2, cross packaged into AAV9 capsids (AAV2/9) allows for temporal expression, cardiac tropism, and is non integrative, minimizing potential off-target side effects. JBT-miR2 constitutes an innovative approach for regeneration of human cardiomyocytes. The proposed research in Aim 1 of this Phase I study will determine whether JBT-miR2 can regenerate murine heart muscle after a transient 60 minute ischemic injury when administered intravenously either immediately after reperfusion or one week after reperfusion. [Aim 2 will establish cardiac and tissue distribution of the virus, off-target histopathology, pleiotropic effects, metabolic function blood tests and electrophysiological changes.] Aim 1 is critical to confirm efficacy and timing of delivery of JBT-miR2 to promote cardiomyocyte regeneration. Whereas Aim 2 provides information on the safety of the virus. These studies are pivotal for future preclinical and clinical study design.

项目摘要缺血性心脏病（IHD）是全球死亡的最大原因。心脏病发作或心肌梗塞（MI）是由于冠状动脉血液流向心脏的限制，导致缺血和不可逆的死亡心肌细胞。梗塞的最终大小与心脏功能的恶化程度相关，收缩储备的妥协以及心力衰竭死亡的可能性（HF）。迅速修复经皮冠状动脉干预期间的溶栓和抗血小板疗法的动脉灌注已导致 MI的急性死亡率下降。但是，幸存者中HF的患病率已经增加，因为不可逆的心肌细胞死亡导致残留缺血和心肌疤痕，左心室功能障碍。人类成年心肌细胞无法内源性再生的失败，并且夫妇在梗塞后成功地幸免于心肌，这是一个主要的临床问题。这由于缺乏药理学或细胞的辅助治疗，可以在与再灌注成功刺激心肌再生的结合。促进内源性脑缺血感染心脏的心肌细胞再生，随之而来的疤痕大小会提供对这种毁灭性疾病及其不良病理生理后果的有力新对待。抑制四个microRNA（mir-99，miR-100，let-7a和let-7c）的特定组合是关键的调节剂斑马鱼中的心肌细胞去分化和心脏再生。这些的序列和靶蛋白四个microRNA（mir）在人类中是保守的。在体内，腺相关病毒（AAV）的抑制剂递送这些mir以永久性MI的长鼠进入小鼠的心脏，增加了心肌细胞再生通过增殖和细胞因子标记的表达，疤痕组织回归和心脏功能证实改进。 Jaan Biothapeutics L.L.C.已经开发了一种优化的单一病毒配方JBT-MIR2 同时向miR-99/100和let-7a/c表示抑制剂。使用此AAV2，交叉包装到AAV9中衣壳（AAV2/9）允许时间表表达，心脏向上主义，并且是非整合的，最小化的电位非目标副作用。 JBT-MIR2构成了人类心肌细胞再生的创新方法。 I阶段I研究的目标1中提出的研究将确定JBT-MIR2是否可以再生鼠暂时静脉内静脉内施用60分钟的短暂性缺血性损伤后，心肌立即施用再灌注后或再灌注后一周。 [AIM 2将建立病毒的心脏和组织分布，靶标的组织病理学，多效性作用，代谢功能血液测试和电生理学变化。] AIM 1对于确认JBT-MIR2的疗效和促进心肌细胞再生的疗效至关重要。而AIM 2提供了有关病毒安全性的信息。这些研究对于未来的临床前都是关键和临床研究设计。