Hydrogel injection molded islet macroencapsulation devices to treat diabetes in a non-human primate model

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is a disease affecting approximately 1.7 million adults and children in the United States, and typically results in life-long dependence on injected insulin for survival. Clinical islet transplantation is a promising FDA approved alternative therapy for T1D, with the potential to reduce or eliminate secondary complications. However, islet transplantation has limited widespread application due to short-term transplant lifespans caused by poor graft vascularization, ineffective and toxic immunosuppressive drug regimens, and immune rejection. Newer stem cell-derived insulin secreting cell technologies will almost certainly be necessary to address patient accessibility concerns, but still pose significant potential safety concerns. Methods to eliminate graft rejection in the absence of chronic systemic immunosuppression and devices to isolate the graft from the patient and enable full graft retrieval will vastly expand the eligible patient population, reduce risks associated with this therapy, and are critical to translation of cell therapy for the treatment of T1D. Macroencapsulation in non-degradable hydrogel devices has been proposed as a means to address these limitations, but clinical success has been limited due to challenges with manufacturing complex device geometries with high surface area to volume (SA/V) ratios for adequate oxygen transport and long-term engraftment. To this end, ImmunoShield Therapeutics has recently developed a hydrogel injection molding-based method to generate high SA/V hydrogel macroencapsulation devices and has spent considerable time performing in silico, in vitro, and in vivo experiments, including in our Phase I project, to optimize this technology for islet macroencapsulation, which we have shown can reverse diabetes in preclinical small animal models. Hydrogel injection molding can generate macroencapsulated cell therapy devices with complex geometries faster (≥ 50%) and cheaper than other leading methods, with greater reliability and construct stability and integrity, and it is our expectation that commercialization of this technology will enable facile translation of regenerative medicine products from the laboratory to the clinic, including macroencapsulated islets or stem cell-derived insulin secreting cells. Therefore, in this Phase II project, we will evaluate hydrogel injection molded macroencapsulation devices for islet transplantation in non-human primate studies, with the goal of generating biocompatibility, toxicology, and CMC data for future FDA submissions. This will be achieved through (1) evaluating tissue remodeling responses to hydrogel injection molded macroencapsulation devices, (2) assessing macroencapsulated islet survival and host immune and metabolic responses to devices, and (3) demonstrating macroencapsulated islet function in a diabetic non-human primate model. Completion of this Phase II project will de-risk hydrogel injection molding technology and macroencapsulated cell therapies for type 1 diabetes, which will in turn attract Phase III funding to support commercialization efforts.