Hydrogels for human beta cell survival, function and evasion of immune rejection

用于人类β细胞存活、功能和逃避免疫排斥的水凝胶

• 批准号: 10865870
• 负责人: Andres J Garcia
• 金额: $ 8.27万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10865870
• 关键词: Acceleration; Adult; Affect; Animal Model; Autoimmune Diseases; Beta Cell; Biocompatible Materials; Blood Glucose; Body Weight; C-Peptide; Cadaver; Cell Survival; Cell Transplantation; Cell physiology; Cells; Child; Chronic; Clinical; Clinical Trials; Collagen; Complications of Diabetes Mellitus; Development; Devices; Disease; Encapsulated; Engineering; Engraftment; Fasting; Formulation; Future; Gel; Glucose tolerance test; Graft Survival; Health Care Costs; Homologous Transplantation; Human; Hydrogels; Hypoglycemia; Immune; Immune Evasion; Immune system; Immunocompetent; Immunocompromised Host; Immunologics; Immunology; Immunosuppression; Injectable; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Lead; Modeling; Monitor; Mus; Patients; Pilot Projects; Prevention; Risk; SCID Beige Mouse; Signal Transduction; Site; Source; Structure of beta Cell of islet; Technology; Translations; Transplantation; Vascular Endothelial Growth Factors; Vascularization; Work; cell replacement therapy; clinical translation; delivery vehicle; diabetes risk; diabetic; euglycemia; glycemic control; graft function; human pluripotent stem cell; human stem cells; humanized mouse; hypoglycemia unawareness; immunoregulation; improved; innovation; islet; mouse model; nephrotoxicity; nonhuman primate; prevent; response; stem cell biology; subcutaneous

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 (SC-β cells) represent a transformative, unlimited source of insulin- producing cells for the treatment of T1D. Despite advances in engineering functional insulin-producing SC-β cells, significant barriers related to long-term engraftment and function without chronic immunosuppression hinder the clinical translation of these promising cells. Furthermore, the use of encapsulation devices to protect transplanted cells has not been successful in large animal models due to fibrotic responses and lack of direct vascularization. Our objective is to engineer advanced biomaterial delivery technologies to (i) enhance vascularization, survival, and engraftment of SC-β cells and (ii) protect them from rejection by the immune system without the need for encapsulation or chronic immunosuppression. We hypothesize that synthetic hydrogels with controlled presentation of vasculogenic and immunomodulatory signals will provide an injectable delivery vehicle that directs SC-β cell survival, engraftment, and function without chronic immunosuppression or encapsulation. Aim 1: Engineer injectable VEGF-delivering hydrogels to promote vascularization, survival, and function of SC- β cells transplanted in the subcutaneous space of diabetic, immunocompromised mice. Aim 2: Evaluate our SA- FasL-microgel technology to promote SC-β cell immune acceptance and function in diabetic, immunocompetent humanized mice without chronic immunosuppression. Aim 3: Examine the ability of VEGF/SA-FasL hydrogels to enhance SC-β cell survival and function in diabetic nonhuman primates with no or reduced chronic immunosuppression in a pilot study. This highly significant and innovative strategy is fundamentally different from ongoing work in the field in terms of engineering advanced injectable biomaterials that promote SC-β cell vascularization, local immune acceptance, survival, and function without encapsulation in devices or systemic immunosuppression. Furthermore, the focus on humanized murine and nonhuman primate models will accelerate the development of an effective and broadly applicable cure for T1D.

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 T1D 影响了美国 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， 并且异体胰岛移植对于预防长期并发症仅部分有效。 最近证明，尸体捐献者与慢性免疫抑制相结合可有效 然而，从长远来看，T1D 细胞替代疗法需要恢复正常血糖。 可靠且可补充的 β 细胞来源，消除对慢性免疫抑制的需要。 源自人类多能干细胞（SC-β 细胞）代表一种革命性的、无限的胰岛素来源 尽管在工程化功能性胰岛素生产 SC-β 方面取得了进展。 细胞，与长期植入和功能相关的重大障碍，无需慢性免疫抑制 此外，使用封装装置来保护这些细胞的临床转化。 由于纤维化反应和缺乏直接的证据，移植细胞在大型动物模型中尚未成功。 我们的目标是设计先进的生物材料输送技术，以 (i) 增强血管化。 SC-β 细胞的血管形成、存活和植入，以及 (ii) 保护它们免受免疫系统的排斥 我们捕获了合成水凝胶，无需封装或长期免疫抑制。 血管生成和免疫调节信号的受控呈现将提供可注射的递送载体 指导 SC-β 细胞存活、移植和功能，无需长期免疫抑制或封装。 目标 1：设计可注射的 VEGF 递送水凝胶，以促进 SC-的血管化、存活和功能 β 细胞移植到患有糖尿病、免疫功能低下的小鼠的皮下空间中。 目标 2：评估我们的 SA-。 FasL-微凝胶技术可促进糖尿病、免疫功能健全患者的 SC-β 细胞免疫接受和功能 目的 3：检查 VEGF/SA-FasL 的能力。 水凝胶可增强糖尿病非人灵长类动物的 SC-β 细胞存活和功能，而慢性糖尿病无或减少 这项非常重要且创新的策略与试点研究中的免疫抑制有着根本的不同。 来自该领域正在进行的工程先进可注射生物材料促进 SC-β 细胞的工作 血管化、局部免疫接受、存活和功能，无需封装在装置或系统中 此外，对人源化鼠类和非人灵长类动物模型的关注将会增加。 加速开发有效且广泛适用的 T1D 治疗方法。

项目成果

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates.

生物工程网膜移植位点可促进非人类灵长类同种异体胰岛移植物的存活。

• 发表时间: 2023-03-21
• 作者: Deng, Hongping;Zhang, Alexander;Pang, Dillon Ren Rong;Xi, Yinsheng;Yang, Zhihong;Matheson, Rudy;Li, Guoping;Luo, Hao;Lee, Kang M;Fu, Qiang;Zou, Zhongliang;Chen, Tao;Wang, Zhenjuan;Rosales, Ivy A;Peters, Cole W;Yang, Jibing;Coronel, María M
• 通讯作者: Coronel, María M