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.

总结 尽管最近在组织工程和再生医学方面取得了进展，但心肌梗死后心力衰竭（HF）仍是一个严重的问题。 梗死（MI）仍然是美国的主要死亡原因，和其他西方世界。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，但初始细胞疗法的荟萃分析表明， 治疗试验表明对心脏功能只有适度的影响。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，因为治疗仍然可以最小限度地提供 通过导管侵入，但可以现成的，并显着降低成本和并发症 与细胞产品相比。PI的实验室开发了第一种心脏特异性可注射水凝胶， 基质水凝胶，其来源于脱细胞的猪心肌细胞外基质（ECM）， 可通过经血管内注射导管输送。这种材料在室温下是液体， 多孔和纤维支架注射后，我们已经表明，促进促重塑免疫细胞 极化、其他内源性细胞浸润和心脏修复。该初始 这项工作导致了在心肌梗死后患者中成功的I期临床试验。然而，这种方法并不适用于 治疗急性心肌梗死患者，因为与经血管内注射相关的安全性问题。因此，重要的 心脏的损伤和重塑将在患者甚至有资格接受这种治疗之前发生。相比 在急性MI患者中，经血管内输送、冠状动脉内输注可作为介入性 心脏病专家已经在做球囊血管成形术了因此，我们最近开发了一种新的不溶性形式， ECM（iECM），可通过冠状动脉内输注输送，以涂覆和填充受损血管的间隙， 治愈组织我们已经证明，在大鼠再灌注后立即给予这一药物是有效的 急性心肌梗死模型和中试猪研究。在急性心肌梗死中，我们假设iECM促进内皮细胞存活， 以及浸润免疫细胞向促重塑表型的极化，其沿着 已经证实血管通透性的降低导致心肌细胞存活率的提高。我们 初步结果为使用我们的新iECM技术治疗急性MI提供了强有力的支持。在这 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，目的是开发急性心肌梗死的新疗法。