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.

概括尽管组织工程和再生医学最近取得了进展，但心肌病引起的心力衰竭（HF）梗死（MI）仍然是美国和西方世界其他地区的主要原因之一。我们的目标是开发新的微创组织工程疗法来治疗心肌梗死。虽然细胞疗法主要研究用于治疗 MI 和 HF，但初始细胞的荟萃分析治疗试验表明，刺激内源性的可注射生物材料对心脏功能仅产生适度的影响。修复是一种有吸引力的、可能更有效的替代方案，因为治疗仍然可以进行最低限度的治疗通过导管进行侵入性治疗，但可以是现成的，并且显着降低了成本和并发症与细胞产品相比，PI 的实验室开发了第一个心脏特异性可注射水凝胶，即心肌。基质水凝胶，源自脱细胞猪心肌细胞外基质 (ECM)，该材料在室温下为液体，可通过经心内膜注射导管输送。注射后的多孔纤维支架，我们已经证明它可以促进免疫细胞的促重塑亚急性和慢性 MI 模型中的极化、其他内源性细胞浸润和心脏修复。这项工作在心肌梗死后患者中进行了成功的 I 期临床试验，但这种方法并不适合。由于与经心内膜注射相关的安全问题，治疗急性心梗患者具有重要意义。与此相反，在患者有资格接受这种治疗之前，心脏的损伤和重塑就会发生。急性心肌梗死患者可进行经心内膜递送、冠状动脉内灌注作为介入治疗心脏病专家已经在进行球囊血管成形术，因此我们最近开发了一种新的输注形式。 ECM (iECM) 可以通过冠状动脉内输注来覆盖和填充受损脉管系统的间隙，从而我们已经证明，在大鼠再灌注后立即进行治疗是有效的。在急性 MI 模型和试点猪研究中，我们研究了 iECM 促进内皮细胞存活。以及浸润免疫细胞极化为促重塑表型，其次还伴随着已经证明血管通透性降低可以改善心肌细胞的存活率。初步结果为使用我们的新 iECM 技术治疗急性心梗提供了有力支持。提案，我们将更好地了解 iECM 技术的免疫调节和再生潜力并进行转化研究，目标是开发一种治疗急性心肌梗死的新疗法。