Islet Protection from Hypoxia Posttransplant

描述（由申请人提供）：胰岛移植（ITx），特别是异种移植的新兴潜力，为1型糖尿病（T1 D）的治疗带来了重大希望。然而，在其更大规模、具有成本效益的应用之前，仍然存在重大挑战。缺氧是移植后的主要应激，估计会导致大约40-50%的移植胰岛死亡。有效保护移植的胰岛免受缺氧诱导的死亡（HID）有可能大大提高ITx的成功率。我们实验室的初步研究表明，α-和γ-生育酚及其琥珀酸酯在24小时内对猪和人胰岛提供了显著的保护作用。此外，当在移植前24小时开始注射α-和γ-生育酚时，将移植相同胰岛质量的裸鼠的治愈率提高了约70%。口服给药，如果有效，将提供一个首选的，更实际和更安全的替代注射。本I期STTR的目的是：（i）确定α-生育酚和γ-生育酚的琥珀酸酯（其可以作为注射或口服补充剂提供额外的优点）与相同和/或更低剂量的相应生育酚相比，当通过腹膜内注射施用给移植有猪胰岛的糖尿病裸鼠时，同样有效或更有效;和（ii）确定口服给药方案是否是注射的有效和有效的替代方案。由于α-和γ-生育酚和α-生育酚琥珀酸酯已被批准用于人类消费，因此如果该技术有效，则可以快速评估其安全性并将其纳入T1 D的临床治疗中。在第二阶段，有效的化合物将被配制用于稳定性，并在临床前胰岛移植模型中测试其功效，包括非人灵长类动物，这些模型在明尼苏达大学已经建立。所提出的工作的成功完成可能会导致一个显着的，潜在的突破性的贡献，在胰岛移植的发展作为一个安全和成本效益的治疗T1 D显着提高胰岛移植后的活力。公共卫生相关性：STTR可以产生非常安全的产品，大大提高胰岛移植的成功率。本品对促进胰岛移植治疗1型糖尿病的实用化具有深远的影响。除了提高这些患者的生活质量和生产力外，该产品还有助于降低医疗保健成本。

DESCRIPTION (provided by applicant): Islet transplantation (ITx), especially with the emerging potential of xenotransplantation, holds significant promise for the treatment of type 1 diabetes (T1D). There are, however, major challenges that remain prior to its larger scale, cost-effective application. Hypoxia is a leading stress post-transplantation and is estimated to cause the death of approximately 40-50% of transplanted islets. Effective protection of transplanted islets from hypoxia-induced death (HID) has the potential to greatly enhance the success rate of ITx. Preliminary research in our labs demonstrated that alpha- and gamma-tocopherol and their succinate esters offer remarkable protection to porcine and human islets from HID at 24 hrs. Furthermore alpha- and gamma-tocopherol, when administered by injection starting 24 h pretransplantation, improved the cure rates of nude mice transplanted with the same islet mass as untreated controls by ~70%. Oral administration, if effective, would provide a preferred, more practical and safer alternative to injections. The objectives of this Phase I STTR are to: (i) Determine whether the succinate esters of alpha- plus gamma-tocopherol (which may provide additional advantages either as injectable or oral supplements) are equally or more effective than the corresponding tocopherols at the same and/or a lower dose when administered by intraperitoneal injections to diabetic nude mice transplanted with porcine islets; and (ii) Determine whether an oral administration protocol is an effective and efficacious alternative to injections. Because alpha- and gamma-tocopherol and alpha-tocopheryl succinate are approved for human consumption, this technology, if effective, can be rapidly evaluated for safety and incorporated in the clinical treatment of T1D. In Phase II, the effective compounds will be formulated for stability and tested for efficacy in preclinical islet transplantation models including nonhuman primates, which are well established at the University of Minnesota. The successful completion of the proposed work may lead to a significant, potentially breakthrough contribution in the development of islet transplantation as a safe and cost effective therapy for T1D by markedly improving islet viability post-transplantation. PUBLIC HEALTH RELEVANCE: This STTR can lead to a very safe product, which increases substantially the success rate of islet transplantation. This product can have reaching effects in advancing the practical use of islet transplantation in treating Type 1 diabetes. In addition to improving the quality of life and productivity of these patients, this product can help reduce the cost of health care.