The concept of islet allotransplantation as a treatment for Type I Diabetes has been demonstrated as feasible by the pioneering work done in Edmonton, Miami, Minneapolis, Philadelphia and other sites during the last five years. However, there still exists a considerable shortage of tissue for transplantation. The focus of Microlslet, Inc is to meet the increased demand for endocrine tissue by providing immune-isolated adult porcine islet xenografts. To date we have developed novel cold storage and islet processing solutions and generated modified islet culturing conditions. We have processed over 87 pancreata at the time of this writing and our average yields have increased to 437,000 q34,000 lEq per pancreas with approximately 90% purity (>90% successful islet isolation rate). Though not proposed in the Phase 1 aims, islets generated during Phase I of this proposal were encapsulated in 2 types of Ca2+-alginate microcapsules and were tested for function in two streptozotocin-induced diabetic mouse models. In 4 experiments, naked and encapsulated porcine islets were transplanted into the peritoneal cavities of 47 immunodeficient, diabetic mice (NOD/SCID). Animals received varying amounts of graft tissue ranging from 500 to 104 IE per animal, with a return to normoglycemia occurring in 100% of the animals within 2 days of transplantation. To date, these animals have maintained graft function for more than 6 months post-transplantation. In the second series of studies, encapsulated islets were transplanted into immune competent mice (C57BL/6) with a return to normoglycemia achieved within 2 days in 100% of animals without any immunosuppression. Presently, 3 groups of streptozotocin-induced diabetic C57BL/6 transplanted with islets coated with our core technology, a gelled-core Ca2+-alginate bead, where 40% of the animals have been normoglycemic for over 200 days. These data demonstrate that encapsulated adult porcine islets are functional and biocompatible when transplanted intraperitoneally in a diabetic rodent model. To ascertain whether this xenograft has the potential to function in humans, the next step is to test it in diabetic nonhuman primates, an established large animal preclinical model. Therefore, the objective of Phase II is to demonstrate the long-term function of encapsulated porcine islets in non-human primates.
SPECIFIC AIM 1 : Demonstrate the safety and efficacy of alginate microencapsulated pig islet xenografts in streptozotocin-induced diabetic non-human primates. The goal of Aim I is to determine the safety, efficacy and fate of adult porcine islet xenografts encapsulated in a proprietary alginate-based formulation, in diabetic rhesus macaques.
SPECIFIC AIM 2 : Qualification of methods and materials for islet isolation, microencapsulation and transplantation for END preparation. The objective of Aim 2 is to validate and qualify the methods and materials described by Good Laboratory Practice (GLP) standards in preparation for an Investigative New Drug/Device (IND) application.
