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，对1型糖尿病（T1D）的治疗具有重要的前景。然而，在大规模、经济有效地应用之前，仍存在重大挑战。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。有效保护移植胰岛免于缺氧性死亡（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小时内对猪和人的胰岛具有显著的保护作用。此外，从移植前24小时开始注射α -和γ -生育酚，可使移植胰岛质量相同的裸鼠的治愈率提高约70%。口服给药如果有效，将是比注射更可取、更实用和更安全的选择。第一阶段STTR的目的是：(I)确定α - + γ -生育酚琥珀酸酯（可作为注射或口服补充剂提供额外的优势）是否与相应的生育酚在相同和/或较低剂量下腹腔注射给猪胰岛移植的糖尿病裸鼠时相同或更有效；（二）确定口服给药方案是否为有效和有效的注射剂替代方案。由于α -和γ -生育酚以及α -生育酚琥珀酸酯已被批准用于人类消费，如果这项技术有效，可以快速评估其安全性并将其纳入T1D的临床治疗。在第二阶段，有效的化合物将用于稳定性和临床前胰岛移植模型的有效性测试，包括非人类灵长类动物，这些模型在明尼苏达大学已经建立。这项工作的成功完成可能会对胰岛移植的发展做出重大的、潜在的突破性贡献，通过显着提高胰岛移植后的活力，将胰岛移植作为一种安全、经济有效的T1D治疗方法。公共卫生相关性：这种STTR可以产生一种非常安全的产品，大大提高了胰岛移植的成功率。该产品对推进胰岛移植治疗1型糖尿病的实际应用具有深远的影响。除了提高这些患者的生活质量和生产力外，该产品还可以帮助降低医疗保健成本。

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.