Genetically-engineered pig organ transplantation into nonhuman primates

描述(由申请人提供)：所有研究将使用GalTKO.CD46CD55猪(指定为GE猪)进行，并进行额外的基因修改。 项目1：基因修饰对狒狒移植心脏和肾脏存活的影响。目的：研究临床适用的免疫抑制方案对(A)GE猪和(B)GE/CIITA猪异位心脏移植(TX)后先天和获得性免疫反应的预防效果，并探讨其是否与延迟或预防凝血功能障碍有关。目的：研究(A)异位心脏移植(n=6)或(B)生命支持性肾移植(n=6)加转人血栓调节蛋白(TBM)基因的GE/CIITA猪免疫抑制后的凝血功能障碍，并探讨移植物衰竭和凝血功能障碍的原因。目的：观察(A)异位心脏移植(6例)或(B)生命支持性肾移植(6例)后，在临床适用的免疫抑制方案下，外源性转人内皮细胞蛋白C受体(EPCR)基因的狒狒发生凝血功能障碍的情况，并探讨移植物衰竭和凝血功能障碍的原因。 项目2：凝血控制以保护GalTKO肺和肝移植：目的1：确定GE肺移植的血小板隔离是由GP1b/vWF相互作用、糖蛋白缺失还是两者的组合引起的。目的：探讨猪全血基质或猪外周血与人血基质的分子不相容是否能增强GE猪肺对凝血通路的激活作用。目的：根据前两个目标中确定的最佳猪表型和药物干预，评估狒狒异种肺和肝移植的生命维持性能。 核心A(猪核心)：目标1：生产和供应足够数量的转基因猪作为心、肾、肝和肺的来源，以满足项目1和2的目标。目标2：在GE/CIITA遗传背景下生产和供应额外表达转基因TBM和/或EPCR的转基因猪，作为调节与器官异种移植相关的血栓形成和凝血障碍的手段。 核心B(行政核心)：将促进和协调联盟成员之间以及他们与科学咨询委员会4名成员之间的沟通，这些成员都将是联盟的顾问。

DESCRIPTION (provided by applicant): All Studies will be carried out using GalTKO.CD46CD55 pigs (designated GE pigs) with additional genetic modifications. Project 1: Effect of genetic modifications on pig heart and kidney graft survival in baboons. Aim 1: To investigate the efficacy in baboons of a clinically-applicable immunosuppressive regimen in preventing the innate and adaptive immune responses after heterotopic heart transplantation (Tx) from (A) GE pigs and (B) GE/CIITA pigs, and to determine whether prevention of elicited xenoimmunity correlates with delay in the onset or prevention of coagulation dysfunction. Aim 2: To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) life-supporting kidney Tx (n=6) from GE/CIITA pigs additionally transgenic for human thrombomodulin (TBM) in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction. Aim 3: To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) life-supporting kidney Tx (n=6) from GE/CIITA/TBM pigs additionally transgenic for human endothelial cell protein C receptor (EPCR) in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction. Project 2: Coagulation control to protect GalTKO lung and liver xenografts: Aim 1: Determine whether platelet sequestration by a GE lung xenograft is caused by GP1B/vWF interaction, glycoprotein desialylation, or a combination of both mechanisms. Aim 2: Establish whether molecular incompatibilities between porcine TBM or EPCR and their human blood substrates amplify coagulation pathway activation by GE pig lung. Aim3: Evaluate life supporting performance of lung and liver xenografts in baboons based on optimal pig phenotype and pharmacologic interventions as identified in the first two aims. Core A (Pig Core): Aim 1: Production and supply of genetically-engineered pigs as a source of heart, kidney, liver and lung, in sufficient numbers to meet the goals of Projects 1 and 2. Aim 2: Production and supply of genetically-engineered pigs on the GE/CIITA genetic background which additionally express the transgene, TBM and/or EPCR, as a means to modulate thrombosis and coagulopathy associated with organ xenotransplantation. Core B (Administrative Core): Will facilitate and coordinate communications between the members of the Consortium themselves and between them and the 4 members of the Scientific Advisory Board, all of whom will be Consultants to the Consortium.