1. Academic Validation
  2. The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice

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

  • Surgery. 2011 Jul;150(1):48-55. doi: 10.1016/j.surg.2011.02.023.
Michael McCall 1 Christian Toso Juliet Emamaullee Rena Pawlick Ryan Edgar Joy Davis Allison Maciver Tatsuya Kin Robert Arch A M James Shapiro
Affiliations

Affiliation

Abstract

Background: Islet 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.

Methods: Mice 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.

Results: In 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.

Conclusion: Taken together, these results demonstrate the effectiveness of Caspase inhibition with IDN-6556 on islet transplantation and in particular islet engraftment and survival.

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