Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model.
BACKGROUND
Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model.


METHODS
Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month.


RESULTS
There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group.


CONCLUSIONS
IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation.
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. mmccall@ualberta.ca
Michael D
MD
McCall
Allison M
AM
Maciver
Tatsuya
T
Kin
Juliet
J
Emamaullee
Rena
R
Pawlick
Ryan
R
Edgar
A M James
AM
Shapiro
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D061945:Caspase Inhibitors; D005260:Female; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation; D023421:Models, Animal; D010421:Pentanoic Acids / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D014182:Transplantation, Autologous
C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D001786:Blood Glucose; D061945:Caspase Inhibitors; D007328:Insulin; D010421:Pentanoic Acids; D011480:Protease Inhibitors