Emamaullee Juliet A, Davis Joy, Pawlick Rena, Toso Christian, Merani Shaheed, Cai Sui-Xiong, Tseng Ben, Shapiro A M James
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Diabetes. 2008 Jun;57(6):1556-66. doi: 10.2337/db07-1452. Epub 2008 Mar 20.
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.
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.
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.
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.
临床胰岛移植可使1型糖尿病患者实现胰岛素非依赖，但已观察到慢性移植物衰竭。这部分归因于移植后初期60%及以上的移植胰岛丧失，导致植入的胰岛数量不足。旨在使初始胰岛数量的存活率最大化的策略可能对改善长期临床结果产生重大影响。EP1013（N-苄氧羰基-缬氨酸-天冬氨酸-氟甲基酮[zVD-FMK]）是一种广谱半胱天冬酶选择性抑制剂，在啮齿动物中未观察到毒性。
在同基因啮齿动物胰岛移植模型中，使用已故供体的人胰岛来研究EP1013的治疗效果，以确定恢复糖尿病动物正常血糖所需的组织量是否可以减少。
与之前使用泛半胱天冬酶抑制剂N-苄氧羰基-缬氨酸-丙氨酸-天冬氨酸-氟甲基酮（zVAD-FMK）的研究相比，EP1013（移植前胰岛联合培养2小时并在移植后第0至5天进行体内治疗）即使在较低剂量下，也能显著改善同基因胰岛移植后小鼠边缘胰岛团的功能。体外补充EP1013可提高长时间培养后人胰岛的产量，并在将边缘人胰岛团（减少80 - 90%）植入小鼠后逆转糖尿病。
我们的数据表明，EP1013治疗将显著减少临床胰岛移植所需胰岛数量，提高单次供体输注后的胰岛素非依赖率。
