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

Juliet A. Emamaullee, Joy Davis, Rena Pawlick, Christian Toso, Shaheed Merani, Sui Xiong Cai, Ben Tseng, A. M.James Shapiro

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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) signiflcantly 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-benzy-loxycabonyl-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.

Original languageEnglish (US)
Pages (from-to)1556-1566
Number of pages11
JournalDiabetes
Volume57
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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