SBIR-STTR Award

Islet allotransplatation has been demonstrated to greatly reduce or eliminate the requirement for exogenous insulin injection in patients with insulin-dependent diabetes mellitus. This experimental procedure offers diabetic patients hope for improved blood glucose regulation and, consequently, a reduced risk of long-term complications of the disease. In order to circumvent the problem of human donor tissue availability, the use of animal tissue, particularly that from the pig, has been studied in combination with a technology such as microencapsulation to "immunoisolate" the cells and prevent xenograft rejection. MicroIslets Inc. is developing an improved method for preparation of microencapsulated porcine islet cells for the treatment of Type I diabetes. MicroIslet has used technology licensed from Duke as a basis for generating improved methodology for the isolation, conditioning, storage and microencapsulation of islet cells. Here, we outline new methodology for porcine islet isolation whereby 400,000 islets will be harvested per pancreas. Preliminary data demonstrate that a singe intraperitoneal (ip) injection of encapsulated porcine islet cells prepared using this technology resulted in maintenance of normal blood glucose levels (100-150 mg/dl) in a previously diabetic baboon for 14 months, without the need for additional insulin injections or potentially harmful immunosuppressive drugs to prevent graft rejection.

Thesaurus Terms:
biomedical automation, cell sorting, method development, pancreatic islet, tissue /cell preparation blood glucose, cell proliferation, cell transplantation, diabetes mellitus, diabetes mellitus therapy baboon, swine

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.

Thesaurus Terms:
diabetes mellitus, diabetes mellitus therapy, nonhuman therapy evaluation, pancreatic islet transplantation, therapy design /development, xenotransplantation Macaca mulatta, laboratory mouse, laboratory rat