Development of a safer stem cell-based diabetes therapy via suicide gene-mediated ablation of proliferative cells

Project Summary/Abstract Diabetes represents a growing global health crisis. Despite continuous advancement in medical management of diabetes, achievement of good blood glucose control remains elusive for many patients. Evidence from patients who receive donor pancreas or islet transplants demonstrates that replenishment of pancreatic islets can restore euglycemia. Unfortunately, the relative scarcity of such organs, plus the lifelong burden of immunosuppression required for their maintenance, puts such therapy out of reach for a majority of diabetics. In this proposed project, Regenerative Medical Solutions (RMS) will build upon its success in generating pancreatic islet-like clusters (ILC) from genetically engineered induced pluripotent stem cells (iPSC) to produce a cell-based diabetes therapy that can be manufactured in abundant quantities, and that will not require immunosuppression for graft maintenance. Specifically, RMS will extend its partnership with Pluristyx, which has created an iPSC line (iACT) with two novel features: 1) the over-expression of 7 immunomodulatory transgenes which enable it to evade destruction by the host immune system without triggering a “missing self” response; 2) the integration of FailSafeTM technology, which facilitates the elimination of dividing cells from an engrafted cell population via the administration of the FDA-approved drug ganciclovir. The utility of the FailSafeTM system for elimination of proliferative cells from ILC grafts was demonstrated in our recently concluded SBIR Phase I project. In the current proposed project, RMS will work in partnership with the University of Wisconsin-Madison to demonstrate that ILC produced from iACT cells can restore euglycemia in a mouse model of diabetes, and that these ILC can evade rejection by the immune system of humanized mice. Further, RMS will demonstrate the utility of two independent methods of ensuring graft safety in vivo. First, the FailSafeTM system will be used to control undesired graft outgrowth in vivo while retaining graft function. Second, antibodies developed for cancer immunotherapy will be used to facilitate graft elimination by the immune system of humanized mice. Following completion of the proposed project, extension of RMS’s ongoing manufacturing partnership with Pluristyx will facilitate seamless transition toward cGMP production of the cell therapy and evaluation in IND-enabling studies.