Islet Transplantation with Chimeric Donor Pigs

嵌合供体猪的胰岛移植

• 批准号: 7447045
• 负责人: WILLIAM Edward BESCHORNER
• 金额: $ 44.7万
• 依托单位: XIMEREX, 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447045
• 关键词: Adolescent; Adult; Age; American; Animal Model; Antigens; Aorta; Cells; Child; Chronic; Clinical Trials; Competence; Condition; Confidential Information; Devices; Diabetes Mellitus; Digestion; Donor person; Dose; Early Diagnosis; Engraftment; Family suidae; Goals; Graft Rejection; Grant; Heart Transplantation; Hematopoietic; Human; Immune; Immune Tolerance; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Legal patent; Lymphocyte; Macaca mulatta; Medical center; Methods; Monitor; Opportunistic Infections; Organ; Organ Donor; Patients; Phase; Pilot Projects; Positioning Attribute; Primates; Procedures; Protocols documentation; Relative (related person); Risk; Role; Safety; Sheep; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Splenocyte; Sus scrofa; Technology; Tissue Donations; Tissues; Total Pancreatectomy; Transplantation; United States Food and Drug Administration; Xenograft procedure; diabetic; diabetic rat; fetal; graft failure; immune function; improved; islet; islet xenograft; nonhuman primate; pathogen; preclinical study; prevent; programs; prospective; transmission process

PROVIDED. More than 1 million Americans have type I (insulin dependent) diabetes. Transplantation of human islets, with the appropriate immune suppression, can provide a long-term insulin free cure. However, there is a severe shortage of human islet donors available, sufficient for only about 1000 transplants annually. Furthermore, chronic immune suppression could exclude this application to children. The transplantation of islets from donor pigs could resolve the shortage. However, with current technology, increased immune suppression would be needed to prevent rejection. Ximerex, Inc. has developed technology for transplantating pig xenografts while eliminating the need for severe immune suppression. By engrafting lymphocytes from the intended recipient within fetal pigs destined to become the donors, the transplant goals ofimmtme tolerance and tissue accommodation are achieved within the donor pig, prior to transplantation. The recipient is spared the risks associated with severe immune suppression. In a pilot study, we have cured two diabetic rhesus monkeys (total pancreatectomy) with pig islet transplants. They received minimal pretransplant immune suppression and no post-transplant suppression. The long term islet xenografts provided an insulin free state for both recipients. Using this propeitary technology, protected with a dominant patent position, Ximerex, Inc. would provide medical centers with islets and splenoeytes prepared from chimeric donor pigs for transplantation. This proposal will extend develop the technology and complete the definitive preelinical studies needed for clinical trials. The specific aims are to: Aim 1. Determine the donor factors responsible for prolonged pig xenograft acceptance. The relative roles of specific immune tolerance and pig tissue accommodation in prolonging pig islet xenograft acceptance will be determined. The critical dose of islets will be established. Aim 2. Improve Porcine Islet-Like Cell Cluster (PlCC)grafts to obtain the most rapid onset of robust euglycemia. A delay is typically observed in the maturation of the transplanted pig islet cell clusters. The function of the islet grafts will be enhanced with the goal of accelerating the maturation, leading to a cure of their diabetes. Aim 3. Develop a certifiable source herd of swine for tissue donation. Ximerex has preferred access to a unique herd of biomedical grade swine, monitored for 47 potential pathogens. The herd will developed appropriately for initial clinical trials. Aim 4. Develop protocols for post-transplant assessment of the islet cells and immune competence Improved methods for pig islet function and immune competence of the recipient will be developed. These will permit earlier detection of rejection or graft failure, and establish the safety of xenotransplantation with regards to risk of zoonotie or opportunistic infections.

假如。 超过100万美国人患有I型（胰岛素依赖性）糖尿病。人类胰岛的移植， 适当的免疫抑制可以提供长期的无胰岛素治疗。但是，严重短缺 人类胰岛供体可用，每年仅适用于大约1000次移植。此外，慢性免疫 抑制可以将此申请排除在儿童中。从供体猪的胰岛移植可以解决 短缺。但是，使用当前的技术，将需要增加免疫抑制以防止排斥。 Ximerex，Inc。开发了用于移植猪异种移植的技术，同时消除了严重的需求 免疫抑制。通过从胎猪中的预期接受者中雕刻淋巴细胞，注定要成为 捐助者，在供体猪内实现了IMMTME公差和组织适应的移植目标 移植。接收者免除了与严重的免疫抑制有关的风险。 在一项试点研究中，我们用猪胰岛移植治愈了两只糖尿病恒河猴（总胰腺切除术）。他们 接受了移植前的免疫抑制作用最少，没有移植后抑制。长期胰岛异种移植物 为两个接受者提供了无胰岛素的状态。 Ximerex，Inc。使用这种具有主导专利位置保护的Propoitary技术将提供医疗 用嵌合供体猪制备的胰岛和脾脏的中心进行移植。 该建议将扩大发展技术并完成临床所需的明确主管研究 试验。具体目的是： 目标1。确定负责长时间猪异种移植接受的供体因素。 特异性免疫耐受性和猪组织的相对作用在延长的猪胰岛异种移植物中 将确定接受。将建立胰岛的关键剂量。 AIM 2。改善猪胰岛样细胞簇（PLCC）移植物，以获得最快的稳定性开始 尤古西亚。 在移植的猪胰岛细胞簇的成熟中通常观察到延迟。胰岛的功能 随着加速成熟的目标，将增强移植物，从而可以治愈其糖尿病。 AIM 3。开发可认证的猪群来捐赠猪。 Ximerex优先使用了独特的生物医学级猪群，并监测了47种潜在病原体。这 牛群将适当开发用于初始临床试验。 目标4。制定胰岛细胞移植后评估和免疫能力的方案 将开发改进的猪胰岛功能的方法和受体的免疫能力。这些会 允许早期检测拒绝或移植失败，并在风险方面建立异种移植的安全性 zoonotie或机会性感染。