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: 10557968
• 负责人: Andres J Garcia
• 金额: $ 7.98万
• 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/10557968
• 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.

项目摘要 1型糖尿病（T1D）是一种自身免疫性疾病，胰腺产生胰岛素的β细胞为 被摧毁。 T1D在美国影响300万儿童和成人，其医疗保健费用超过150亿美元。 外源胰岛素的标准疗法是燃烧的，与低血糖的显着危险有关 并且仅部分有效地预防长期并发症。从同种异体胰岛移植 尸体供体与慢性免疫抑制结合最近已被证明是有效的 在临床试验中恢复尤利克血症。但是，T1D细胞替代疗法的长期未来需要 可靠且可复制的β细胞源，并消除了对慢性免疫抑制的需求。 β细胞 源自人多能干细胞（HPSC）代表胰岛素 - 胰岛素的无限来源 产生用于治疗T1D的细胞。但是，由此产生的细胞群是异质的， 成熟胰岛素产生细胞的发展是不一致的。此外，与长期有关的重大障碍 术语植入和功能没有慢性免疫抑制阻止这些承诺的应用 细胞。该项目的目的是设计（i）促进人类成熟和功能的生物材料 多能干细胞（HPSC）衍生的β细胞，（ii）保护它们免受免疫系统的排斥，而没有免疫系统 需要慢性免疫抑制。假设具有最佳生物物理的合成水凝胶 生化特征将提供一个材料平台，该平台指导HPSC衍生的β细胞成熟， 没有慢性免疫抑制的植入和功能。目标1：工程师合成水凝胶配方 目标2：评估工程水凝胶为 糖尿病，免疫功能低下的小鼠中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HPSC衍生的β细胞免疫感受和糖尿病的功能， 没有慢性免疫抑制的免疫能力人性化小鼠。这种高度创新的小说策略 从（i）提供的工程材料方面，与现场正在进行的工作根本不同 微环境提示以促进β细胞的成熟和局部免疫接受度以消除需求 慢性系统性免疫抑制药物，（ii）移植到临床上可转移的e脚神经部位 具有高血管形成和锻炼潜力，以及（iii）人源化小鼠的评估，以提供证明 作为临床翻译的前奏的功效。该项目将为翻译提供重要的基础 有希望的人类细胞来源，并将建立创新的材料，以促进生存，植入和 人类干细胞衍生的β细胞在免疫能力糖尿病宿主中的功能。