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.

项目概要缺血性心脏病 (IHD) 是工业化国家最大的单一死因，也是导致成人心力衰竭 (HF) 的发展 1-2。 IHD 可由心肌梗塞 (MI) 引起，限制冠状动脉血流到心脏，导致缺血并最终导致心肌细胞不可逆转的死亡。心肌梗塞的面积与心功能恶化程度相关3、折衷收缩储备，以及随着时间的推移，心力衰竭死亡的可能性 4. 迅速恢复动脉灌注经皮冠状动脉介入治疗期间溶栓和抗血小板治疗导致急性发作率下降心肌梗死死亡率。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留的诱导性缺血和永久性疤痕。主要病理问题是成人心肌细胞在心肌梗死后无法内源性再生。由于缺乏可以在体内施用的药物或细胞辅助治疗，这一问题变得更加复杂。与再灌注相结合，刺激心肌再生并防止转变为心力衰竭。这有效促进缺血心脏中的内源性心肌细胞再生可能会提供针对 MI 及其不良病理生理后果的强大新疗法。抑制特定的四种 MicroRNA (miR) 的组合； miR-99、miR-100、let-7a 和 let-7c 是哺乳动物心肌细胞去分化和增殖 6. JBT 设计并测试了腺苷相关病毒称为 JBT-miR2，它允许瞬时、心脏和非整合性表达这四种 miR 的抑制剂。对患有心脏缺血再灌注 (IR) 损伤的年轻小鼠进行初步研究静脉注射单剂量 JBT-miR2 的有效性和安全性将再灌注与对照病毒进行比较。 JBT-miR2 增强心脏功能并降低心脏功能与 IR 后 2 周的体积相比，IR 后 8 周的疤痕组织相应减少约 47% 与对照病毒。为了继续进行临床试验所需的研究和开发，有必要确认临床转化大型老年动物的有效性和安全性。第一阶段的具体目标 SBIR 资助旨在： 1：开展剂量范围研究，以发现 JBT-miR2 在中年人群中的功效、安全性和 PK 研究小型猪的 IR 损伤，评估多效性效应和作用机制。显着的、可重复的、 JBT-miR2 中预计心脏尺寸和功能测量的临床相关终点变化与对照病毒相比，治疗的动物。 2. 开发并验证 PK 和体外生物活性测定。评估用于免疫原性、中和抗体和病毒颗粒滴度水平，以确定猪体内的病毒脱落情况。一个将起草目标产品简介，了解药品特性、活性和纯度。 3. 这些结果将有助于准备和与 FDA 举行 C 类会议，以提供就临床转化所需的良好实验室规范安全毒理学研究的设计达成一致。