Protecting Pancreatic Islet Grafts from Rejection

保护胰岛移植物免遭排斥

• 批准号: 7488758
• 负责人: Uwe D. Staerz
• 金额: $ 99.81万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488758
• 关键词: Adverse effects; Affect; Allogenic; American; Animals; Autoimmune Diseases; Blindness; Blood Glucose; CD8B1 gene; Cardiovascular system; Cells; Child; Chronic; Clinical; Complications of Diabetes Mellitus; Data Files; Development; Diabetes Mellitus; Family; Goals; Graft Rejection; Health Expenditures; Homologous Transplantation; Immune; Insulin; Insulin-Dependent Diabetes Mellitus; Investigational Drugs; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Diseases; Longevity; Mission; Modeling; Organ Transplantation; Pancreas; Patients; Peripheral; Personal Satisfaction; Pharmacology; Production; Protocols documentation; Societies; Staging; Technology; Testing; Toxic effect; Transplantation; Transplanted tissue; Treatment Protocols; United States Food and Drug Administration; Viral Vector; base; improved; innovation; mortality; nervous system disorder; nonhuman primate; novel; pancreatic islet function; preclinical study; prevent; reconstitution; vector

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，会破坏胰腺产生胰岛素的细胞。 1 型糖尿病影响了大约 100 万美国人，通常发病于年轻人。它是导致肾脏疾病、周围神经系统疾病和失明的主要原因之一。它主要通过心血管疾病过早死亡来缩短寿命。它给患者、其家庭和整个社会带来巨额医疗保健支出。虽然胰岛素替代疗法可以很好地控制血糖水平，但某些糖尿病并发症却不能。因此，重建正常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移植。免疫抑制方案已经开发出来，可以成功移植胰岛。不幸的是，它们充满了显着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。目前，只有患有不稳定型糖尿病的患者才被视为移植候选者。 Isogenis 的使命是开发创新的免疫抑制剂，采用高度特异性且有效的免疫抑制方法。 Isogenis 的技术基于自然否决免疫抑制现象。 Isogenis 使用病毒载体转移 CD8 a 链，从而对移植物进行特异性免疫抑制。 Isogenis 已经达到了其否决向量方法的功能实用性证明的重要发展里程碑。 Isogenis 证实，简单的体外否决载体转导可永久保护胰岛免受完全同种异体受体动物的排斥。 Isogenis现提议使用非人灵长类动物模型来测试临床版veto载体的功能、药理学和毒性，从而完成veto载体在胰岛移植中的临床前试验阶段。与此同时，Isogenis 将优化否决载体生产和纯化方案以及基于否决载体的免疫抑制方案。这些研究将使 Isogenis 能够收集数据，以便向“食品和药物管理局”提交“研究性新药”(IND)。 1 型糖尿病 (DM) 是一种自身免疫性疾病，会破坏胰腺产生胰岛素的细胞。 1 型糖尿病影响了大约 100 万美国人，是导致肾脏疾病、周围神经系统疾病和失明的主要原因之一。胰岛移植可以提供永久性治愈。然而，目前用于器官移植的免疫抑制方案充满了显着的即时和慢性副作用，这使得它们的使用对于儿童来说尤其成问题。 Isogenis 正在开发新型免疫抑制化合物，毒性较小，可短期使用；但可以防止移植组织的排斥，即使没有改善，也具有类似的功效。