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Targeting a ectonucleotidase in the heart with a monoclonal antibody to prevent post-infarct heart failure

用单克隆抗体靶向心脏中的核酸外切酶以预防梗死后心力衰竭

基本信息

批准号：
10711469
负责人：
Arjun Deb
金额：
$ 74.98万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711469
关键词：
Acute Acute myocardial infarction Adenine Adenosine Adrenergic beta-Antagonists Affect Aldosterone Aldosterone Antagonists Anabolism Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Animals Apoptosis Apoptotic Attenuated Biodistribution Biological Biological Response Modifier Therapy Biotechnology CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular system Catalytic Domain Cell Cycle Cell Death Cell Death Induction Cell Proliferation Cells Chronic Cicatrix Clinical Collaborations Computational Biology DNA Damage Data Development Diagnosis Dilatation - action Dose Drug Kinetics Endothelial Cells Engineering Enzymes Fibroblasts Fibrosis Functional disorder Future Generations Genetic Genetic Transcription Genetically Engineered Mouse Goals Half-Life Heart Heart Injuries Heart failure Human Impairment Infarction Inflammation Inflammatory Integral Membrane Protein Investments Journals Macrophage Medical Metabolic Metabolism Modeling Molecular Monoclonal Antibodies Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Necrosis Nuclear Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylases Physiological Physiology Prevention Proteins Publishing Purine Nucleosides Purines Pyrimidine Role Signal Transduction Survival Rate Technology Testing Therapeutic Therapeutic Uses Time Tissue-Specific Gene Expression Tissues Toxic effect Transgenes United States Ventricular Ventricular Remodeling Western World antagonist antibody engineering base cardiac repair cardiovascular pharmacology clinical candidate clinical investigation ecto-nucleotidase efficacy study extracellular gain of function healing heart function hemodynamics humanized monoclonal antibodies humanized mouse insight ischemic injury loss of function metabolomics mouse model multidisciplinary novel pharmacologic phosphoric diester hydrolase plasma cell membrane glycoprotein PC-1 porcine model preclinical study preservation prevent pyrophosphatase repaired response response to injury safety study treatment strategy wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT The mammalian heart possesses a poor ability to regenerate after myocardial infarction and heals via a fibrotic repair response. Scar tissue increases the hemodynamic burden on the remaining cardiac muscle and over time, the ventricle fails leading to the development of heart failure. Myocardial infarction contributes to almost 40-70% of all cases of heart failure and 700,000 patients are annually diagnosed with heart failure in the United States alone. The main thrust of cardiovascular pharmacology for the treatment /prevention of heart failure after heart attacks has centered on chronic antagonism of the sympatho-adrenal-angiotensin- aldosterone axis (Beta blockers, ACE inhibitors, Angiotensin receptor blockers and aldosterone antagonists) but despite available pharmacological therapies, the 5 year survival rate of heart failure is less than 50%. There thus exists an immense unmet need to identify novel pharmacological strategies for the treatment and prevention of heart failure. We have recently demonstrated the role of a specific ectonucleotidase, ENPP1 (ectonucleotide pyrophosphatase/ phosphodiesterase 1) in cardiac repair following myocardial infarction. ENPP1 is induced by orders of magnitude after myocardial infarction and show that hydrolytic products generated by ectonucleotidase activity contribute to inflammation and impair the cardiac injury response. Using genetic loss of function approaches, we showed that inhibition of ENPP1 in the infarcted heart leads to decreased non- myocyte cell death, decreased inflammation and significantly superior post infarct cardiac function. Considering these observations, in collaboration with an antibody engineering biotech company, we in this proposal have engineered a humanized monoclonal antibody targeting ENPP1 as a therapeutic biologic to treat post infarct decline in cardiac function. We provide proof of concept efficacy studies demonstrating the ability of the administered clinical candidate to modulate inflammation in the infarcted heart and lead to significantly better preservation of post infarct function and decreased post infarct ventricular remodeling. Further development of the monoclonal antibody combined with definitive preclinical studies in humanized mice models as well as large animal infarct models forms the substance of the proposal. Using a variety of “omics” approaches and genetically engineered mice, we will also interrogate in depth the downstream pathways that are affected by the ENPP1mAb to exert salutary effects on cardiac repair and post infarct heart function. If our studies are successful, the proposal will directly lead to the identification of a clinical monoclonal antibody candidate to attenuate post infarct cardiac remodeling and dysfunction.

项目概要/摘要哺乳动物心脏在心肌梗塞后再生能力较差，并通过纤维化愈合修复响应。疤痕组织增加了剩余心肌的血流动力学负担随着时间的推移，心室衰竭导致心力衰竭的发展。心肌梗塞几乎导致每年有 700,000 名患者被诊断为心力衰竭，占所有心力衰竭病例的 40-70% 唯有美国。心血管药理学治疗/预防心脏病的主旨心脏病发作后的衰竭集中在交感-肾上腺-血管紧张素的慢性拮抗作用上醛固酮轴（β 受体阻滞剂、ACE 抑制剂、血管紧张素受体阻滞剂和醛固酮拮抗剂）但尽管有可用的药物治疗，心力衰竭的 5 年生存率仍低于 50%。因此，对于确定治疗和治疗的新药理学策略存在着巨大的未满足的需求。预防心力衰竭。我们最近证明了一种特定的核酸外切酶 ENPP1（核酸外切酶）的作用焦磷酸酶/磷酸二酯酶 1) 在心肌梗塞后的心脏修复中。 ENPP1 是由心肌梗死后的数量级，并表明由产生的水解产物核酸外切酶活性会导致炎症并损害心脏损伤反应。利用遗传损失在功能方法方面，我们发现在梗塞心脏中抑制 ENPP1 会导致非心肌细胞死亡，炎症减少，梗死后心脏功能显着增强。考虑到这些观察结果，我们与一家抗体工程生物技术公司合作，提案设计了一种针对 ENPP1 的人源化单克隆抗体作为治疗性生物制剂治疗梗塞后心功能下降。我们提供概念验证功效研究，证明所施用的临床候选者调节梗塞心脏炎症并导致显着更好地保存梗塞后功能并减少梗塞后心室重塑。单克隆抗体的进一步开发与人源化的明确临床前研究相结合小鼠模型以及大型动物梗塞模型构成了该提案的实质内容。使用各种 “组学”方法和基因工程小鼠，我们也会深入拷问下游受 ENPP1mAb 影响的途径对心脏修复和梗塞后心脏发挥有益作用功能。如果我们的研究成功，该提案将直接导致临床单克隆抗体的鉴定减轻梗塞后心脏重塑和功能障碍的候选抗体。