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

• 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
• 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

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国家的主要死亡原因。心力衰竭（HF）发生于 20-30%的患者在心肌梗死（MI）后由于广泛瘢痕形成而加重， 梗死边缘区和远端心肌中的炎症巨噬细胞成倍增加。细胞因子 如白细胞介素-10（IL-10）和细胞因子抑制剂，如白细胞介素-1受体拮抗剂（IL-1 Ra）， 免疫调节剂，调节炎症，减少梗死面积，改善心室功能。然而，在这方面， 细胞因子治疗对患者的转化受到不良生物分布、毒性和矛盾的前体作用的限制。 持续给药的炎症反应。细胞治疗分泌的局部免疫调节 细胞因子有希望，但细胞存活率低（<1%）和体内效力降低仍然是关键障碍 防止临床转化。我们已经克服了这些关键的限制，开发了一个创新的， 本发明提供了一种翻译细胞治疗平台，其能够在MI后持续局部施用至心脏。我们有 工程化视网膜色素上皮（RPE）细胞以更生理相关的方式产生IL-1 Ra和IL-10， 以局部高浓度旁分泌方式存在，不会被全身吸收，并将其包裹在 基于海藻酸盐的核壳胶囊，保护它们免受宿主免疫系统的影响，并允许它们作为 一种可调节的原位细胞因子“工厂”。我们已经证明，局部递送调节炎症， 改善急性心肌梗死后的预后。在这个提议中，我们假设心外膜植入RPE-IL 10和 RPE-IL 1 Ra将维持MI后慢性炎症的减少并逆转心肌病性重塑， HF。在目标1中，将开发和优化RPE细胞囊系统，用于持续6个月分泌IL-10。 10和IL-1 Ra，并整合凋亡细胞安全开关以在给药后停止治疗。在目标2中， 这些IL-10和IL-1 Ra细胞因子工厂将被验证为慢性后炎症的单一或联合治疗。 通过证实心脏炎性体减少、促进修复性巨噬细胞来建立MI大鼠HF模型 表型和逆转不良心脏重塑。在目标3中，滴定和停止治疗后的能力 将在猪模型中评价以临床相关方式的植入。RPE治疗的疗效将是 在慢性猪梗塞模型中测试超过100天。这项拟议中的工作有望产生一种新的免疫 心肌梗死的调控策略，阐明细胞因子治疗心肌炎性小体的机制。 重要的是，开发的生物技术将准备进行临床前测试，并具有转化效益 除了单独的细胞因子之外，因为它可以用于广泛的蛋白质和局部药物递送，直接递送到 心