The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice

BackgroundIslet transplantation has become a viable option for selected type 1 diabetic patients; however, a significant portion need to return to exogenous insulin. The predominant factors include impaired islet engraftment and early islet loss. Caspase inhibition is a potent way to improve islet engraftment, but all tested compounds so far have not been clinically relevant. IDN-6556 (PF3491390) has already been used clinically and can be delivered orally with high portal vein concentrations.MethodsMice were given a marginal mass islet graft of either mouse or human islets and treated with either IDN-6556 (10 or 20 mg/kg ip bid) or vehicle and followed for diabetes reversal. At 1 month post-transplant, mice were subjected to a glucose tolerance test and an assessment of graft mass. In separate experiments, human islets were cultured with IDN-6556 or vehicle to assess for islet survival and viability.ResultsIn both syngeneic mouse islets and human islets transplanted into immunodeficient mice, IDN-6556 (20 mg/kg) given for 7 days post-transplant led to a significantly enhanced rate of diabetes reversal as compared to vehicle. In addition, mice receiving caspase inhibitor displayed improved glucose tolerance and graft survival at the 1-month point. We also found protective effects in vitro for islet viability and marked reduction in apoptosis in vivo.ConclusionTaken together, these results demonstrate the effectiveness of caspase inhibition with IDN-6556 on islet transplantation and in particular islet engraftment and survival.