Year 1

Currently, the shortage of donor organ tissue and risks associated with lifelong immunosuppression limit islet transplantation to only the most severely impacted brittle patients with diabetes. Thus, successful development of a universal cell therapy to treat diabetes requires a renewable safe source of glucose responsive human islet cells and a means for their delivery without the use of chronic immunosuppression. While human embryonic stem cells (hESCs) represent an excellent starting material for the generation of numerous islet cells, the clinical use of hESC-derived cell products is hampered by safety concerns over the potential growth of unwanted cell types and the formation of teratomas. A cell delivery system that allows for both segregation of the hESC-derived graft from host tissues and complete retrieval of the engrafted cells would provide an additional level of safety for hESC-derived cell therapies. The rationale behind this proposal, therefore, is to evaluate an immunoisolation device in combination with hESC-derived pancreatic progenitors as a means for the widespread treatment of diabetes without immunosuppression.
Immunoisolation involves the encapsulation of therapeutic graft cells in a membrane (essentially a sealed pouch) thereby protecting the graft from direct contact with the host immune cells and potentially reducing and/or eliminating the need for chronic co-administration of potent anti-rejection drugs for the life of the graft. The encapsulating membrane physically separates the graft cells from host tissues and vasculature. Therefore, to maintain viability and functional metabolism of the graft, the membrane must permit adequate diffusion of oxygen, nutrients, and waste-products, while also preventing exposure to host immune cells. Finally, an encapsulating membrane ideally allows for the timely delivery of insulin at levels that maintain safe and stable blood sugar levels.
Our hESC-derived pancreatic progenitor cells are first implanted and the cells complete their maturation to fully functional glucose-responsive islet cells several weeks after engraftment into a host animal. One of the notable achievements over the past year has been the demonstration that the encapsulation device can not only sustain the viability of the pancreatic progenitor cells, but also supports the maturation of those cells to fully functional glucose responsive endocrine tissue. We also have demonstrated that encapsulated grafts prevent the development of diabetes in animals that are treated with a toxin that selectively kills their endogenous pancreatic insulin producing beta cells. The encapsulated grafts maintained normal blood sugar levels in these animals, essentially functioning in place of their beta cells. Finally, all of the encapsulated grafts were fully contained in the interior of the device and there were no breached or ruptured devices observed, even when highly proliferative cells were encapsulated in the device. These results suggest that such an encapsulation device may be a viable system to safely deliver an hESC-derived cell therapy for diabetes.