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: 10512947
• 负责人: Andres J Garcia
• 金额: $ 82.23万
• 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/10512947
• 关键词: 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; 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; base; cell replacement therapy; clinical translation; delivery vehicle; diabetes risk; diabetic; euglycemia; glycemic control; graft function; human pluripotent stem cell; human stem cells; humanized mouse; 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