Stem Cell-Based Therapy of Chronic Kidney Disease

慢性肾脏病的干细胞疗法

• 批准号: 8821217
• 负责人: Christof Westenfelder
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821217
• 关键词: Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Address; Adipose tissue; Adult; Adverse effects; Affect; Albuminuria; Allogenic; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Blood Glucose; Blood Pressure; Bone Marrow; Cardiac Surgery procedures; Caring; Cell Therapy; Cells; Centers for Disease Control and Prevention (U.S.); Cholesterol; Chronic; Chronic Kidney Failure; Clinic; Clinical; Comorbidity; Complication; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Disease Progression; Disease model; Dose; End stage renal failure; Enrollment; Fatty acid glycerol esters; General Population; Goals; Guidelines; Health; Healthcare Systems; Heart Diseases; Hemodialysis; Hospitalization; Hypertension; Incidence; Individual; Infection; Injury; Intervention; Intravenous; Kidney; Kidney Transplantation; Lead; Mediator of activation protein; Medical; Mesenchymal Stem Cells; Modality; Modeling; Monitor; Myocardial Infarction; Nephrectomy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Population; Postoperative Period; Prevention; Proteinuria; Protocols documentation; Rat-1; Rattus; Renal function; Research; Research Design; Risk; Small Interfering RNA; Source; Staging; Stem cells; Stroke; Study Subject; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Translations; Treatment Efficacy; Treatment Protocols; Veterans; Work; World Health Organization; Zucker Rats; adult stem cell; base; clinical application; combat; cost; design; diabetic; effective therapy; epidemiologic data; experience; glomerulosclerosis; high risk; improved; knock-down; male; mortality; non-diabetic; novel; pre-clinical; preclinical study; prevent; protective effect; public health relevance; stem cell therapy; tool

DESCRIPTION (provided by applicant): SIGNIFICANCE and LONG-TERM OBJECTIVE: Chronic kidney disease (CKD), a progressive disorder that results in end stage renal disease (ESRD) requiring chronic hemodialysis or renal transplant, affects 400 million individuals globally and 26 million in the US. In ~50% of all cases CKD is caused by type 2 diabetes mellitus (T2DM). CKD and its comorbidities constitute a major financial burden to the health care system, warranting the development of new therapies to arrest or ameliorate the progression of the disease. Data obtained from this proposal are expected eventually to translate into clinical applications that will benefit those afflicted with CKD. RATIONALE and HYPOTHESES: We demonstrated that administration of allogeneic, bone marrow- derived mesenchymal stem cells (MSCs) to rats 1) affords renoprotection from Acute Kidney Injury (AKI), even with underlying CKD, and 2) prevents progression of CKD. This is achieved through MSC's anti- inflammatory and trophic anti-apoptotic, mitogenic and vasculoprotective actions. Results from our Phase I Clinical Trial, wherein at-risk cardiac surgery patients, the majority of whom had underlying CKD, were administered MSCs to prevent post-operative AKI, confirm those of preclinical studies, and indicate MSC administration is a safe, effective preventative therapy for AKI and both progression to CKD and of CKD itself. A Phase II Clinical Trial is currently enrolling study subjects. We hypothesize, therefore, that allogeneic MSC therapy effectively treats rats with CKD induced by 5/6th nephrectomy or T2DM (male Zucker, obese, rats), arresting or slowing the progression of CKD. Indeed, our preliminary work in the 5/6th nephrectomy CKD model in rats indicates that MSC administration given early or late post induction of CKD is effective, to variable degrees, in improving several manifestations of this form of CKD, i.e., systolic blood pressure, renal function, albuminuria and glomerular sclerosis. SPECIFIC AIMS: The present work is designed to fully investigate the therapeutic utility of adult stem cells for the treatment of CKD and underlying diabetes mellitus in rat models. Specifically, Aim 1. will test and develop optimal earl and late stem cell based intervention protocols in rats with CKD due to 5/6th nephrectomy or T2DM; Aim 2, will elucidate the mediator mechanisms that underlie the kidney protective effects of stem cells in rats with CKD caused by 5/6th nephrectomy or T2DM; and Aim 3 will assess whether the therapy found to be optimally effective in 5/6th Nephrectomy induced CKD (Specific Aim 1) is equally effective in CKD of diabetic Zucker rats. RESEARCH DESIGN and METHODS: Specific Aim 1 (SA): Using rat 5/6 nephrectomy CKD models, the optimal therapeutic efficacy of repeated and different intravenous cell doses, given early and/or late in the course of CKD will be determined by monitoring, over time or at study end, alterations in GFR, proteinuria, glomerulosclerosis, blood pressure, and other variables. SA 2: Mediator mechanisms that correlate with the therapeutic effects of MSCs that are documented in the studies of SA 1 are investigated, using as a guideline the anti-inflammatory, anti-fibrotic, anti-thrombotic and trophic actions of MSC that have been identified in AKI and other organ injuries. The importance of individual therapeutically effective factors expressed by MSCs will be further corroborated by knocking down their expression in MSCs (siRNA) or by blocking their identified mechanisms of actions. SA 3: It will be tested in male, obese, diabetic Zucker rats, whether MSC treatment improves blood sugar control per se and thereby the development of and/or progression of diabetic nephropathy.

