Genetically-engineered pig organ transplantation in baboons: immunological and functional studies

狒狒基因工程猪器官移植：免疫学和功能研究

• 批准号: 10427408
• 负责人: DAVID KC COOPER
• 金额: $ 159.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427408
• 关键词: Antigen Targeting; Clinical Trials; Destinations; Doctor of Philosophy; Endothelial Cells; Ensure; Family suidae; Fat emulsion; Funding; Genes; Genetic; Genetic Engineering; Goals; Graft Survival; Growth Hormone Receptor; Heart; Heart Transplantation; Histopathology; Human; Immune response; Immunobiology; Immunologics; Immunology procedure; Infusion procedures; Innate Immune Response; Intervention; Kidney; Kupffer Cells; Life; Liver; Methods; Mitochondria; Modeling; Modification; Monitor; Myocardium; Organ; Organ Transplantation; Organ failure; Papio; Patients; Phagocytosis; Pharmacology; Preservation Technique; Primates; Procedures; Regimen; Renal function; Research; Science; Source; Techniques; Therapeutic; Therapeutic immunosuppression; Thrombocytopenia; Transgenes; Transplantation; Triiodothyronine; Work; Xenograft procedure; adaptive immune response; allotransplant; clinical application; genetic manipulation; graft failure; heart function; improved; liver function; liver transplantation; natural antibodies; nonhuman primate; novel; organ growth; organ injury; organizational structure; prevent; programs; rapid growth; success

GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES (PI/PD: David K.C. Cooper) OVERVIEW OF THE PROGRAM PROJECT SUMMARY/ABSTRACT Our program has produced genetically-engineered pigs that protect the pig organ from injury by the primate innate immune response. Organs transplanted from these pigs, together with an effective (and potentially clinically-applicable) immunosuppressive regimen, have markedly extended pig graft survival in baboons to months or even years. The current proposal aims to confirm that the combination of a multi-gene pig and an effective immunosuppressive regimen will allow consistent function of life- supporting pig kidneys (Project 1) and hearts (Project 3) for 6 months or longer, and of life-supporting livers for 1 month (to act as a bridge to liver allotransplantation [Project 2]). The work in the 3 Projects will be supported by 4 Cores. Core A (Pig Core) will provide specific multi-gene pigs (to Projects 1-3) that have 8 or more genetic manipulations that will help overcome the remaining barriers to moving towards clinical trials. Core B (Immunobiology Core) and Core C (Histopathology Core) will provide evidence of the mechanisms for the problems being investigated and the therapeutic approaches being explored. Core D (Administrative Core) will provide an organizational structure to facilitate the success of the proposed Projects. Our Aims include (i) exploring methods of preventing or suppressing the adaptive immune response through either novel pig genetics or pharmacologic interventions, (ii) preventing or reducing the thrombocytopenia that immediately follows pig liver transplantation in baboons, (iii) preventing or reducing the rapid growth of pig organs documented early after transplantation into baboons, and (iv) comprehensively monitoring function of the kidney, liver, and heart after transplantation into baboons in the presence of a controlled immune response (i.e., in the relative absence of an immune response). The mechanisms whereby the combination of genetic modification and refinements to the immunosuppressive regimen prolong graft survival will be investigated by immunological assays and histopathology techniques. Success in Projects 1 and 3 would allow immediate consideration of limited clinical trials of kidney and/or heart xenotransplantation. Success in Project 2 would allow immediate consideration of a limited clinical trial in which a pig liver is transplanted as a life-sustaining bridge to allotransplantation. The overall goal of the 3 projects, therefore, is to advance the science during this 5-year period of funding so that clinical trials of kidneys and hearts can be initiated as destination therapies (or, in the case of the heart, possibly initially as a bridging therapy), and of pig livers as bridging to allotransplantation.

狒狒中的遗传工程猪器官移植：免疫学 和功能研究（PI/PD：David K.C. Cooper） 该程序的概述 项目摘要/摘要 我们的计划生产了遗传工程的猪，可保护猪器官免受损伤 灵长类动物先天免疫反应。从这些猪移植的器官，有效 （并且潜在的临床上适用）免疫抑制治疗方案显着延长了猪移植 在狒狒到几个月甚至几年的生存。当前的提议旨在确认该组合 多基因猪和有效的免疫抑制方案将允许生命的一致功能 - 支撑猪肾脏（项目1）和心脏（项目3）6个月或更长时间，并支持生命 肝脏1个月（充当通往肝脏同种异体移植的桥梁[项目2]）。三个项目的工作 将得到4个核心的支持。 核A（猪核）将提供具有8个或更多遗传的项目的特定多基因猪（1-3个项目） 操纵将有助于克服朝着临床试验的剩余障碍。核心b （免疫生物学核心）和核心C（组织病理学核心）将提供有关机制的证据 正在研究的问题和正在探索的治疗方法。核心D（管理 核心）将提供组织结构，以促进拟议项目的成功。 我们的目标包括（i）探索预防或抑制适应性免疫的方法 通过新颖的猪遗传学或药理干预措施的反应，（ii）防止或减少 直接跟随狒狒猪肝移植的血小板减少症，（iii）预防或 减少移植到狒狒后尽早记录的猪器官的快速生长，（iv） 移植到狒狒中的肾脏，肝脏和心脏的全面监测功能 受控免疫反应的存在（即，在相对不存在免疫反应的情况下）。这 结合了遗传修饰和对遗传改进的机制 免疫抑制疗法延长移植物生存率将通过免疫学测定和 组织病理学技术。 项目1和3的成功将立即考虑肾脏的临床试验有限 和/或心脏异种移植。项目2的成功将允许立即考虑有限的 临床试验，其中猪肝脏被移植为具有生命的同种异体移植的桥梁。这 因此，这三个项目的总体目标是在这5年的资金期间推进科学 可以作为目的地疗法开始对肾脏和心脏进行的临床试验（或者在 心脏，最初可能是一种桥接疗法），并且是猪肝脏作为同种异体移植的桥接。