Genetically-engineered Pig Organ Transplantation into Non-human Primates

基因工程猪器官移植到非人类灵长类动物中

• 批准号: 9115981
• 负责人: DAVID KC COOPER
• 金额: $ 40.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115981
• 关键词: Achievement; Address; Adhesives; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Attention; Attenuated; Biological Assay; Blood; Blood Coagulation Disorders; Blood Platelets; Cells; Clinical; Clinical Trials; Coagulation Process; Consensus; Ethics; Event; Failure; Family suidae; Functional disorder; Funding; Funding Mechanisms; Gene-Modified; Genes; Genetic; Genetic Engineering; Goals; Graft Survival; Heart; Heart Transplantation; Hemorrhage; Hour; Human; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Intervention; Investigation; Kidney; Kidney Transplantation; Laboratories; Life; Liver; Liver Failure; Lung; Maryland; Methods; Modeling; Modern Medicine; Modification; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Papio; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevention; Primates; Proteins; Reagent; Regimen; Residual state; Risk; Role; Selectins; Staging; TFPI; Technology; Testing; Thromboplastin; Tissues; Transgenes; Transplantation; Treatment Protocols; Work; Xenograft Model; Xenograft procedure; adaptive immunity; clinical application; experience; genetic manipulation; graft failure; heart xenograft; human tissue; improved; innovation; kidney xenograft; liver transplantation; liver xenograft; lung xenograft; member; nonhuman primate; novel; organizational structure; pre-clinical; prevent; programs; public health relevance; response; success; von Willebrand Factor

 DESCRIPTION (provided by applicant): The success of clinical transplantation is one of modern medicine's hallmark achievements. Unfortunately, a severe shortage of human organs, cells, and tissues constrains application of this life-saving technology. This RFA recognizes the potential for transplants from another species to humans (xenotransplantation) to fulfill the fields potential. For scientific and ethical reasons, a consensus has formed around discerning how to safely use pig organs for this purpose. Clinical application of pig-to-human xenografts is currently prevented by vigorous immunologic barriers. Major progress has been made over the past two decades to understand and overcome these barriers, with key contributions over the past 9 years from our Program and other NIAID Consortium members. Most importantly, our Program has produced pigs that express a large number of human proteins that each protects the pig organ from injury by the primate immune response. The lung xeno model has been particularly useful to demonstrate the value of each of these modifications, and to identify remaining problems. With a combination of three to six gene modifications to the pig, and a carefully tailored drug treatment regimen to the recipient, current results have advanced from minutes to hours (lung) or days (liver), with more significant progress for kidneys (from weeks to months) and hearts, where survivals past one and even two years have recently been accomplished by members of our consortium. Our proposals in response to the current RFA concentrate attention largely on the residual problem of the inflammatory response to pig organs. We shall explore methods of preventing or suppressing this response through either novel pig genetics or pharmacologic interventions. We will investigate transplantation of organs from these novel pigs, modifications to our already successful immunosuppressive regimen (in an effort to minimize infectious complications), and several anti-inflammatory agents that might allow consistent long-term (>6 months) pig kidney and heart graft survival, while significantly extending survival of livers and lungs. These studies will be carried out in our established kidney (Pittsburgh), heart (NHLBI), liver and lung (Maryland) models, with all of which we have many years' experience and expertise. The outcomes of our studies will be comprehensively evaluated by numerous laboratory assays, with all of which we have experience at one or more of our participating centers. We hypothesize that, within the 5-year funding period, this will enable consideration to be given to clinical trials of pig kidney, heart, and liver transplantation and will improve lung survival markedly.

 临床移植的成功是现代医学的标志性成就之一。不幸的是，人体器官、细胞和组织的严重短缺限制了这项拯救生命技术的应用。该RFA认识到从另一个物种移植到人类（异种移植）以实现该领域潜力的潜力。出于科学和伦理的原因，人们已经就如何安全地使用猪器官达成了共识。 猪-人异种移植物的临床应用目前受到强有力的免疫屏障的阻碍。在过去的二十年里，我们在理解和克服这些障碍方面取得了重大进展，在过去的九年里，我们的计划和其他NIAID联盟成员做出了重要贡献。最重要的是，我们的项目已经培育出了表达大量人类蛋白质的猪，每种蛋白质都能保护猪的器官免受灵长类免疫反应的伤害。肺异种模型已特别有用，以证明这些修改中的每一个的价值，并确定剩余的问题。通过对猪进行三到六次基因修饰，并为受体精心定制药物治疗方案，目前的结果已经从几分钟提高到几小时（肺）或几天（肝），肾脏（从几周到几个月）和心脏的进展更显着，我们的联盟成员最近已经完成了一年甚至两年的生存期。 我们针对当前RFA的建议主要集中在猪器官炎症反应的残留问题上。我们将探索通过新的猪遗传学或药物干预来预防或抑制这种反应的方法。我们将研究这些新猪的器官移植，对我们已经成功的免疫抑制方案的修改（以尽量减少感染并发症），以及几种抗炎剂，这些抗炎剂可能允许一致的长期（>6个月）猪肾和心脏移植物存活，同时显着延长肝脏和肺的存活。这些研究将在我们已建立的肾脏中进行 （匹兹堡），心脏（NHLBI），肝脏和肺（马里兰州）模型，我们拥有多年的经验和专业知识。我们的研究结果将通过大量实验室检测进行全面评价，我们在一个或多个参与中心都有经验。我们假设，在5年的资助期内，这将使猪肾脏，心脏和肝脏移植的临床试验得到考虑，并将显着提高肺存活率。