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 >or=60% of the transplanted islets in the peritransplant 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 (N-benzyloxycabonyl-Val Asp-fluoromethyl ketone [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 using deceased donor human islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS: EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0-5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (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 suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion.
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 >or=60% of the transplanted islets in the peritransplant 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 (N-benzyloxycabonyl-Val Asp-fluoromethyl ketone [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 using deceased donorhuman islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS: EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0-5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (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 suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion.
Authors: Catherine Hajmrle; Mourad Ferdaoussi; Gregory Plummer; Aliya F Spigelman; Krista Lai; Jocelyn E Manning Fox; Patrick E MacDonald Journal: Am J Physiol Endocrinol Metab Date: 2014-08-19 Impact factor: 4.310
Authors: Juliet A Emamaullee; Joy Davis; Rena Pawlick; Christian Toso; Shaheed Merani; Sui-Xiong Cai; Ben Tseng; A M James Shapiro Journal: Diabetes Date: 2010-03-23 Impact factor: 9.461
Authors: Undine Schubert; Janine Schmid; Susann Lehmann; Xian Y Zhang; Henning Morawietz; Norman L Block; Waldemar Kanczkowski; Andrew V Schally; Stefan R Bornstein; Barbara Ludwig Journal: Proc Natl Acad Sci U S A Date: 2013-01-23 Impact factor: 11.205