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Presenter: M.D., McCall, Edmonton, Canada
Authors: M.D. McCall, C. Toso, J.A. Emamaullee, R. Pawlick, R. Edgar, J. Davis, A. Maciver, T. Kin, A.M.J. Shapiro
The caspase inhibitor IDN6556 enhances marginal mass islet engraftment in a mouse model of diabetes
M.D. McCall1, C. Toso2, J.A. Emamaullee1, R. Pawlick1, R. Edgar1, J. Davis1, A. Maciver1, T. Kin1, A.M.J. Shapiro1
1 University of Alberta, Edmonton, Canada; 2 University of Geneva, Geneva, Switzerland
Objective: While up to 80% ofpatients may achieve insulin independence one year post islet transplant, mostpatients need to return to insulin by 3-5 years. Up to 60% of the transplanted b -cell mass islost to apoptosis within the first few days. This would imply thatanti-apoptotic interventions could enhance initial islet engraftment. Onecompound that has shown promise is IDN6556 (Conatus Pharmaceuticals), a broad-spectrumcaspase inhibitor. We aim to explore this new drug in a mouse islet transplantmodel before advancing to pre-clinical and clinical trials .
Methods: Balb/C mice were rendered diabetic usingstreptozotocin and transplanted with a marginal mass of syngeneic islets underthe kidney capsule. Mice were split into three groups and received one week of 1)IDN655610mg/kg or 2)20mg/kg or 3)vehicle. Blood glucose was monitored daily. Twentyfour hours after transplantation N=3 mice per group were sacrificed and grafts collectedfor TUNEL analysis. Four weeks post-transplant, graft function was assessedusing a glucose tolerance test. To assess islet survival the graft-bearingkidneys were removed and the graft insulin content measured. These transplantswere repeated using a marginal mass of human islets transplanted into B6 Rag-/-immunodeficient mice.
Results: Balb/C mice treated with 20mg/kgIDN6556 showed a significant improvement in obtaining euglycemia when receivinga syngeneic islet graft (62.3% euglycemic vs 16.1%, p<0.05). They also displayedimproved glucose tolerance and increased insulin content of their grafts. At 24hours after transplantation, there was substantially less apoptosis in thegroup receiving IDN6556 than in the control group (4.02% vs 51.12%, p<0.05).Immunodeficient mice receiving IDN656 and human islet grafts also showedsignificantly improved diabetes reversal (87.5% vs 30%, p<0.05) glucosetolerance and islet survival.
Conclusions: IDN6556 enhances marginal mass islet engraftmentthrough the prevention of early post-transplant apoptosis leading to improvedglucose tolerance and islet survival.
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