描述（由申请人提供）： 意义和长期目标：慢性肾脏病 (CKD) 是一种进行性疾病，会导致需要长期血液透析或肾移植的终末期肾病 (ESRD)，影响着全球 4 亿人和美国 2,600 万人。约 50% 的 CKD 病例是由 2 型糖尿病 (T2DM) 引起的。 CKD 及其合并症对医疗保健系统构成了重大的经济负担，需要开发新疗法来阻止或改善疾病的进展。从该提案中获得的数据预计最终将转化为临床应用，使 CKD 患者受益。基本原理和假设：我们证明，对大鼠施用同种异体骨髓间充质干细胞 (MSC) 1) 可以提供对急性肾损伤 (AKI) 的肾脏保护，即使患有潜在的 CKD，2) 可以预防 CKD 的进展。这是通过 MSC 的抗炎和营养抗凋亡、促有丝分裂和血管保护作用来实现的。我们的 I 期临床试验的结果，其中大多数患有潜在 CKD 的高危心脏手术患者接受 MSC 治疗以预防术后 AKI，证实了临床前研究的结果，并表明 MSC 治疗是一种安全、有效的预防措施AKI 的治疗以及 CKD 进展和 CKD 本身的治疗。 II 期临床试验目前正在招募研究对象。因此，我们假设同种异体 MSC 疗法可以有效治疗 5/6 肾切除术或 T2DM 诱导的 CKD 大鼠（雄性 Zucker，肥胖大鼠），阻止或减缓 CKD 的进展。事实上，我们在大鼠 5/6 肾切除 CKD 模型中的初步工作表明，在 CKD 诱导后早期或晚期给予 MSC 给药在不同程度上有效改善这种形式 CKD 的几种表现，即收缩压、肾功能、蛋白尿和肾小球硬化。具体目标：目前的工作旨在全面研究成体干细胞在大鼠模型中治疗 CKD 和潜在糖尿病的治疗效用。具体来说，目标 1. 将在因 5/6 肾切除术或 T2DM 导致的 CKD 大鼠中测试和开发基于早期和晚期干细胞的最佳干预方案；目标 2，将阐明干细胞对 5/6 肾切除术或 T2DM 引起的 CKD 大鼠肾脏保护作用的中介机制；目标 3 将评估在 5/6 肾切除术诱发的 CKD 中最有效的疗法（具体目标 1）是否对糖尿病 Zucker 大鼠的 CKD 同样有效。研究设计和方法：具体目标 1 (SA)：使用大鼠 5/6 肾切除 CKD 模型，在 CKD 病程早期和/或晚期给予重复和不同静脉注射细胞剂量的最佳治疗效果将通过监测来确定，随着时间的推移或在研究结束时，GFR、蛋白尿、肾小球硬化、血压和其他变量的变化。 SA 2：以已确定的 MSC 的抗炎、抗纤维化、抗血栓和营养作用为指导，研究 SA 1 研究中记录的与 MSC 治疗效果相关的调节机制AKI 和其他器官损伤。间充质干细胞表达的个体治疗有效因子的重要性将通过敲低其在间充质干细胞（siRNA）中的表达或通过阻断其已确定的作用机制得到进一步证实。 SA 3：将在雄性、肥胖、糖尿病 Zucker 大鼠中测试 MSC 治疗是否改善血糖控制本身，从而改善糖尿病肾病的发生和/或进展。