Renal repair effects of senolytic preconditioned mesenchymal stromal cells in diabetic kidney disease

senolytic 预处理间充质基质细胞对糖尿病肾病的肾修复作用

基本信息

批准号：
10170555
负责人：
LaTonya J Hickson
金额：
$ 10.39万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-25 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170555
关键词：
Adipocytes Adipose tissue Affect Age Aging Albuminuria Allogenic Angiotensin II Anti-Inflammatory Agents Apoptotic Autologous Blood Blood flow CCL2 gene Cell Aging Cell Proliferation Cell Therapy Cell physiology Cells Chronic Disease Clinical Trials Collagen Type I Country Crohn&apos s disease DNA Damage Dasatinib Development Diabetic Nephropathy Disease Disease Progression Down-Regulation E-Cadherin Elements Epithelial Cells Excision Exhibits Fibrosis Flavonoids Functional disorder Future Genes Glucose Goals Harvest Health Human Hypertension Hypoxia Immune In Vitro Individual Inflammation Inflammatory Infusion procedures Injury to Kidney Intervention Kidney Kidney Diseases Kidney Failure Kidney Transplantation Lead Magnetic Resonance Imaging Measures Mediating Methods Microalbuminuria Modeling Mus Natural regeneration Oral Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Pilot Projects Progressive Disease Quercetin Randomized Refractory Regimen Renal function Renal tubule structure Research Design Resistance Safety Sampling Signal Transduction Stem cell transplant Testing Therapeutic Therapy Clinical Trials Therapy trial Transforming Growth Factor beta Translations Tyrosine Kinase Inhibitor Urine Work bench to bedside cytokine db/db mouse diabetic effective therapy epithelial to mesenchymal transition first-in-human glomerulosclerosis graft vs host disease immunoregulation improved in vivo injury and repair innovation kidney cell kidney preservation kidney vascular structure mesenchymal stromal cell mouse model non-diabetic novel open label paracrine pilot trial preconditioning prevent programs regenerative renal damage repaired response risk minimization safety testing senescence sex stem cell therapy stem cells tissue injury tissue regeneration

项目摘要

ABSTRACT / PROJECT SUMMARY Diabetic kidney disease (DKD), the leading driver of the global burden of kidney disease, is resistant to most treatment options. Thus, development of effective therapies to slow the progression of DKD is crucial. Mesenchymal stromal cells (MSC), approved for treating refractory inflammatory diseases elsewhere, possess paracrine anti-fibrotic, anti-apoptotic, pro-angiogenic and immunomodulatory regenerative activities, offering hope for DKD. Interim analyses from our Phase I clinical trial delivering patient-derived MSC in non- diabetic renovascular disease demonstrated safety, preserved kidney function, and improved kidney blood flow. In experimental DKD, MSC decrease glomerulosclerosis, microalbuminuria, inflammation and fibrosis. We wish to test the potential of patient-derived MSC therapy to minimize the risk of allosensitization or cell destruction with allogeneic stem cell treatment approaches. However, MSC from individuals with DKD may function suboptimally due to senescence. Cellular senescence, an irreversible arrest of cell proliferation, is induced by DNA damage and promotes inflammation, contributing to tissue injury and cell dysfunction. In our Phase I randomized, open label trial, we are currently testing the safety and efficacy of senolytics, drugs that clear senescent cells, to repair the health of MSC in individuals with DKD. Preliminary studies show reductions in senescent adipose cells and improved MSC function. However, it remains unclear whether these changes affect MSC reparative capacity on injured renal cells or in DKD. Our long-term goal is to promote the development of a novel cell-based therapy for DKD. We hypothesize that senolytic agents taken by subjects with DKD will improve the renal repair capacity of the patient’s own MSC, by enhancing anti- inflammatory, anti-fibrotic and pro-angiogenic paracrine activities. Using adipose-derived MSCs harvested from subjects with advanced DKD (eGFR 15-45 ml/min/1.73m2) in the ongoing senolytic therapy trial, the proposed project will: (1) Test the hypothesis that DKD MSCs from subjects treated in vivo with senolytics (SenDKD-MSC) will achieve greater reduction in inflammation and epithelial-to-mesenchymal transition (EMT) program in injured renal tubule epithelial cells (TEC) in vitro, via paracrine-mediated actions, as compared to untreated DKD-MSC. (2) Test the hypothesis that SenDKD-MSC infusion will exhibit greater potency vs. DKD-MSC in the repair of mouse kidneys in vivo, by reducing albuminuria, fibrosis, hypoxia, and inflammation in experimental DKD with angiotensin II-induced hypertension. These pilot studies will allow the assessment of senolytic-induced MSC renal repair effects in experimental DKD and enhance successful testing of a novel, senolytic MSC preconditioning strategy in human DKD. Significance and Impact: Cell-based therapy to delay DKD progression is very promising. Senolytic therapy may improve stem cell function and multiple aging-related conditions. Unravelling the mechanisms by which these novel interventions may work to synergistically regenerate the diabetic kidney could lead to successful large-scale clinical trials in the future.

