Porcine marginal mass islet engraftment is facilitated by the caspase inhibitor IDN6556

M.D. McCall, A. Maciver, T. Kin, R. Pawlick, R. Edgar, A.M.J. Shapiro
University of Alberta, Edmonton, Canada

Objective: Strategies toprevent early post-transplant islet loss and to enhance islet engraftment areactively being sought. We have previously shown that the caspase inhibitorIDN6556 can enhance islet engraftment in a mouse model through prevention of apoptosis.IDN6556 is a promising candidate for clinical islet transplantation due to thehigh portal vein concentrations after oral administration. Here we aim tofurther study this compound in a large animal (porcine) islet transplant model.

Methods: Yucatanporcine were subjected to total pancreatectomy with marginal mass islet autotransplantation (1000-1500 IE/kg) into the portalvein. Pigs were treated with either IDN6556 20mg/kg orally bid (N=7) or vehicle(N=6) for one week post-transplant. Transplanted pigs were monitored as per ourpostoperative protocol including blood glucose sampling, insulinadministration, pain control and enoxaparin for thrombosis prophylaxis. At onemonth after islet transplantation, pigs underwent a glucose tolerance test andarginine stimulation to assess islet function. Liver samples were collected forhistology.

Results: There were nosignificant differences between the two groups with respect to cold ischemictime, islet viability, function or score. Pancreatectomy was complete in allcases (no insulin response to an arginine bolus after pancreatectomy). Pigsreceiving the caspase inhibitor displayed lower post-transplant daily bloodglucose levels and a significantly higher proportion achieved euglycemia (100%vs 33.3%, p<0.05 by Kaplan Meier). While there was no significant differencein glucose tolerance at one month, the group treated with IDN6556 displayed asignificantly higher acute insulin response to an arginine bolus (p<0.05).

Conclusion: The caspaseinhibitor IDN6556 improves marginal mass islet engraftment in a porcine modelof diabetes. This data, in combination with our prior small animal results,demonstrates the effectiveness of this compound in preserving the transplantedislet mass.