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.

提供了 超过100万美国人患有I型（胰岛素依赖型）糖尿病。人类胰岛移植， 适当的免疫抑制，可以提供一个长期的胰岛素免费治愈。然而，严重缺乏 人类胰岛捐赠者，每年仅够大约1000例移植。此外，慢性免疫 禁止可排除对儿童适用这一规定。供体猪胰岛移植可解决胰岛移植后的胰岛功能障碍。 短缺然而，在目前的技术下，需要增加免疫抑制来防止排斥反应。 Ximerex，Inc.已经开发出了移植猪异种移植物的技术，同时消除了严重的 免疫抑制通过将来自预期受体的淋巴细胞移植到注定成为 在供体猪中，在移植之前，在供体猪内实现了移植耐受性和组织适应性的目标。 移植接受者避免了与严重免疫抑制相关的风险。 在一项初步研究中，我们用猪胰岛移植治愈了两只糖尿病恒河猴（全胰腺切除术）。他们 接受最小的移植前免疫抑制和没有移植后抑制。长期异种胰岛移植 为两个接受者提供无胰岛素状态。 Ximerex，Inc.利用这项受主导专利地位保护的专有技术，将提供医疗 用嵌合供体猪制备的胰岛和脾细胞进行移植。 该提案将扩展开发技术并完成临床所需的确定性临床前研究。 审判具体目标是： 目标1.确定延长猪异种移植物接受的供体因素。 特异性免疫耐受和猪组织调节在延长猪胰岛移植中的相关作用 接受将被确定。将确定胰岛的临界剂量。 目标二。改善猪胰岛样细胞簇（PlCC）移植物，以获得最快的稳健起效 真的。 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 移植物将被增强，目标是加速成熟，从而治愈他们的糖尿病。 目标3。开发一个可认证的来源猪群用于组织捐赠。 Ximerex优先使用独特的生物医学级猪群，监测47种潜在病原体。的 将适当开发牛群用于初始临床试验。 目标4。制定移植后胰岛细胞和免疫能力评估方案 将开发用于猪胰岛功能和受体免疫能力的改进方法。这些将 允许早期检测排斥反应或移植失败，并确定异种移植的安全性， 人畜共患病或机会性感染。