title: The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice.
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 >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.
  
  
  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.
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. juliete@ualberta.ca
authors: Juliet A
authors: JA
authors: Emamaullee
authors: Joy
authors: J
authors: Davis
authors: Rena
authors: R
authors: Pawlick
authors: Christian
authors: C
authors: Toso
authors: Shaheed
authors: S
authors: Merani
authors: Sui-Xiong
authors: SX
authors: Cai
authors: Ben
authors: B
authors: Tseng
authors: A M James
authors: AM
authors: Shapiro
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D002096:C-Peptide / Q000097:blood; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006085:Graft Survival / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014185:Transplantation, Isogeneic
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D002096:C-Peptide; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D007328:Insulin; C484771:benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone; C064658:RAG-1 protein; D005947:Glucose