Infusible Extracellular Matrix for Treating Myocardial Infarction

可溶性细胞外基质治疗心肌梗死

• 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
• 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

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） 梗塞（MI）仍然是美国和西方世界其他地区的首要死因。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。 虽然细胞疗法已被广泛研究用于治疗 MI 和 HF，但初始细胞的荟萃分析 治疗试验表明对心脏功能仅产生适度影响。刺激内源性的可注射生物材料 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)， 可通过经心内膜注射导管输送。该材料在室温下为液体并形成 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重塑 亚急性和慢性心肌梗死模型中的极化、其他内源性细胞浸润和心脏修复。这个初始的 这项工作导致在心肌梗死后患者中进行了成功的 I 期临床试验。然而，这种方法并不适合 由于与经心内膜注射相关的安全问题，治疗急性心肌梗死患者。因此，意义重大 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。相比之下 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不熔形式 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 治愈组织。我们已经证明，在大鼠再灌注后立即给药是有效的 急性心肌梗死模型和中试猪研究。在急性 MI 中，我们假设 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。我们的 初步结果为使用我们的新iECM技术治疗急性心肌梗死提供了强有力的支持。在这个 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。