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

Emamaullee, Juliet A.
Davis, Joy
Pawlick, Rena
Merani, Shaheed
Cai, Sui-Xiong
Tseng, Ben
Shapiro, A M James
Published in Diabetes. 2008, vol. 57, no. 6, p. 1556-1566
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.
Keywords Amino Acid Chloromethyl Ketones/*pharmacologyAnimalsC-Peptide/bloodCaspases/*antagonists & inhibitorsEnzyme Inhibitors/*therapeutic useGlucose/pharmacologyGlucose Tolerance TestGraft Survival/*drug effectsHomeodomain Proteins/geneticsHumansInsulin/secretionIslets of Langerhans Transplantation/*physiologyMiceMice, Inbred BALB CMice, KnockoutTransplantation, Isogeneic
PMID: 18356409
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Research group Transplantation et hépatologie (905)
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EMAMAULLEE, Juliet A. et al. The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice. In: Diabetes, 2008, vol. 57, n° 6, p. 1556-1566. https://archive-ouverte.unige.ch/unige:19083

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Deposited on : 2012-03-27

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