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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：
10315988
负责人：
Hongjun Wang
金额：
$ 63.22万
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/10315988
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

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.

项目总结: