Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients

自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能

基本信息

批准号：
10474572
负责人：
Hongjun Wang
金额：
$ 64.08万
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：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474572
关键词：
Address Adverse event Allogenic Animals Area Under Curve Autologous Autologous Transplantation Beta Cell Bone Marrow C-Peptide Cell Culture Techniques Cell Death Cell Survival Cells Clinical Research Clinical Trials Complement Factor B Complex Constitution Cyclic GMP Cytoprotection DNA Data Diabetes Mellitus Disease Dose Engraftment Enzyme-Linked Immunosorbent Assay Flow Cytometry Functional disorder Funding Gene Expression Goals Grant Growth Factor HGF gene Human Immune response Inflammatory Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Islets of Langerhans Transplantation Measures Mediator of activation protein Mesenchymal Mesenchymal Stem Cells MicroRNAs Modeling Nature Operative Surgical Procedures Patient Recruitments Patients Prevention Production Protocols documentation Quality of life Randomized Controlled Clinical Trials Research Rodent Safety Serum Testing Therapeutic Total Pancreatectomy Transforming Growth Factors Translating Transplant Recipients Transplantation United States National Institutes of Health base bench to bedside chemokine chronic pancreatitis cytokine effective therapy experience glycemic control improved insight islet molecular marker monocyte non-diabetic nonhuman primate pain relief paracrine patient population post-transplant primary endpoint response secondary endpoint single-cell RNA sequencing stem cell therapy stem cells transplant model

Address Adverse event Allogenic Animals Area Under Curve Autologous Autologous Transplantation Beta Cell Bone Marrow C-Peptide Cell Culture Techniques Cell Death Cell Survival Cells Clinical Research Clinical Trials Complement Factor B Complex Constitution Cyclic GMP Cytoprotection DNA Data Diabetes Mellitus Disease Dose Engraftment Enzyme-Linked Immunosorbent Assay Flow Cytometry Functional disorder Funding Gene Expression Goals Grant Growth Factor HGF gene Human Immune response Inflammatory Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Islets of Langerhans Transplantation Measures Mediator of activation protein Mesenchymal Mesenchymal Stem Cells MicroRNAs Modeling Nature Operative Surgical Procedures Patient Recruitments Patients Prevention Production Protocols documentation Quality of life Randomized Controlled Clinical Trials Research Rodent Safety Serum Testing Therapeutic Total Pancreatectomy Transforming Growth Factors Translating Transplant Recipients Transplantation United States National Institutes of Health base bench to bedside chemokine chronic pancreatitis cytokine effective therapy experience glycemic control improved insight islet molecular marker monocyte non-diabetic nonhuman primate pain relief paracrine patient population post-transplant primary endpoint response secondary endpoint single-cell RNA sequencing stem cell therapy stem cells transplant model

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项目摘要

Project Summary: Total pancreatectomy and islet autotransplantation (TP-IAT) are currently performed in around 20 centers worldwide for the treatment of chronic pancreatitis (CP). Major problems associated with TP-IAT are poor islet engraftment and dysfunction after intraportal infusion. Because of these issues, only around 20% of the non- diabetic CP patients are insulin-independent after surgery. Currently, interventional protocols to increase the survival of the islet graft following transplantation are empiric. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Multiple studies including our own demonstrate that islet co-transplantation with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia in rodent and nonhuman primate islet transplantation models. MSCs exert such effects mainly via direct cell-cell contact and their paracrine secretion of protective molecules including insulin growth factor-1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor β (TGF- β) and others. We are the first group who performed a pilot NIH-funded clinical trial evaluating the feasibility of autologous bone marrow-derived ex vivo-expanded MSCs (BM-MSCS) and islet co-transplantation in CP patients. Although only three subjects received MSC and islet co- transplantation due to the pilot nature of the grant, our data showed that BM-MSCs and islet co-transplantation was a safe and promising strategy to improve islet engraftment after transplantation. Based on this unique clinical trial experience and animal studies, the goal of this study is to further evaluate the safety and efficacy of autologous MSCs and islet co-transplantation in a larger TP-IAT patient population. Our hypothesis is that co- transplantation of islets with autologous BM-MSCs can enhance islet survival and function after transplantation, resulting in more CP patients being diabetes free after TP-IAT. A critical part of this trial will be to define the mechanisms by which MSCs modulate β cell survival and explore cellular and molecular biomarkers that can be used as indicator(s) for β cell death and the potential response/efficacy of MSC therapy. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but also may offer useful information on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes.

项目摘要：目前在大约20个中心进行胰腺切除术和胰岛自动移植（TP-AIT）全球治疗慢性胰腺炎（CP）。与TP-AIT相关的主要问题是较差的胰岛体内输注后植入和功能障碍。由于这些问题，只有大约20％的非 - 糖尿病性CP患者手术后独立于胰岛素。目前，介入方案以增加移植后胰岛移植物的存活是经验性的。那是可以促进胰岛的有效疗法迫切需要细胞植入和促进移植后的生存。多项研究，包括我们自己的证明，胰岛与间充质干细胞共转移（MSC）增强胰岛植入，减少在啮齿动物中实现正常血糖所需的胰岛数量非人类灵长类动物移植模型。 MSC主要通过直接细胞触点执行此类效果和它们对受保护分子的旁分泌分泌，包括胰岛素生长因子1（IGF-1），肝细胞生长因子（HGF），转化生长因子β（TGF-β）等。我们是第一个执行飞行员的小组 NIH资助的临床试验评估自体骨骨髓衍生的EX体内MSC的可行性 CP患者（BM-MSC）和胰岛共转移。尽管只有三名受试者获得了MSC和ISLET共同由于赠款的试验性质，我们的数据表明，BM-MSC和Islet共转移，我们的数据表明是一种安全且有希望的策略，可以在移植后改善胰岛植入。基于这个独特的临床试验经验和动物研究，本研究的目的是进一步评估较大的TP-IAT患者人群中的自体MSC和胰岛共转移。我们的假设是自体BM-MSC的胰岛移植可以增强移植后的胰岛存活和功能， TP-AIT后，越来越多的CP患者无糖尿病。该试验的关键部分是定义 MSC调节β细胞存活并探索可以是细胞和分子生物标志物的机制用作β细胞死亡的指标以及MSC治疗的潜在反应/疗效。这些结果迫切需要研究CP患者的手术后糖尿病，而且还需要研究提供有用的信息，以解决患者的更复杂的同种异体胰岛移植与1型糖尿病。