摘要/项目摘要糖尿病肾病 (DKD) 是全球肾脏疾病负担的主要驱动因素，对大多数疾病都有抵抗力因此，开发有效的疗法来减缓 DKD 的进展至关重要。间充质基质细胞 (MSC) 已被批准用于治疗其他地方的难治性炎症性疾病，具有旁分泌抗纤维化、抗细胞凋亡、促血管生成和免疫调节再生活性，我们的 I 期临床试验为非 DKD 提供了希望，该试验提供患者来源的 MSC。糖尿病肾血管疾病表现出安全性、保留肾功能并改善肾血液在实验性 DKD 中，MSC 可以减少肾小球硬化、微量白蛋白尿、炎症和纤维化。我们希望测试患者来源的 MSC 疗法的潜力，以尽量减少同种异体致敏或细胞然而，来自 DKD 患者的 MSC 可能会被同种异体干细胞治疗方法破坏。细胞衰老是细胞增殖不可逆的停滞，导致功能欠佳。 DNA 损伤引起并促进炎症，导致组织损伤和细胞功能障碍。 I 期随机、开放标签试验，我们目前正在测试 senolytics 的安全性和有效性，这些药物清除衰老细胞，修复 DKD 患者 MSC 的健康状况。衰老脂肪细胞和间充质干细胞功能的改善然而，目前尚不清楚这些变化是否存在。影响 MSC 对受损肾细胞或 DKD 的修复能力。我们开发了一种新型的基于细胞的 DKD 疗法。 DKD 治疗将提高患者自身 MSC 的肾脏修复能力，通过增强抗使用脂肪来源的 MSC 发挥炎症、抗纤维化和促血管生成的旁分泌活性。从正在进行的 senolytic 治疗中的晚期 DKD（eGFR 15-45 ml/min/1.73m2）受试者中采集试验中，拟议的项目将：（1）检验以下假设：来自体内治疗的受试者的 DKD MSC senolytics (SenDKD-MSC) 将更大程度地减少炎症和上皮间质细胞通过旁分泌介导的作用，在体外损伤的肾小管上皮细胞（TEC）中进行过渡（EMT）程序， (2) 检验 SenDKD-MSC 输注将表现出更大的假设与 DKD-MSC 相比，通过减少白蛋白尿、纤维化、缺氧和体内修复小鼠肾脏的能力血管紧张素 II 诱导的高血压实验性 DKD 中的炎症这些试点研究将允许评估 senolytic 诱导的 MSC 对实验性 DKD 肾修复效果并增强成功率测试一种新型的 senolytic MSC 预处理策略在人类 DKD 中的意义和影响：基于细胞。 Senolytic 疗法可延缓 DKD 进展，并可改善干细胞功能。揭示这些新的干预措施可能发挥作用的机制。协同再生糖尿病肾脏可能会在未来带来成功的大规模临床试验。