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.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，其中胰腺的胰岛素产生β细胞被破坏， 摧毁. T1 D影响美国300万儿童和成人，医疗费用超过150亿美元。 使用外源性胰岛素的标准治疗是繁重的，与低血糖的显著危险相关， 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 最近已经证明，尸体供体与慢性免疫抑制剂联合使用， 在临床试验中恢复Euclidin。然而，T1 D细胞替代疗法的长期未来需要 一种可靠的和易消化的β细胞来源，并且消除了对慢性免疫抑制的需要。β细胞 来源于人类多能干细胞（hPSC）的胰岛素是一种转化性的、无限的胰岛素来源， 产生用于治疗T1 D的细胞。然而，所得的细胞群体是异质的， 成熟的胰岛素产生细胞的发育是不一致的。此外，与长期- 长期植入和功能没有慢性免疫抑制阻止了这些有前途的应用。 细胞该项目的目标是工程生物材料，（i）促进人类的成熟和功能， 多能干细胞（hPSC）衍生的β细胞和（ii）保护它们免受免疫系统的排斥， 需要长期免疫抑制。假设具有最佳生物物理特性的合成水凝胶 和生物化学特性将提供指导hPSC衍生的β细胞成熟的物质平台， 植入和功能，而无慢性免疫抑制。目标1：设计合成水凝胶制剂 促进未成熟β细胞的存活、成熟和功能。目标2：评价工程水凝胶， 用于糖尿病免疫受损小鼠中β细胞移植的递送载体。目标3：工程师 免疫调节水凝胶在糖尿病患者中促进hPSC衍生的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。这种高度创新的新策略 从根本上不同于正在进行的工作，在该领域方面（i）工程材料，提供 微环境线索，以促进β细胞的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）移植到临床可转移的肝外部位 具有高血管形成和移植潜力，和（iii）在人源化小鼠中进行评估以提供 作为临床翻译的前奏。该项目将为翻译这本书提供重要的基础。 有前途的人类细胞来源，并将建立创新的材料，促进生存，植入， 人干细胞衍生的β细胞在免疫活性糖尿病宿主中的功能。