Cellular Therapy for Type 1 Diabetes using Mesenchymal Stem Cells

使用间充质干细胞进行 1 型糖尿病的细胞疗法

基本信息

批准号：
10599910
负责人：
Hongjun Wang
金额：
$ 62.86万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599910
关键词：
Adult Aftercare Age Allogenic Area Under Curve Attenuated Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Autologous Beta Cell Biological Markers Bone Marrow C-Peptide CD80 gene CD86 gene Cell Count Cell Death Cell Therapy Cell physiology Cells Clinical Data Clinical Treatment Clinical Trials DNA Data Diabetes Mellitus Disease Dose Double-Blind Method Enrollment Fatty acid glycerol esters Funding Goals Grant Harvest Hyperglycemia Immune Immune response Immune system Immunosuppression Immunotherapy Inbred NOD Mice Inflammatory Infrastructure Infusion procedures Institution Insulin-Dependent Diabetes Mellitus Interdisciplinary Study Interleukin-2 Intervention Lupus MHC Class II Genes Measures Mesenchymal Mesenchymal Stem Cells Metabolic Morbidity - disease rate Natural regeneration Newly Diagnosed Pancreas Pancreatic Injury Patient Recruitments Patients Peripheral Blood Mononuclear Cell Placebo Control Placebos Plastic Surgical Procedures Procedures Proliferating Property Randomized Regulatory T-Lymphocyte Reperfusion Injury Reporting Running Safety Serious Adverse Event Serum Signal Transduction Source Structure of beta Cell of islet Sweden Testing Th2 Cells Therapeutic Tissues Transforming Growth Factor beta Receptors Umbilical cord structure United States Wound healing therapy adult stem cell autoreactive B cell clinical center cytokine efficacy evaluation experience immune system function immunoregulation improved insulin dependent diabetes mellitus onset insulin secretion islet mRNA Expression mouse model participant enrollment patient retention pre-clinical preconditioning preservation receptor regeneration potential regenerative response safety and feasibility standard of care stem cell expansion stem cell migration stem cell therapy stem cells

Adult Aftercare Age Allogenic Area Under Curve Attenuated Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Autologous Beta Cell Biological Markers Bone Marrow C-Peptide CD80 gene CD86 gene Cell Count Cell Death Cell Therapy Cell physiology Cells Clinical Data Clinical Treatment Clinical Trials DNA Data Diabetes Mellitus Disease Dose Double-Blind Method Enrollment Fatty acid glycerol esters Funding Goals Grant Harvest Hyperglycemia Immune Immune response Immune system Immunosuppression Immunotherapy Inbred NOD Mice Inflammatory Infrastructure Infusion procedures Institution Insulin-Dependent Diabetes Mellitus Interdisciplinary Study Interleukin-2 Intervention Lupus MHC Class II Genes Measures Mesenchymal Mesenchymal Stem Cells Metabolic Morbidity - disease rate Natural regeneration Newly Diagnosed Pancreas Pancreatic Injury Patient Recruitments Patients Peripheral Blood Mononuclear Cell Placebo Control Placebos Plastic Surgical Procedures Procedures Proliferating Property Randomized Regulatory T-Lymphocyte Reperfusion Injury Reporting Running Safety Serious Adverse Event Serum Signal Transduction Source Structure of beta Cell of islet Sweden Testing Th2 Cells Therapeutic Tissues Transforming Growth Factor beta Receptors Umbilical cord structure United States Wound healing therapy adult stem cell autoreactive B cell clinical center cytokine efficacy evaluation experience immune system function immunoregulation improved insulin dependent diabetes mellitus onset insulin secretion islet mRNA Expression mouse model participant enrollment patient retention pre-clinical preconditioning preservation receptor regeneration potential regenerative response safety and feasibility standard of care stem cell expansion stem cell migration stem cell therapy stem cells

