Genetically-engineered pig orthotopic (life-supporting) heart transplantation (OHTx) in baboons: establishing consistent graft survival and overcoming rapid post-Tx organ growth

狒狒基因工程猪原位（生命支持）心脏移植（OHTx）：建立一致的移植物存活并克服 Tx 后器官的快速生长

• 批准号: 10621199
• 负责人: Muhammad M Mohiuddin
• 金额: $ 85.25万
• 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/10621199
• 关键词: Cardiac; Circulation; Clinical Trials; Complex; Ensure; Family suidae; Functional disorder; Genes; Genetic Engineering; Goals; Graft Survival; Growth; Growth Hormone Receptor; Heart; Heart Transplantation; Heart failure; Immune response; Immunologics; Impairment; Innate Immune Response; Investigation; Knock-out; Knowledge; Laboratories; Left Ventricular Hypertrophy; Life; Light; Measures; Mitochondria; Myocardial; Organ; Organ Transplantation; Outcome; Papio; Perioperative; Primates; Receptor Gene; Regimen; Reporting; Source; System; Testing; Therapeutic; Transplantation; Triiodothyronine; Xenograft procedure; adaptive immune response; experimental study; follow-up; genetic manipulation; graft failure; graft function; heart function; heart preservation; heart xenograft; hemodynamics; immunosuppressed; mitochondrial dysfunction; nonhuman primate; novel; organ growth; preservation; prevent; rapid growth; success

GENETICALLY-ENGINEERED PIG ORGAN TRANSPLANTATION IN BABOONS: IMMUNOLOGICAL AND FUNCTIONAL STUDIES PROJECT 3: Genetically-engineered pig orthotopic (life-supporting) heart transplantation (Tx) in baboons: establishing consistent xenograft survival and overcoming rapid post-Tx organ growth (PI: Muhammad Mohiuddin). SUMMARY/ABSTRACT The field of xenotransplantation has made significant progress in the last few years. However, successful life-supporting (orthotopic) pig heart transplantation (OHTx) in nonhuman primates is currently limited by two major problems – (i) immediate graft failure from a poorly-understood, non-immunologic cause (known as `peri- operative cardiac xenograft dysfunction' or `PCXD'), and (ii) rapid growth of the heart in the first few post-Tx months, potentially resulting in cardiac compression and dysfunction. We propose investigating and resolving these two problems. (i) We hypothesize that PCXD is associated with impaired mitochondrial function that results from inadequate myocardial preservation during OHTx and low post-Tx triiodothyronine (T3) levels. We shall use a novel system of preservation (the `Steen' system) and combine this with T3 therapy in the immediate post-Tx period. Our detailed studies on mitochondrial function will throw light on the mechanisms involved in PCXD. We have already carried out preliminary testing of the Steen system, with encouraging results, and have confirmed that T3 levels remain grossly subnormal during the first few weeks after pig OHTx in baboons. (ii) We hypothesize that excessive growth of the pig cardiac xenograft will be prevented by the Tx of hearts from pigs in which the gene for growth hormone receptors has been knocked out. Pigs in which 8 genetic manipulations have been carried out (all aimed at protecting the heart from the primate immune response) – which have not been available to any group previously - will form the basis of all our experiments but, in addition, growth hormone receptors will be deleted by a ninth genetic manipulation. If these two problems can be resolved, control of the innate immune response (by the genetic manipulations in the organ-source pig) and of the adaptive immune response (by a costimulation blockade-based immunosuppressive regimen introduced by us with proven success) will allow a comprehensive investigation of the hemodynamic function of the pig heart in supporting the baboon's circulation over a follow-up period of 6 months. We anticipate that the results of these studies will enable consideration to be given to initiating a clinical trial of cardiac xenotransplantation.

基因工程猪器官移植在狒狒体内的免疫学和生物学研究 功能研究 项目3：基因工程猪原位(维持生命)心脏移植(TX) 狒狒：建立一致的异种移植存活并克服TX后器官的快速生长(PI： 穆罕默德·穆希丁)。 摘要/摘要 在过去的几年里，异种移植领域取得了重大进展。然而，成功地 维持生命的(原位)猪心移植(OHTx)目前在非人类灵长类动物中仅限于两种 主要问题--(一)由于了解不多的非免疫学原因(称为“围绝经期”)造成的移植物立即衰竭。 外科异种心脏移植功能障碍“或”PCXD“)，以及(Ii)心脏在TX后的最初几个月快速生长 数月，可能会导致心脏受压和功能障碍。我们建议调查和解决 这两个问题。 (I)我们假设PCXD与以下原因引起的线粒体功能受损有关 OHTX期间心肌保护不足和TX后三碘甲腺原氨酸(T3)水平低。我们将使用 新的保存系统(‘Steen’系统)，并将其与TX后即刻的T3治疗相结合 句号。我们对线粒体功能的详细研究将有助于揭示PCXD的相关机制。我们 已经对Steen系统进行了初步测试，结果令人鼓舞，并已确认 在猪OHTX后的最初几周里，狒狒体内的T3水平仍然严重低于正常水平。 (Ii)我们假设猪异种心脏移植物的过度生长将被TX 来自生长激素受体基因已经被敲除的猪的心脏。其中8头猪遗传 已经进行了操纵(所有目的都是为了保护心脏免受灵长类免疫反应的影响)- 它们将构成我们所有实验的基础，但除此之外， 通过第九次基因操作，生长激素受体将被删除。 如果这两个问题能够解决，控制先天免疫反应(通过基因操作 在器官来源猪中)和适应性免疫反应(通过基于共刺激抑制的 我们推出的免疫抑制方案(已被证明成功)将允许对 猪心脏的血流动力学功能在6年随访期内对狒狒循环的支持作用 月份。我们预计，这些研究的结果将使我们能够考虑启动临床 异种心脏移植试验。