Caspase Inhibitor IDN6556 Facilitates Marginal Mass Islet Engraftment in a Porcine Islet Autotransplant Model

Background. Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis,necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors inmouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, acaspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model.Methods. Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniatureswine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kgorally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitoredfor 1 month. Glucose tolerance and acute insulin release were determined at 1 month.Results. There were no differences in islet procurement, isolation, or islet functional parameters between the twogroups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage(100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolicreserve and acute insulin release for pigs in the treatment group.Conclusions. IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although thisstudy has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justifyearly clinical trials of IDN6556 in islet transplantation.Keywords: Islets, IDN6556, Engraftment, Caspase inhibitor.(Transplantation 2012;94: 30Y35)