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项目摘要

: Two major hurdles must be overcome to cure type 1 diabetes (T1D): (i) the autoimmune response and (ii) destruction of insulin-secreting islets/β cells. Immunotherapies, including improved immune regulation using ex vivo expanded regulatory T-cell (Tregs) or low-dose interleukin-2 (IL-2), may be able to suppress autoimmunity. However, immunomodulation is not expected to directly stimulate regeneration of β cells. On the other hand, mesenchymal stromal/stem cells (MSCs) possess both immunomodulatory and regenerative properties and represent a promising new intervention for autoimmune diseases. MSCs are an accepted therapeutic for wound healing in plastic surgery applications and are being tested in clinical trials for the treatment of autoimmune and inflammatory diseases, ischemia reperfusion injuries, diabetes and other diseases. Our group and others found that after infusion into spontaneous non-obese diabetic (NOD) mice, MSCs migrated into the injured pancreas, reduced hyperglycemia and attenuated Th1 immune responses concomitant with the expansion/proliferation of Tregs. Most importantly, MSC infusion led to increased mRNA expression of IL-2 and TGF-β receptors in pancreatic Treg cells in NOD mice. A pilot clinical trial in Sweden showed that a single infusion of autologous bone marrow-derived MSCs preserved insulin secretion in adult patients with new-onset T1D. This study has yet to be systemically tested in patients in the United States and no mechanistic studies have been reported that explain the benefit observed. MSCs derived from umbilical cord (UC-MSCs) show greater cell yield, a less invasive harvesting procedure with associated reduced morbidity, and stronger immunosuppressive and regenerative potential and are a popular source for cell therapy. Based on the above principles and the successful patient enrollment in our one-year R01 grant, we propose a renewal of a randomized, double-blind, placebo- controlled, single-center clinical trial to determine the efficacy of UC-MSC therapy in patients with new-onset T1D. Our working hypothesis is that systemic administration of MSCs freshly expanded ex vivo reduces progression of diabetes and preserves insulin secretion through restoring normal function of the immune system and preservation/improvement of pancreatic β cells in patients with T1D. We will test this hypothesis by the following aims: (i). Determine the safety and efficacy of MSC therapy in patients with new-onset T1D when added to standard-of-care, and (ii) Define the mechanisms of protection and elucidate biomarker(s) of efficacy of MSC therapy in T1D patients. The early safety of MSC therapy is documented in our first 7 adult patients age 18-30 enrolled over 7 months and from multiple MSC Trials for various diseases. MSCs may constitute an important therapeutic advancement for T1D.

：必须克服两个主要障碍，以治愈1型糖尿病（T1D）：（i）自身免疫反应和（ii）破坏胰岛素分泌胰岛/β细胞。免疫疗法，包括使用离体扩展的调节T细胞（TREG）或低剂量白介素-2（IL-2）改善免疫调节的免疫调节，可能能够抑制自身免疫性。然而，预期不会直接刺激β细胞再生。另一方面，间充质基质/干细胞（MSC）潜在的免疫调节和再生特性，代表了自身免疫性疾病的新干预。 MSC是整形外科手术中伤口愈合的一种接受疗法，正在临床试验中对自身免疫性疾病和炎症性疾病，缺血再灌注损伤，糖尿病和其他疾病进行测试。我们的小组和其他人发现，在输注自发性非肥胖糖尿病（点头）小鼠后，MSC迁移到受伤的胰腺中，减少了高血糖症并减轻了TH1免疫调查，与Tregs的扩张/增殖相关。最重要的是，MSC输注导致NOD小鼠胰腺Treg细胞中IL-2和TGF-β受体的mRNA表达增加。瑞典的一项试点临床试验表明，新发作T1D的成年患者中，单次输注自体骨髓衍生的MSC胰岛素分泌。这项研究尚未在美国的患者中进行系统的测试，尚无机械研究来解释观察到的好处。源自脐带（UC-MSC）的MSC显示出更大的细胞产量，侵入性的收集程序较少，且相关的发病率降低以及更强的免疫抑制和再生潜力，并且是细胞疗法的流行来源。基于上述原则和一年R01赠款的成功患者入学率，我们提出了一项随机，双盲，安慰剂对照的单中心临床试验的续签，以确定UC-MSC治疗对新发作T1D患者的有效性。我们的工作假设是，新鲜扩展的过扩展的MSC的系统给药可通过恢复免疫系统的正常功能以及T1D患者的胰腺β细胞的制备/改善，从而降低糖尿病的进展，并保留胰岛素分泌。我们将通过以下目的检验该假设：（i）。确定MSC治疗在添加到标准标准时，MSC治疗在新发行T1D患者中的安全性和有效性，（ii）定义了保护和阐明MSC治疗在T1D患者中有效性的生物标志物的机制。 MSC治疗的早期安全记录在我们的前7名成年患者中，18-30岁，在7个月内招收，以及多种MSC试验的各种疾病。 MSC可能构成T1D的重要治疗进步。