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Principal Investigator: Andres J Garcia
Organization: GEORGIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $82,702
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <0-11 years old><21+ years old><Acceleration><Adult><Adult Human><Affect><Allogeneic Transplantation><Animal Model><Animal Models and Related Studies><Autoimmune Diseases><Beta Cell><Biocompatible Materials><Biomaterials><Blood Glucose><Blood Sugar><Body Weight><Brittle Diabetes Mellitus><C-Peptide><Cadaver><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Transplantation><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Children (0-21)><Chronic><Clinical><Clinical Trials><Collagen><Complications of Diabetes Mellitus><Development><Devices><Diabetes Complications><Diabetes-Related Complications><Diabetic Complications><Disease><Disorder><Encapsulated><Engineering><Engraftment><Fasting><Formulation><Future><Gel><Glucose tolerance test><Graft Survival><Health Care Costs><Health Costs><Healthcare Costs><Homologous Transplantation><Human><Humulin R><Hydrogels><Hypoglycemia><IDDM><IPGTT><Immune><Immune Evasion><Immune system><Immunes><Immunochemical Immunologic><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Immunomodulation><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Injectable><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Islands of Langerhans Transplantation><Islands of Pancreas Transplantation><Islets of Langerhans Grafting><Islets of Langerhans Transplantation><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Lead><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><Nephrotoxic><Novolin R><Pancreatic Islets Transplantation><Pancreatic beta Cell><Pancreatic β-Cell><Patients><Pb element><Pilot Projects><Prevention><Regular Insulin><Risk><SCID Beige><SCID Beige Mouse><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Structure of beta Cell of islet><Subcellular Process><Sudden-Onset Diabetes Mellitus><T1 DM><T1 diabetes><T1D><T1DM><Technology><Translations><Transplantation><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><VEGF><VEGFs><Vascular Endothelial Growth Factors><Vascularization><Vasculogenic><Work><adulthood><autoimmune condition><autoimmune disorder><autoimmunity disease><autologous islet transplantation><biological material><biological signal transduction><cadaveric><cadavers><cell replacement therapy><cell replacement treatment><cellular transplant><clinical translation><clinically translatable><connecting peptide><delivery vector><delivery vehicle><developmental><diabetes risk><diabetic><euglycemia><fasted><fasts><glycemic control><graft function><heavy metal Pb><heavy metal lead><human pluripotent stem cell><human progenitor><human stem cells><humanized mice><humanized mouse><hypoglycemia unawareness><hypoglycemic><hypoglycemic episodes><immune competent><immune evasive><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><innovate><innovation><innovative><insulin dependent diabetes><insulin dependent type 1><intraperitoneal glucose tolerance test><islet><islet auto transplantation><islet beta cell transplantation><islet cell transplant><islet cell transplantation><islet transplantation><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><kidney toxicity><kids><model of animal><mouse model><murine model><nephrotoxicity><non-human primate><nonhuman primate><pancreas beta cell><pancreas β cell><pancreatic b-cell><pilot study><prevent><preventing><progenitor biology><progenitor cell biology><response><stem and progenitor biology><stem cell biology><subcutaneous><subdermal><translation><transplant><type I diabetes><type one diabetes><youngster><β-cell><β-cells><βCell>