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Infusible Extracellular Matrix for Treating Myocardial Infarction

可溶性细胞外基质治疗心肌梗死

基本信息

批准号：
10504948
负责人：
Karen L Christman
金额：
$ 73.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504948
关键词：
Acute myocardial infarction Address Aging Alternative Therapies Animals Apoptosis Arrhythmia Balloon Angioplasty Binding Biocompatible Materials Cardiac Cardiac Myocytes Catheters Cause of Death Cell Survival Cell Therapy Cells Chronic Clinical Development Echocardiography Endothelial Cells Endothelium Extracellular Matrix Family suidae Fibrosis Functional disorder Geometry Germ Cells Goals Heart Heart failure Histologic Histology Holter Electrocardiography Hydrogels Immune Immunohistochemistry Infiltration Infusion procedures Injectable Injections Intervention Intravenous Knowledge Lead Left Left Ventricular Function Liquid substance Magnetic Resonance Imaging Mediating Meta-Analysis Metabolism Modeling Myocardial Myocardial Infarction Myocardium Patients Phase I Clinical Trials Phenotype Pre-Clinical Model Rattus Regenerative Medicine Reperfusion Therapy Rest Route Safety Technology Temperature Therapy trial Tissue Engineering Tissues Treatment Efficacy Tumor-infiltrating immune cells Vascular Permeabilities Ventricular Western World Work aged base cardiac repair cost cytokine healing heart function immunoregulation improved minimally invasive neovascularization novel therapeutics polarized cell receptor regeneration potential repaired response scaffold sex single-cell RNA sequencing transcriptomics translational study

项目摘要

Summary Despite recent advances in tissue engineering and regenerative medicine, heart failure (HF) following myocardial infarction (MI) continues to be the leading cause of death in the U.S., and the rest of the western world. One of our goals is the development of new, minimally invasive tissue-engineered therapies for the treatment of MI. While cell therapies have been extensively studied for the treatment of MI and HF, meta-analyses of initial cell therapy trials suggest only a modest effect on cardiac function. Injectable biomaterials that stimulate endogenous repair are an attractive, potentially more effective alternative since therapies could still be delivered minimally invasively via catheter, yet could be off the shelf and have significantly reduced costs and complications compared to cell products. The PI’s lab developed the first cardiac specific injectable hydrogel, a myocardial matrix hydrogel, which is derived from decellularized porcine myocardial extracellular matrix (ECM) and is deliverable via a transendocardial injection catheter. This material is liquid at room temperature and forms a porous and fibrous scaffold upon injection, which we have shown promotes pro-remodeling immune cell polarization, other endogenous cell infiltration and cardiac repair in subacute and chronic MI models. This initial work led to a successful Phase I clinical trial in post-MI patients. However, this approach is not amenable to treating acute MI patients because of safety issues related to transendocardial injections. Therefore, significant damage and remodeling of the heart will occur before a patient is even eligible for this therapy. In contrast to transendocardial delivery, intracoronary infusion can be performed in acute MI patients as interventional cardiologists are already performing a balloon angioplasty. We therefore recently developed a new infusible form of ECM (iECM) that can be delivered via intracoronary infusion to coat and fill gaps of damaged vasculature to heal the tissue. We have already shown this is effective when delivered immediately post-reperfusion in a rat acute MI model and in a pilot pig study. In acute MI, we hypothesize that iECM promotes endothelial cell survival and polarization of infiltrating immune cells to a pro-remodeling phenotype, which secondarily along with an already demonstrated reduction in vascular permeability results in improved cardiomyocyte survival. Our preliminary results provide strong support for the use of our new iECM technology for treating acute MI. In this proposal, we will better understand the immunomodulatory and regenerative potential of our iECM technology and perform translational studies with the goal of developing a novel therapy for acute MI.

总结