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

  1. Juliet A. Emamaullee1,
  2. Joy Davis1,
  3. Rena Pawlick1,
  4. Christian Toso1,
  5. Shaheed Merani1,
  6. Sui-Xiong Cai2,
  7. Ben Tseng2 and
  8. A.M. James Shapiro13
  1. 1Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
  2. 2Epicept, San Diego, California
  3. 3Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
  1. 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

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 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 20 March 2008. DOI: 10.2337/db07-1452.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 14, 2008.
    • Received October 11, 2007.
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  1. Diabetes vol. 57 no. 6 1556-1566
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