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: 10621195
• 负责人: DAVID KC COOPER
• 金额: $ 157.68万
• 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/10621195
• 关键词: Antigen Targeting; Clinical Trials; Destinations; Doctor of Philosophy; Endothelial Cells; 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 Inhibition; 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; pharmacologic; 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.

基因工程猪器官移植在狒狒体内的免疫学研究 和功能研究(PI/PD：David K.C.Cooper) 该计划概述 项目摘要/摘要 我们的项目已经培育出基因工程猪，通过以下方式保护猪器官免受伤害 灵长类的先天免疫反应。从这些猪身上移植的器官，连同一个有效的 (可能在临床上适用的)免疫抑制方案显著延长了猪的移植物 狒狒的存活时间可达数月甚至数年。目前的提案旨在确认这一组合 多基因猪和有效的免疫抑制方案将允许生命的持续功能- 支持猪肾(项目1)和心脏(项目3)6个月或更长时间，以及维持生命 肝脏移植1个月(作为同种异体肝移植的桥梁[项目2])。3个项目中的工作 将由4个内核支持。 核心A(猪核心)将提供具有8个或更多基因的特定多基因猪(至项目1-3) 将有助于克服迈向临床试验的剩余障碍的操纵。核心B (免疫生物学核心)和核心C(组织病理学核心)将提供机制的证据 正在调查的问题和正在探索的治疗方法。核心D(管理 (核心)将提供一个组织结构，以促进拟议项目的成功。 我们的目标包括：(1)探索预防或抑制获得性免疫的方法 通过新的猪遗传学或药物干预反应，(Ii)预防或减少 (Iii)预防和预防：(I)预防和预防；(Ii)预防和预防； 减少猪器官移植到狒狒体内后早期记录的快速生长，以及(Iv) 猕猴移植后肾、肝、心功能的综合监测 受控免疫反应的存在(即相对缺乏免疫反应)。这个 基因修改和精炼相结合的机制 免疫抑制方案延长移植物存活将通过免疫学分析和 组织病理学技术。 项目1和3的成功将使人们能够立即考虑有限的肾脏临床试验。 和/或异种心脏移植。在项目2中取得成功将允许立即考虑有限的 将猪的肝脏移植作为同种异体移植的生命桥梁的临床试验。这个 因此，这3个项目的总体目标是在这5年的资金支持期间推动科学的发展 肾脏和心脏的临床试验可以作为目标疗法启动(或者，在 心脏移植最初可能是一种搭桥疗法)，猪肝作为同种异体移植的搭桥。

项目成果

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

• DOI: 10.1111/ajt.15712
• 发表时间: 2020-01-03
• 期刊: AMERICAN JOURNAL OF TRANSPLANTATION
• 影响因子: 8.8
• 作者: Zhang, Guoqiang;Iwase, Hayato;Hara, Hidetaka
• 通讯作者: Hara, Hidetaka

Xenotransplantation-A Basic Science Perspective.

• DOI: 10.34067/kid.0000000000000173
• 发表时间: 2023-08-01
• 期刊: Kidney360
• 作者: Cooper DKC;Hara H
• 通讯作者: Hara H

Patient informed consent for a clinical trial of gene-edited pig kidney transplantation: A representative consent form.

基因编辑猪肾移植临床试验的患者知情同意书：代表性同意书。

• DOI: 10.1111/xen.12790
• 发表时间: 2023
• 期刊: Xenotransplantation
• 影响因子: 3.9
• 作者: Cooper,DavidKC

A Standardized Approach to Orthotopic (Life-supporting) Porcine Cardiac Xenotransplantation in a Nonhuman Primate Model.

非人灵长类动物模型中原位（维持生命）猪心脏异种移植的标准化方法。

• DOI: 10.1097/tp.0000000000004508
• 发表时间: 2023
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Goerlich,CorbinE;Griffith,BartleyP;Shah,Aakash;Treffalls,JohnA;Zhang,Tianshu;Lewis,Billeta;Tatarov,Ivan;Hershfeld,Alena;Sentz,Faith;Braileanu,Gheorghe;Ayares,David;Singh,AvneeshK;Mohiuddin,MuhammadM
• 通讯作者: Mohiuddin,MuhammadM

Genetically engineered pig kidney transplantation in a brain-dead human subject.

• DOI: 10.1111/xen.12718
• 发表时间: 2021-11
• 期刊: Xenotransplantation
• 影响因子: 3.9
• 作者: Cooper DKC