BIOMATERIALS FOR STEM CELL-DERIVED BETA CELL TRANSPLANTATION

用于干细胞衍生的 β 细胞移植的生物材料

• 批准号: 10306891
• 负责人: Andres J Garcia
• 金额: $ 40.76万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306891
• 关键词: Address; Adhesives; Adult; Adverse effects; Affect; Autoimmune; Autoimmune Diseases; Beta Cell; Biochemical; Biocompatible Materials; Biophysics; Blood Glucose; Body Weight; C-Peptide; Cadaver; Cell Maturation; Cell Transplantation; Cell physiology; Cells; Characteristics; Child; Chronic; Clinical; Clinical Trials; Cues; Development; Diagnosis; Encapsulated; Engineering; Engraftment; Evaluation; Extrahepatic; Fasting; Fatty acid glycerol esters; Formulation; Foundations; Future; Gel; Glucose; Glucose tolerance test; Greater omentum; Health Care Costs; Hematopoietic stem cells; Homologous Transplantation; Human; Hydrogels; Hypoglycemia; Immune; Immune mediated destruction; Immune system; Immunocompetent; Immunocompromised Host; Immunology; Immunosuppression; Immunosuppressive Agents; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Ligands; Lymphocyte; Maleimides; Modeling; Monitor; Mus; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Permeability; Phase III Clinical Trials; Population; Signal Transduction; Site; Source; Structure of beta Cell of islet; Technology; Translations; Transplantation; Vascularization; Work; arm; base; cell replacement therapy; clinical translation; clinically translatable; diabetic; ethylene glycol; euglycemia; glycemic control; human embryonic stem cell; human embryonic stem cell transplantation; human pluripotent stem cell; human stem cells; humanized mouse; immunoregulation; improved; induced pluripotent stem cell; innovation; insulin secretion; islet; mechanical properties; mouse model; nonhuman primate; novel; novel strategies; prevent; stem cell biology; stem cells

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells of the pancreas are destroyed. T1D affects 3 million children and adults in the US with healthcare costs exceeding $15 billion. Standard therapy with exogenous insulin is burdensome, associated with a significant danger of hypoglycemia, and only partially efficacious in preventing long-term complications. Transplantation of allogeneic islets from cadaveric donors in conjunction with chronic immunosuppression has been recently shown to be effective in restoring euglycemia in clinical trials. However, the long-term future of cell replacement therapy for T1D requires a reliable and replenishable β-cell source and elimination of the need for chronic immunosuppression. β-cells derived from human pluripotent stem cells (hPSC) represent a transformative, unlimited source of insulin- producing cells for the treatment of T1D. However, the resulting cell population is heterogeneous and the development of mature insulin-producing cells is inconsistent. Furthermore, significant barriers related to long- term engraftment and function without chronic immunosuppression prevent the application of these promising cells. The objective of this project is to engineer biomaterials that (i) promote maturation and function of human pluripotent stem cell (hPSC)-derived β-cells and (ii) protect them from rejection by the immune system without the need for chronic immunosuppression. It is hypothesized that synthetic hydrogels with optimal biophysical and biochemical characteristics will provide a material platform that directs hPSC-derived β-cell maturation, engraftment and function without chronic immunosuppression. Aim 1: Engineer synthetic hydrogel formulations that promote survival, maturation, and function of immature β-cells. Aim 2: Evaluate engineered hydrogels as delivery carriers for β-cell transplantation in diabetic, immunocompromised mice. Aim 3: Engineer immunomodulatory hydrogels to promote hPSC-derived β-cell immune-acceptance and function in diabetic, immunocompetent humanized mice without chronic immunosuppression. This highly innovative novel strategy is fundamentally different from ongoing work in the field in terms of (i) engineering materials that provide microenvironmental cues to promote maturation of β-cells and local immune acceptance to eliminate the need of chronic systemic immunosuppressive drugs, (ii) transplantation into a clinically-translatable extrahepatic site with high vascularization and engraftment potential, and (iii) evaluation in humanized mice to provide proof-of- efficacy as a prelude to clinical translation. This project will provide a significant foundation for translation of this promising human cell source and will establish innovative materials that promote survival, engraftment, and function of human stem cell-derived β-cells in immunocompetent diabetic hosts.

项目概要 1 型糖尿病 (T1D) 是一种自身免疫性疾病，其中胰腺中产生胰岛素的 β 细胞受到影响 被毁了。 T1D 影响美国 300 万儿童和成人，医疗费用超过 150 亿美元。 外源性胰岛素的标准治疗是繁重的，与低​​血糖的显着危险相关， 并且在预防长期并发症方面仅部分有效。同种异体胰岛移植 最近证明，尸体捐献者与慢性免疫抑制相结合可有效 在临床试验中恢复正常血糖。然而，从长远来看，T1D 细胞替代疗法需要 可靠且可补充的 β 细胞来源，消除慢性免疫抑制的需要。 β细胞 源自人类多能干细胞 (hPSC) 代表了一种革命性的、无限的胰岛素来源 生产用于治疗 T1D 的细胞。然而，所得的细胞群是异质的，并且 成熟的胰岛素生成细胞的发育不一致。此外，与长期相关的重大障碍 没有长期免疫抑制的足月植入和功能阻碍了这些有前途的应用 细胞。该项目的目标是设计生物材料，以（i）促进人类的成熟和功能 多能干细胞 (hPSC) 衍生的 β 细胞，并且 (ii) 保护它们免受免疫系统的排斥，而无需 需要长期免疫抑制。据推测，具有最佳生物物理特性的合成水凝胶 和生化特性将提供一个指导 hPSC 衍生的 β 细胞成熟的材料平台， 无需慢性免疫抑制即可植入和发挥功能。目标 1：设计合成水凝胶配方 促进未成熟 β 细胞的存活、成熟和功能。目标 2：评估工程水凝胶 用于糖尿病、免疫功能低下小鼠的 β 细胞移植的递送载体。目标 3：工程师 免疫调节水凝胶可促进糖尿病患者的 hPSC 衍生 β 细胞免疫接受和功能 没有慢性免疫抑制的免疫活性人源化小鼠。这一极具创新性的新颖策略 与该领域正在进行的工作在以下方面有根本不同：(i) 提供的工程材料 微环境线索促进 β 细胞成熟和局部免疫接受，以消除需要 慢性全身性免疫抑制药物，(ii) 移植到临床可移植的肝外部位 具有高血管化和植入潜力，以及（iii）在人源化小鼠中进行评估以提供证据- 疗效作为临床转化的前奏。该项目将为该书的翻译奠定重要基础。 有希望的人类细胞来源，并将建立促进存活、移植和移植的创新材料 人类干细胞衍生的 β 细胞在免疫功能正常的糖尿病宿主中的功能。