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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.

项目总结/文摘