Genetically-engineered pig organ transplantation into nonhuman primates

描述（由申请方提供）：所有研究均将使用附加遗传修饰的GalTKO.CD46CD55猪（指定为GE猪）进行。 项目1：基因修饰对狒狒猪心脏和肾脏移植存活率的影响。目标1：在狒狒中研究临床适用的免疫抑制方案在预防（A）GE猪和（B）GE/CIITA猪异位心脏移植（Tx）后先天性和适应性免疫应答方面的疗效，并确定预防诱发的异种免疫是否与延迟凝血功能障碍发作或预防凝血功能障碍相关。目标二：研究采用临床适用方案免疫抑制狒狒中的人血栓调节蛋白（TBM）转基因GE/CIITA猪（A）异位心脏Tx（n =6）或（B）生命维持肾脏Tx（n=6）后发生的凝血障碍，并确定移植物衰竭和凝血功能障碍的原因。目标3：研究采用临床适用方案免疫抑制狒狒中的人内皮细胞蛋白C受体（EPCR）转基因GE/CIITA/TBM猪（A）异位心脏Tx（n = 6）或（B）生命维持肾脏Tx（n=6）后发生的凝血障碍，并确定移植物衰竭和凝血功能障碍的原因。 项目二：凝血控制以保护GalTKO肺和肝异种移植物：目的1：确定GE肺异种移植物的血小板隔离是否由GP 1B/vWF相互作用、糖蛋白去唾液酸化或两种机制的组合引起。目标二：确定猪TBM或EPCR与其人血基质之间的分子不相容性是否会放大GE猪肺的凝血途径激活。目标3：根据前两个目标中确定的最佳猪表型和药理学干预，评价狒狒肺和肝异种移植物的生命支持性能。 芯A（猪芯）：目标1：生产和供应足够数量的基因工程猪，作为心脏、肾脏、肝脏和肺的来源，以满足项目1和2的目标。目标二：在GE/CIITA遗传背景下生产和供应基因工程猪，其额外表达转基因、TBM和/或EPCR，作为调节与器官异种移植相关的血栓形成和凝血病的手段。 核心B（行政核心）：将促进和协调联合会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，他们都将是联合会的顾问。

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.