Genetically-engineered pig organ transplantation into nonhuman primates

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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.