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

• 批准号: 10376342
• 负责人: Hongjun Wang
• 金额: $ 62.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10376342
• 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; Insulin; 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; 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; Time; Tissues; Transforming Growth Factor beta Receptors; Umbilical cord structure; United States; Wound healing therapy; adult stem cell; autoreactive B cell; base; clinical center; cytokine; experience; immune system function; immunoregulation; improved; insulin dependent diabetes mellitus onset; insulin secretion; islet; mRNA Expression; mouse model; participant enrollment; pre-clinical; preconditioning; preservation; receptor; regeneration potential; regenerative; response; safety and feasibility; standard of care; stem cell therapy; stem cells

: 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.

: 要治愈 1 型糖尿病 (T1D)，必须克服两个主要障碍：(i) 自身免疫反应和 (ii) 破坏胰岛素分泌胰岛/β 细胞，包括使用体外扩增的调节性 T 细胞改善免疫调节。 Tregs）或低剂量白介素-2（IL-2）可能能够抑制自身免疫，但免疫调节预计不会直接刺激 β 细胞的再生。间充质基质/干细胞（MSC）具有免疫调节和再生特性，是治疗自身免疫性疾病的一种有前途的新疗法。间充质干细胞是整形外科应用中公认的伤口愈合疗法，并且正在临床试验中进行测试，用于治疗自身免疫和炎症。我们小组和其他人发现，在自发性非肥胖糖尿病（NOD）小鼠体内输注后，间充质干细胞迁移到受损的胰腺中，瑞典的一项试点临床试验表明，随着 Tregs 的扩增/增殖，高血糖降低并减弱 Th1 免疫反应。单次输注自体骨髓来源的间充质干细胞可以维持新发 T1D 成年患者的胰岛素分泌。这项研究尚未在患者中进行系统测试。美国尚未有机制研究报道能够解释脐带间充质干细胞 (UC-MSC) 的益处，其具有更高的细胞产量、更少的侵入性采集过程以及更低的发病率，并且具有更强的免疫抑制和再生潜力，因此是一种流行的治疗方法。基于上述原则以及我们一年期 R01 资助中成功的患者入组，我们建议更新一项随机、双盲、安慰剂对照、单中心临床试验，以确定细胞疗法的来源。 UC-MSC 疗法对新发 T1D 患者的疗效我们的工作假设是，系统性施用新鲜体外扩增的 MSC 可以通过恢复免疫系统的正常功能和保存/改善胰腺 β 来减少糖尿病的进展并保持胰岛素分泌。我们将通过以下目标来检验这一假设：(i) 确定 MSC 疗法在纳入标准治疗后对新发 T1D 患者的安全性和有效性。 (ii) 定义保护机制并阐明 MSC 治疗对 T1D 患者疗效的生物标志物 我们的前 7 名 18-30 岁成年患者在 7 个月内进行了多次 MSC 试验，记录了 MSC 治疗的早期安全性。 MSCs 可能为 T1D 的治疗带来重要进展。