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The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

¹ Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
² Epicept, San Diego, California
³ Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada

Corresponding author: Juliet A. Emamaullee, PhD, 1074 Dentistry-Pharmacy Centre, Surgical Medical Research Institute, University of Alberta, Edmonton, AB T6G 2N8, Canada. E-mail: juliete{at}ualberta.ca

Abbreviations: AUC, area under the curve; CMRL, Connaught Medical Research Laboratories; IE, islet equivalent; IPGTT: intraperitoneal glucose tolerance test; zVAD-FMK: N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone; zVD-FMK, N-benzyloxycabonyl-Val Asp-fluoromethyl ketone

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 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.

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