Cell Based Immunomodulation to Promote Post-Infarct Myocardial Repair

基于细胞的免疫调节促进梗死后心肌修复

基本信息

批准号：
10586781
负责人：
RAVI K GHANTA
金额：
$ 70.75万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2022-12-10 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586781
关键词：
AP 1903 reagent Acute myocardial infarction Affect Alginates Animal Model Apoptotic Biodistribution Biological Biological Assay Biotechnology CASP9 gene Cardiac Cardiovascular system Catheters Cause of Death Cell Survival Cell Therapy Cell Transplantation Cell physiology Cells Chronic Cicatrix Clinical Combined Modality Therapy Congestive Heart Failure Contact Inhibition Cytometry Dose Encapsulated Endothelial Cells Endothelium Engineering Event Family suidae Fibroblasts Fibrosis Formulation Heart Heart failure Histology Human Hydrogels Image Immune Immune Evasion Immune response Immune system Immunomodulators Immunosuppression Implant In Situ Individual Industrialization Infarction Infection Inflammasome Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-10 Leukocytes Link Macrophage Magnetic Resonance Imaging Measures Modeling Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Pathologic Patients Pericardial body location Phenotype Physiological Population Pre-Clinical Model Preclinical Testing Proteins Rattus Recovery of Function Regulatory T-Lymphocyte Route Safety Structure of retinal pigment epithelium System Testing Therapeutic Time Tissues Titrations Toxic effect Translating Translations Ventricular Function Ventricular Remodeling Work absorption anakinra angiogenesis biomaterial compatibility capsule cell capsule clinical translation clinically relevant cytokine cytokine therapy design healing heart function immunomodulatory strategy immunoregulation implantation improved improved outcome in vivo inhibitor innovation insight ischemic cardiomyopathy local drug delivery nonhuman primate novel novel strategies paracrine porcine model prevent repaired response retina implantation secretory protein single-cell RNA sequencing small molecule subcutaneous success tissue repair

项目摘要

PROJECT SUMMARY Ischemic heart disease is the leading cause of death in the industrialized world. Heart failure (HF) develops in 20-30% of patients after myocardial infarction (MI) due to extensive scarring exacerbated by a persistent 2.9- fold increase of inflammatory macrophages in the infarct borderzone and remote myocardium. Cytokines, such as Interleukin-10 (IL-10), and cytokine inhibitors, such as Interleukin-1 receptor antagonists (IL-1Ra), are potent immune modulators that regulate inflammation, reduce infarct size, and improve ventricular function. However, translation of cytokine therapy to patients has been limited by poor biodistribution, toxicity, and paradoxical pro- inflammatory responses with sustained administration. Local immunomodulation with cell therapy secretion of cytokines holds promise, but poor cell survival (<1%) and reduced in vivo potency have remained critical barriers preventing clinical translation. We have overcome these critical limitations by developing an innovative and translational cell therapy platform that enables sustained locally administration to the heart after MI. We have engineered retinal pigment epithelial (RPE) cells to produce IL-1Ra and IL-10 in a more physiologically relevant paracrine fashion at high local concentrations without systemic absorption and have encapsulated them in alginate-based core-shell capsules, shielding them from the host immune system and allowing them to serve as a regulatable in situ cytokine “factories”. We have demonstrated that local delivery modulates inflammation and improves outcomes after acute MI. In this proposal, we hypothesize that epicardial implantation of RPE-IL10 and RPE-IL1Ra will sustain reductions in post-MI chronic inflammation and reverse cardiomyopathic remodeling in HF. In Aim 1, RPE cell capsule systems will be developed and optimized for sustained 6 month secretion of IL- 10 and IL-1Ra with integration of an apoptotic cell safety switch to cease therapy post-administration. In Aim 2, these IL-10 and IL-1Ra cytokine factories will be validated as mono- or combination therapies in a chronic post- MI rat HF model by confirming reduction of the cardiac inflammasome, promotion of reparative macrophage phenotypes, and reversal of adverse cardiac remodeling. In Aim 3, the ability to titrate and cease therapy post- implantation in a clinically relevant fashion will be evaluated in a porcine model. Efficacy of RPE therapy will be tested in a chronic porcine infarct model over 100 days. The proposed work is expected to result in a new immune modulatory strategy for MI and elucidate mechanisms of cytokine therapy on the cardiac inflammasome. Importantly, the developed biotechnology will be ready for pre-clinical testing and has translational benefit beyond cytokines alone, as it can be utilized for a wide range of protein and local drug delivery directly to the heart.

项目摘要缺血性心脏病是工业化世界中死亡的主要原因。心力衰竭（HF）发展在心肌梗塞（MI）后，有20-30％的患者由于持续的2.9-- 梗塞边界区域和远程心肌中炎症巨噬细胞的折叠增加。细胞因子，这样的如白介素-10（IL-10）和细胞因子抑制剂，例如白介素-1受体拮抗剂（IL-1RA），是有效的免疫调节剂可调节炎症，降低梗塞大小并改善心室功能。然而，细胞因子疗法对患者的翻译受到生物分布不良，毒性和矛盾的促进性的限制。通过持续给药的炎症反应。局部免疫调节，并通过细胞疗法分泌细胞因子有希望，但细胞存活不良（<1％）和体内效力降低仍然是关键的障碍防止临床翻译。我们通过开发创新和转化细胞疗法平台，使MI之后能够持续对心脏进行持续的持续给药。我们有工程性视网膜色素上皮（RPE）细胞在更相关的情况下产生IL-1RA和IL-10 旁分泌时尚以高局部浓度而没有全身性虐待，并将其封装在基于藻酸盐的核壳胶囊，将它们屏蔽到宿主免疫系统中，并允许它们作为受监管的原位细胞因子“工厂”。我们已经证明，本地分娩调节炎症，并且急性MI后改善结果。在此提案中，我们假设RPE-IL10和 RPE-IL1RA将减少MI后慢性炎症和反向心肌病重塑 HF。在AIM 1中，将开发和优化RPE细胞囊系统，以持续6个月的IL-分泌 10和IL-1RA，并将凋亡细胞安全转换整合到管理后停止治疗。在AIM 2中，这些IL-10和IL-1RA细胞因子因子将被验证为慢性后的单或联合疗法 Mi Rat HF模型通过确认心脏炎症体的减少，促进修复性巨噬细胞表型和不良心脏重塑的逆转。在AIM 3中，滴定和停止治疗的能力在以临床相关方式植入将在猪模型中评估。 RPE疗法的功效将是在100天内在慢性猪梗死模型中测试。预计拟议的工作将导致新的免疫力 MI和阐明心脏炎症体上细胞因子疗法机制的调节策略。重要的是，开发的生物技术将准备好进行临床前测试，并转化了好处仅除了细胞因子之外，可以将其用于广泛的蛋白质和局部药物直接递送到心。