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: 10705265
• 负责人: Andres J Garcia
• 金额: $ 77.29万
• 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/10705265
• 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.

项目总结 1型糖尿病(T1D)是一种自身免疫性疾病，胰腺中产生胰岛素的β细胞 被毁了。T1D影响了美国300万儿童和成人，医疗成本超过150亿美元。 外源性胰岛素的标准治疗是繁重的，与低血糖的重大危险有关， 在预防长期并发症方面只有部分有效。同种异体胰岛移植的实验研究 身体供体联合慢性免疫抑制最近被证明是有效的 在临床试验中恢复正常血糖。然而，T1D细胞替代疗法的长期未来需要 一种可靠和可补充的β细胞来源，消除了慢性免疫抑制的需要。β细胞 来自人类多能干细胞(SC-β细胞)的细胞代表着一种变革性的、无限的胰岛素来源- 产生治疗T1D的细胞。尽管工程化功能性胰岛素产生SC-β取得了进展 细胞，与长期植入和功能相关的重要屏障，而不存在慢性免疫抑制 阻碍这些有希望的细胞的临床翻译。此外，使用封装设备来保护 移植细胞在大型动物模型中尚未成功，原因是纤维化反应和缺乏直接的 血管形成。我们的目标是设计先进的生物材料输送技术，以(I)增强 SC-β细胞的血管化、存活和植入，以及(Ii)保护它们免受免疫系统的排斥 不需要包埋或慢性免疫抑制。我们假设合成水凝胶与 血管生成和免疫调节信号的受控呈现将提供一种可注射的递送载体 它可以在没有慢性免疫抑制或包膜的情况下指导SC-β细胞的存活、植入和功能。 目的1：设计可注射的血管内皮生长因子输送水凝胶，以促进血管形成、存活和干细胞功能 将β细胞移植到糖尿病免疫受损小鼠的皮下空间。目标2：评估我们的SA- Fas L-微凝胶技术促进糖尿病患者SC-β细胞免疫接受性和免疫功能 人源化小鼠，没有慢性免疫抑制。目的3：检测血管内皮生长因子/SA-FasL的能力 水凝胶增强糖尿病非人类灵长类动物SC-β细胞的存活和功能 一项初步研究中的免疫抑制。这一极具意义和创新的战略从根本上是不同的 在设计先进的可注射生物材料方面正在进行的工作中促进SC-β细胞 血管形成、局部免疫接受、存活和功能，无需在设备或系统中进行封装 免疫抑制。此外，对人源化的小鼠和非人类灵长类动物模型的关注将 加快开发有效且广泛适用的治疗T1D的药物。