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）： 意义和长期目的：慢性肾脏病（CKD）是一种导致需要长期血液透析或肾移植的终末期肾病（ESRD）的进行性疾病，全球有4亿人受累，美国有2600万人受累。在所有病例中，约50%的CKD由2型糖尿病（T2 DM）引起。CKD及其合并症构成了医疗保健系统的主要经济负担，阻碍了新疗法的开发以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，向大鼠施用同种异体的骨髓源性间充质干细胞（MSC）1）提供针对急性肾损伤（阿基）的肾保护，甚至具有潜在的CKD，和2）防止CKD的进展。这是通过MSC的抗炎和营养性抗凋亡、促有丝分裂和血管保护作用实现的。来自我们的I期临床试验的结果，其中有风险的心脏手术患者，其中大多数患有潜在的CKD，被施用MSC以预防术后阿基，证实了临床前研究的结果，并表明MSC施用是阿基以及进展为CKD和CKD本身的安全，有效的预防性治疗。II期临床试验目前正在招募研究受试者。因此，我们假设，同种异体MSC治疗有效地治疗了由第5/6肾切除术或T2 DM诱导的CKD大鼠（雄性Zucker，肥胖大鼠），阻止或减缓了CKD的进展。事实上，我们在大鼠中第5/6肾切除术CKD模型中的初步工作表明，在诱导CKD后早期或晚期给予MSC施用在不同程度上有效改善这种形式的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：目前的工作旨在充分研究成人干细胞治疗慢性肾脏病和潜在的糖尿病大鼠模型的治疗效用。具体来说，目标1。将测试和开发最佳的基于干细胞和晚期干细胞的干预方案，用于5/6肾切除或T2 DM导致的CKD大鼠;目的2，将阐明干细胞在5/6肾切除或T2 DM导致的CKD大鼠中的肾脏保护作用的介导机制;目标3将评估在5/6肾切除术诱导的CKD中发现最佳有效的治疗（具体目标1）是否在糖尿病Zucker大鼠的CKD中同样有效。研究设计和方法：具体目标1（SA）：使用大鼠5/6肾切除术CKD模型，通过随时间或在研究结束时监测GFR、蛋白尿、肾小球硬化、血压和其他变量的变化，确定在CKD过程早期和/或晚期给予的重复和不同静脉内细胞剂量的最佳治疗功效。SA 2：研究了SA 1研究中记录的与MSC治疗效果相关的介导机制，使用在阿基和其他器官损伤中鉴定的MSC的抗炎、抗纤维化、抗血栓形成和营养作用作为指导。MSC表达的单个治疗有效因子的重要性将通过敲低其在MSC中的表达（siRNA）或通过阻断其鉴定的作用机制来进一步证实。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展和/或进展。