The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice

Abstract

Objective: Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of ≥60% of the transplanted islets in the peri-transplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes. EP1013 (zVD-FMK), is a broad spectrum caspase selective inhibitor with no observed toxicity in rodents.

Research Design and Methods: The therapeutic benefit of EP1013 was examined in a syngeneic rodent islet transplant model and using deceased donor human islets to determine if the amount of tissue required to restore euglycemia in diabetic animals could be reduced.

Results: EP1013 (combined pre-transplant islet culture for 2 hr and in vivo treatment for days 0-5 post-transplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses as compared to previous studies using the pan caspase inhibitor zVAD-FMK. EP1013 supplementation in vitro improved human islet yields following prolonged culture and reversed diabetes following implantation of a marginal human islet mass (80-90% reduction) into mice.

Conclusions: Our data suggests that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single donor infusion.