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Oligonucleotide Inhibition for cardiac regeneration in Ischemia

寡核苷酸抑制缺血心脏再生

基本信息

批准号：
9333618
负责人：
Bhawanjit K Brar
金额：
$ 22.5万
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：
2017-04-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333618
关键词：
Actins Acute Acute myocardial infarction Adult Adverse effects American Animal Model Antibodies Arterial Fatty Streak Biological Response Modifier Therapy Biotechnology Blood flow Businesses California Cardiac Cardiac Catheterization Procedures Cardiac Myocytes Cause of Death Cessation of life Chromatin Cicatrix Clinical Clinical Research Congestive Heart Failure Coronary Coronary artery Cytokinesis DNA Dependovirus Deterioration Development Dimensions Disadvantaged Doctor of Medicine Doctor of Philosophy Dose Failure Family Functional disorder Future Heart Heart failure High Prevalence Histologic Human Imagery Incidence Industrialization Injection of therapeutic agent Injury Institutes Investigational New Drug Application Investigational Therapies Ischemia Label Laboratories Left Legal patent Ligation Mammals Medical Methods MicroRNAs Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Nucleic Acids Oligonucleotides Organ Outcome Pathologic Patient-Focused Outcomes Patients Perfusion Pharmacology Phase Phase II Clinical Trials Physiology Prevalence Probability Procedures Process Proliferating Proteins RNA Recurrence Reperfusion Therapy Research Research Design Residual state Resistance Safety Saline Seaweed Site Survivors Technology Testing Therapeutic Thrombus Time Tissues Toxicology Translating Universities Uridine Viral Woman Zebrafish aging population base cardiac regeneration clinical application clinical development clinically relevant cost design functional improvement heart function improved in vivo inhibitor/antagonist innovation locked nucleic acid medical schools member mortality mouse model muscle regeneration nuclease nucleic acid inhibitor outcome forecast percutaneous coronary intervention preclinical study prevent professor protein farnesyltransferase response 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 ultimately irreversible death of cardiomyocytes. The size of a myocardial infarct correlates with the degree of deterioration of heart function, compromise of contractile reserve, and overtime the likelihood of mortality from heart failure (HF). 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, or after to stimulate regeneration of heart muscle. Effective promotion of endogenous cardiomyocyte regeneration in the ischemic heart with concomitant reduction of scar size would potentially offer a powerful new treatment of MI and its adverse pathophysiologic consequences. Inhibition of a specific combination of four MicroRNAs (miR); 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 miRs are conserved in humans. In vivo, adeno-associated virus (AAV) delivery of inhibitors of these miRs into the hearts of mice with left coronary artery ligation increases the expression of the beta subunit of farnesyl-transferase and SWI/SNF-related matrix associated actin-dependent regulator of chromatin subfamily a, member 5. Cardiac regeneration was confirmed by the expression of proliferation and cytokinesis markers, labeled uridine incorporation into DNA, together with scar tissue regression and heart functional improvement. A disadvantage of viral delivery is the high prevalence of anti-AAV antibodies in humans that could neutralize their effect. As an alternative, JAAN Biotherapeutics will investigate whether two synthetic, specific, potent and nuclease resistant nucleic acid miR inhibitors (anti-miRs) to miR-99/100 and let-7a/c can reduce ischemic injury in an experimental murine model of ischemic reperfusion and constitute an innovative approach to regenerate human cardiomyocytes. [The research in Phase I will define whether the anti-miRs proliferate normal heart muscle, provide information on an effective dose and sustainability of effect, and establish any proliferative or off-target side effects in remote tissues (Aim 1). Aim 2 will study whether the anti- miRs administered after a 60 min cardiac ischemic injury in mice either at the time of reperfusion or 2 days after ischemia can reduce scar size, increase cardiac function and regenerate cardiac muscle. Aim 1 will provide safety information and Aim 2 is critical to confirm efficacy of the anti-miRs in the murine ischemic heart. These studies are pivotal for future preclinical and clinical study design.]

项目总结