Protecting Pancreatic Islet Grafts from Rejection

保护胰岛移植物免遭排斥

• 批准号: 7208928
• 负责人: Uwe D. Staerz
• 金额: $ 99.94万
• 依托单位: ISOGENIS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208928
• 关键词: Adenoviridae; CD8 molecule; Macaca fascicularis; T lymphocyte; biotechnology; chemoprevention; diabetes mellitus therapy; gene delivery system; gene therapy; genetically modified animals; immunopharmacology; immunosuppressive; insulin dependent diabetes mellitus; laboratory mouse; nonhuman therapy evaluation; pancreatic islet transplantation; protein engineering; recombinant proteins; transfection /expression vector; transplant rejection; transplantation immunology

DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (DM) is an autoimmune disease that destroys insulin-producing cells of the pancreas. Type 1 DM affects an estimated one million Americans and usually finds its onset in the young. It is one of the leading causes of kidney disease, peripheral neurological diseases and also blindness. It shortens the lifespan primarily through premature cardiovascular mortality. It results in significant health care expenditures for patients, their families and society as a whole. Although blood glucose levels can be well controlled by insulin substitution therapy, some of the DM complications cannot. Therefore, reconstitution of normal pancreatic islet function has been an important DM treatment goal. This has included the transplantation of allogeneic pancreatic islets. Immune suppression protocols have been developed that allowed the successful transplantation of islets. Unfortunately, they are fraught with significant immediate and chronic side effects that make their use especially problematic for children. Presently, only patients suffering from unstable forms of DM are considered transplantation candidates. Isogenis' mission has been the development of innovative immune inhibitory agents that employ highly specific, yet effective immune suppression approaches. Isogenis based its technology on the natural veto immune inhibitory phenomenon. Isogenis uses viral vectors that transfer the CD8 a-chain and thus specific immune suppression to transplants. Isogenis already reached the crucial developmental milestone of proof-of-functional utility of its veto vector approach. Isogenis established that simple extracorporal veto vector transductions permanent protected pancreatic islets from rejection by fully allogeneic recipient animals. Isogenis now proposes to use a nonhuman primate model to test the functionality, pharmacology and toxicity of the clinical version of a veto vector and thus to complete the pre-clinical trial stage of veto vectors in pancreatic islet transplantation. In parallel, Isogenis will optimize protocols of veto vector production and purification and veto vector-based immune suppression regimens. These studies will allow Isogenis to collect data for the filing of an 'investigational new drug' (IND) with the 'Food and Drug Administration'. Type 1 diabetes mellitus (DM) is an autoimmune disease that destroys insulin-producing cells of the pancreas. Type 1 DM affects an estimated one million Americans and is one of the leading causes of kidney disease, peripheral neurological diseases and also blindness. Transplantation of pancreatic islets can provide a permanent cure. However, present immune suppression regimens used for organ transplantation are fraught with significant immediate and chronic side effects that make their use especially problematic for children. Isogenis is developing novel immune suppressive compounds that are less toxic,a are used short-term; yet prevent the rejection of transplanted tissue with similar if not improved efficacy.

描述(由申请人提供)： 1型糖尿病(DM)是一种自身免疫性疾病，会破坏胰腺的胰岛素分泌细胞。据估计，美国有100万人患有1型糖尿病，通常发病于年轻人。它是导致肾脏疾病、周围神经疾病和失明的主要原因之一。它主要通过过早的心血管死亡来缩短寿命。它导致患者、他们的家人和整个社会的巨额医疗支出。虽然血糖水平可以通过胰岛素替代疗法得到很好的控制，但一些糖尿病并发症却不能。因此，重建正常的胰岛功能一直是糖尿病治疗的重要目标。这包括同种异体胰岛的移植。已经开发出免疫抑制方案，使胰岛移植得以成功。不幸的是，它们充斥着严重的直接和慢性副作用，使它们的使用对儿童来说特别成问题。目前，只有患有不稳定形式的糖尿病的患者才被认为是移植对象。Isgenis的使命一直是开发创新的免疫抑制剂，采用高度特异但有效的免疫抑制方法。Isgenis的技术基于自然的否决权免疫抑制现象。异源病毒使用病毒载体，将CD8 a链转移到移植物上，从而产生特异性免疫抑制。Isgenis已经达到了其否决向量方法的功能实用证明的关键发展里程碑。Isgenis证实，简单的体外否决权载体转导永久保护胰岛免受完全同种异体受体动物的排斥反应。Isgenis现在建议使用非人类灵长类动物模型来测试临床版本的否决权载体的功能、药理和毒性，从而完成胰岛移植中否决权载体的临床前试验阶段。同时，Isgenis将优化否决权载体的生产和纯化方案，以及基于否决权载体的免疫抑制方案。这些研究将使Isgenis能够收集数据，以便向“食品和药物管理局”提交“研究用新药”(IND)。 1型糖尿病(DM)是一种自身免疫性疾病，会破坏胰腺的胰岛素分泌细胞。据估计，1型糖尿病影响着100万美国人，是导致肾脏疾病、周围神经疾病和失明的主要原因之一。胰岛移植可以提供根治方法。然而，目前用于器官移植的免疫抑制方案充满了显著的即时和慢性副作用，这使得它们的使用对儿童来说尤其成问题。Isgenis正在开发毒性较低的新型免疫抑制化合物，这种化合物可以短期使用，但可以防止移植组织的排斥反应，具有类似的效果，如果不是改善的话。