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.

项目概要缺血性心脏病（IHD）是全球最大的单一死因。心脏病发作或心肌梗死梗塞（MI）是由于流向心脏的冠状动脉血流受到限制而导致的，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恶化的程度相关，收缩储备的损害以及心力衰竭（HF）死亡的可能性。及时恢复经皮冠状动脉介入治疗期间进行溶栓和抗血小板治疗的动脉灌注已导致心肌梗死急性死亡率下降。然而，幸存者中心力衰竭的患病率有所增加，因为不可逆的心肌细胞死亡导致残余缺血和心肌疤痕，导致左心室功能障碍。人类成年心肌细胞无法内源性再生，以及与梗死后存活的心肌成功结合构成了一个主要的临床问题。这由于缺乏可以在体内施用的药物或细胞辅助治疗而变得更加复杂。与再灌注相结合，成功刺激心肌再生。促进内生缺血性梗塞心脏中的心肌细胞再生，伴随着疤痕尺寸的减小，将提供针对这种破坏性疾病及其不良病理生理后果的强大新疗法。抑制四种 microRNA（miR-99、miR-100、let-7a 和 let-7c）的特定组合是斑马鱼心肌细胞去分化和心脏再生。这些的序列和靶蛋白四种 microRNA (miR) 在人类中是保守的。在体内，腺相关病毒（AAV）递送抑制剂将这些 miR 注入患有永久性 MI 的小鼠的心脏中会增加心肌细胞的再生，这是通过增殖和胞质分裂标志物的表达、疤痕组织消退和心脏功能来证实改进。 JAAN 生物治疗有限责任公司开发了一种优化的单一病毒制剂 JBT-miR2 同时表达 miR-99/100 和 let-7a/c 的抑制剂。使用这个AAV2，交叉打包成AAV9 衣壳 (AAV2/9) 允许时间表达、向心性，并且是非整合性的，最大限度地减少了潜力脱靶副作用。 JBT-miR2 构成了人类心肌细胞再生的创新方法。本一期研究的目标 1 中拟议的研究将确定 JBT-miR2 是否可以再生小鼠立即静脉注射后 60 分钟短暂缺血性损伤后的心肌再灌注后或再灌注后一星期。 [目标 2 将确定病毒的心脏和组织分布，脱靶组织病理学、多效性效应、代谢功能血液测试和电生理变化。] 目标 1 对于确认 JBT-miR2 促进心肌细胞再生的功效和递送时间至关重要。而目标 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研究至关重要和临床研究设计。