The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice.
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.
Emamaullee
Juliet A
JA
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. juliete@ualberta.ca
Davis
Joy
J
Pawlick
Rena
R
Toso
Christian
C
Merani
Shaheed
S
Cai
Sui-Xiong
SX
Tseng
Ben
B
Shapiro
A M James
AM
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
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