VIRAL DELIVERED CARDIAC REGENERATION

病毒传递的心脏再生

基本信息

批准号：
10377777
负责人：
Bhawanjit K Brar
金额：
$ 5.2万
依托单位：
JAAN BIOTHERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377777
关键词：
Acute Acute myocardial infarction Adult Agreement Animals Applications Grants Biological Biological Assay Biological Markers Biological Response Modifier Therapy Blood Blood Urea Nitrogen Blood flow Cardiac Cardiac Myocytes Cardiac Volume Cause of Death Cessation of life Cicatrix Clinical Clinical Research Clinical Trials Consequentialism Coronary Creatine Kinase Dependovirus Deterioration Dose Evaluation Research Exhibits Failure Family suidae Future Grant Heart Heart Rate Heart failure Human In Vitro Industrialization Injury Intravenous Investigational Drugs Investigational New Drug Application Ischemia Legal patent Mammals Measures Medical Metabolic MicroRNAs Miniature Swine Molecular Morbidity - disease rate Mus Muscle Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Natural regeneration Organ Pathologic Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacology Phase Preparation Prevalence Prevention Procedures Process Prognosis Protocols documentation Reading Regenerative response Reperfusion Injury Reperfusion Therapy Reproducibility Research Design Research Personnel Residual state Retreatment Rodent Safety Shapes Small Business Innovation Research Grant Survivors Testing Therapeutic Uses Time Tissues Toxic effect Toxicology Viral Virus Virus Shedding Work Zebrafish aged cardiac muscle disease cardiac regeneration cardiogenesis clinical development clinical translation clinically relevant design efficacy testing first-in-human good laboratory practice heart dimension/size heart function immunogenicity improved in vivo inhibitor/antagonist innovation intravenous injection meetings middle age mortality mouse model neutralizing antibody particle percutaneous coronary intervention pleiotropism prevent regenerative repaired research and development response to injury restoration safety practice standard of care translational model young adult

项目摘要

PROJECT SUMMARY Ischemic heart disease (IHD) is the single largest cause of death in the industrialized world and contributor to the development of Heart Failure (HF) in adults 1-2. IHD can be caused by a myocardial infarction (MI), which limits coronary blood flow to the heart, causing ischemia and ultimately irreversible death of cardiomyocytes. The size of a myocardial infarct correlates with the degree of deterioration of heart function 3, compromise of contractile reserve, and over time the likelihood of mortality from HF 4. Prompt restoration of arterial perfusion with thrombolytic and antiplatelet therapy during percutaneous coronary intervention has led to a decline in acute mortality from MI. However, the prevalence of HF among survivors has augmented, because irreversible cardiomyocyte death results in a residual inducible ischemia and permanent scarring. A major pathologic problem is the failure of human adult cardiomyocytes to regenerate themselves endogenously following a MI. This is compounded by a lack of adjunctive treatments, pharmacologic or cellular, that can be administered in conjunction with reperfusion to stimulate regeneration of heart muscle and prevent the transition to HF. The effective promotion of endogenous cardiomyocyte regeneration in the ischemic heart would potentially offer a powerful new treatment for MI and its adverse pathophysiologic consequences. Inhibition of a specific combination of four MicroRNAs (miRs); miR-99, miR-100, let-7a and let-7c, is a critical regulator of cardiomyocyte dedifferentiation and proliferation in mammals 6. JBT has designed and tested an adeno associated virus known as JBT-miR2, which allows for temporal, cardiac and non-integrative expression of inhibitors to these four miRs. In preliminary studies in young mice with cardiac Ischemic Reperfusion (IR) injury the efficacy and safety of a single dose of JBT-miR2 administered by intravenous injection at the time of reperfusion was compared with Control virus. JBT-miR2 increased heart function and decreased cardiac volumes at 2-weeks post IR with a corresponding ~47% reduction in scar tissue at 8-weeks post-IR compared with control virus. To continue with Research and Development required for clinical trials it is necessary to confirm the efficacy and safety in clinically translational larger aged animals. The Specific Aims of this Phase I SBIR grant are to: 1: Conduct a dose range finding efficacy, safety and PK study of JBT-miR2 in middle aged mini-pigs with IR injury, evaluating pleiotropic effects and mechanism of action. Significant, reproducible, clinically relevant end-point changes in measures of cardiac dimension and function are expected in JBT-miR2 treated animals compared to Control virus. 2. Develop and validate PK and in vitro bioactivity assays. Assess for immunogenicity, neutralizing antibodies, and viral particle titer levels to determine viral shedding in pigs. A Target Product Profile will be drafted, with an understanding of measures of drug product identity, activity and purity. 3. These results will allow preparation for, and conduction of a type C meeting with FDA to provide agreement on the design of a Good Laboratory Practice safety toxicology studies required for clinical translation.

项目摘要缺血性心脏病（IHD）是工业化世界中最大的死亡原因，并为成人心力衰竭（HF）的发展1-2。 IHD可能是由心肌梗塞（MI）引起的局限性血液流向心脏，导致缺血并最终导致心肌细胞的不可逆死亡。心肌梗塞的大小与心脏功能3的恶化程度相关，妥协收缩储备，随着时间的流逝，HF 4的死亡率。迅速修复动脉灌注经皮冠状动脉干预期间的溶栓和抗血小板治疗导致急性下降 Mi的死亡率。但是，幸存者中HF的患病率增加了，因为不可逆转心肌细胞死亡导致残留的诱导性缺血和永久性疤痕。主要病理问题是人类成年心肌细胞失败无法在MI后内源性地再生。这是由于缺乏药理或细胞的辅助治疗而更加复杂的，可以在与再灌注相结合以刺激心肌再生并防止过渡到HF。这有效促进缺血性心脏中内源性心肌细胞再生可能会提供对MI及其不良病理生理后果的强大新治疗方法。抑制特定四个microRNA（mir）的组合； miR-99，mir-100，let-7a和let-7c是关键的调节剂哺乳动物的心肌细胞去分化和增殖6。JBT设计和测试了Adeno 相关病毒称为JBT-MIR2，它允许时间，心脏和非整合性表达这四个mir的抑制剂。在患有心脏缺血再灌注（IR）损伤的年轻小鼠的初步研究中单剂量的JBT-MIR2的功效和安全性在静脉注射时给予将再灌注与对照病毒进行了比较。 JBT-MIR2增加心脏功能并减少心脏 IR后2周的体积，在IR后8周相应地减少疤痕组织的相应降低〜47％使用控制病毒。要继续进行临床试验所需的研究和开发，有必要确认临床翻译较大的老年动物的功效和安全性。该阶段的具体目的 SBIR Grant是：1：进行剂量范围，发现疗效，JBT-MIR2的安全性和PK研究 IR损伤的迷你小猪，评估了多效效应和作用机理。显着，可重复， JBT-MIR2预计心脏维度和功能的临床相关终点变化治疗的动物与对照病毒相比。 2。开发和验证PK和体外生物活性测定。评估为了进行免疫原性，中和抗体和病毒颗粒滴度水平以确定猪的病毒脱落。一个目标产品概况将被起草，并了解药物标识，活动和纯度。 3。这些结果将允许为与FDA的C类型会议的准备和传导以提供关于临床翻译所需的良好实验室实践安全毒理学研究的设计协议。