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: 10311977
• 负责人: Muhammad M Mohiuddin
• 金额: $ 67.49万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311977
• 关键词: Blood Circulation; Cardiac; 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; base; 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.

狒狒基因工程猪器官移植：免疫学和 功能研究 项目 3：基因工程猪原位（生命支持）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 异种移植领域在过去几年中取得了重大进展。然而，成功的 非人类灵长类动物的生命支持（原位）猪心脏移植（OHTx）目前受到两个限制 主要问题 – (i) 由于了解甚少的非免疫原因导致的直接移植失败（称为“周围移植失败”） 手术心脏异种移植功能障碍”或“PCXD”），以及（ii）心脏在 Tx 后最初几次内快速生长 几个月，可能导致心脏受压和功能障碍。我们建议调查并解决 这两个问题。 (i) 我们假设 PCXD 与线粒体功能受损有关，线粒体功能受损是由于 OHTx 期间心肌保存不充分且 Tx 后三碘甲状腺原氨酸 (T3) 水平较低。我们将使用一个 新颖的保存系统（“Steen”系统），并将其与 Tx 后立即的 T3 疗法相结合 时期。我们对线粒体功能的详细研究将揭示 PCXD 的机制。我们 已经对Steen系统进行了初步测试，取得了令人鼓舞的结果，并确认 狒狒在接受猪 OHTx 治疗后的最初几周内，T3 水平仍然严重低于正常。 (ii) 我们假设猪心脏异种移植物的过度生长将被 Tx 所阻止。 来自猪的心脏，其中生长激素受体的基因已被敲除。猪有8个基因 已经进行了操作（所有目的都是为了保护心脏免受灵长类动物免疫反应的影响）- 以前任何小组都无法使用这些内容 - 将构成我们所有实验的基础，但除此之外， 生长激素受体将通过第九次基因操作被删除。 如果这两个问题能够得到解决，那么先天免疫反应的控制（通过基因操作） 在器官源猪中）和适应性免疫反应（通过基于共刺激阻断的 我们推出的免疫抑制方案已被证明是成功的）将允许对 猪心脏在 6 年内支持狒狒循环的血流动力学功能 几个月。我们预计这些研究的结果将有助于考虑启动临床 心脏异种移植试验。