Background & Purpose

One of JDRF’s therapeutic goals is to restore beta cell function in type 1 diabetes (T1D) by replacement/transplantation of beta cells/islets. Pancreatic islet transplantation has been efficacious in selected patients in improving metabolic control and quality of life, and in preventing severe hypoglycemia in patients with medically unstable T1D. Despite improvements in cadaveric pancreas procurement, islet isolation, and islet purification, major scientific and technical challenges remain that must be addressed before beta cell replacement could be widely incorporated into the clinical management of established T1D; examples include: serious side effects from chronic immunosuppression, islet sensitivity to certain immunosuppressants, the insufficient human islet supply from cadaveric pancreata, and the desire for an alternative transplantation site. JDRF’s role is to enable the scientific community to address these challenges with the ultimate goal of developing safe and effective beta cell replacement approaches available to large numbers of individuals with T1D.

The yield and quality of cadaveric human islets remain variable, and the number of cadaveric pancreata cannot meet the demand of T1D patients. Porcine islets represent a readily available, scalable and better quality-controlled cell source. At the same time, many researchers and commercial entities have begun to position human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC) derived pancreatic progenitors or beta/islet cell preparations as potential cellular therapeutics for T1D. It is therefore expected that more than one clinically applicable, manufactured, replenishable beta/islet cell preparation will become a reality in the near future.

Despite great progress made in generating replenishable beta cell sources, the delivery method practiced by clinical islet transplantation today – intra-portal infusion – is not considered the most promising route of implantation for these new beta/islet cell preparations. It has been widely accepted that infusion of islets into the portal circulation significantly lowers the effective islet mass peritransplant and in long-term follow up. Many alternative transplantation sites have been studied, including the omentum, intra-muscle, subcutaneous space, spleen, bone marrow, kidney capsule, etc. with varying degrees of success. But some of these choices have practical limitations in the clinical setting, such as using the kidney subcapsule or the eye as a potential site. An ideal implantation method should accommodate the characteristics of these replenishable beta cell preparations for a safe and effective clinical treatment. Considerations for explant/re-implant needs and for the risks posed by potential teratoma formation suggest an implantation design that is retrievable. Additionally, future beta/islet cell preparations might be genetically engineered to impart immune privilege, resistance to cell stress, and suicide switches. The yet unknown consequences of genetic engineering on the cells may also demand an implantation design that is retrievable. Therefore JDRF is prioritizing development of a cell delivery vehicle that permits a clinically impactful cell dose and allows full retrieval of the implanted cells.