MicroRNA Inhibition for Cardiac Regeneration in Ischemia

MicroRNA 抑制促进缺血心脏再生

• 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
• 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

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）是全球最大的单一死亡原因。心脏病发作或心肌梗塞 心肌梗死（MI）是由于冠状动脉血流受限而导致的，导致局部缺血和不可逆的死亡 的心肌细胞。梗死的最终大小与心脏功能恶化的程度相关， 收缩储备的损害和心力衰竭（HF）死亡的可能性。迅速恢复 在经皮冠状动脉介入治疗期间进行动脉灌注溶栓和抗血小板治疗， 降低心肌梗死的急性死亡率。然而，幸存者中HF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瘢痕形成， 心室功能障碍成年人心肌细胞不能内源性再生， 与梗死后存活心肌成功偶联构成了主要的临床问题。这 由于缺乏药物或细胞的连续治疗， 结合再灌注，成功刺激心肌再生。促进本土 缺血性心肌梗死的心肌细胞再生，伴随着疤痕大小的减少， 这是一种治疗这种毁灭性疾病及其不良病理生理后果的有效新疗法。抑制 四种microRNA（miR-99，miR-100，let-7a和let-7 c）的特定组合是一个关键的调节因子， 斑马鱼心肌细胞去分化和心脏再生。这些序列和靶蛋白 四种微小RNA（miR）在人类中是保守的。在体内，腺相关病毒（AAV）递送的抑制剂， 这些miR进入患有永久性MI的小鼠心脏增加了心肌细胞再生， 通过增殖和胞质分裂标记物的表达、瘢痕组织消退和心脏功能证实 改进. JAAN Biotherapeutics L.L.C.开发了一种优化的单一病毒制剂JBT-miR 2， 同时表达miR-99/100和let-7a/c的抑制剂。使用这种AAV 2，交叉包装成AAV 9 衣壳（AAV 2/9）允许时间表达、心脏向性，并且是非整合的，最小化了可能性。 脱靶副作用JBT-miR 2构成了一种用于人类心肌细胞再生的创新方法。 本I期研究的目的1中提出的研究将确定JBT-miR 2是否可以再生小鼠 在短暂性60分钟缺血性损伤后， 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， 脱靶组织病理学、多效性效应、代谢功能血液检查和电生理学变化。] 目的1对于确认JBT-miR 2的递送促进心肌细胞再生的功效和时机至关重要。 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。 临床研究设计。