Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

Butler, James; Paris, Leela L.; Blankenship, Ross L.; Sidner, Richard A.; Martens, Gregory R.; Ladowski, Joseph M.; Li, Ping; Estrada, José L.; Tector, Matthew; Tector, A. Joseph

doi:10.1097/tp.0000000000001071

Cited by 37 publications

(32 citation statements)

References 26 publications

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“…Although the importance of vWF as a procoagulant factor has been demonstrated through experiments involving vWF-deficient pigs, complete vWF deficiency causes a bleeding phenotype that can be life-threatening to the pig, and so key segments of pig vWF have been replaced by analogous human vWF segments, coupled with ASGR1 knock-out. 55,61 Adhesion, aggregation, and phagocytosis of primate platelets exposed to livers from these pigs are greatly reduced.…”

Section: Transplantation Absence Of Expression Of Neu5gc (In Cmah-komentioning

confidence: 99%

A review of pig liver xenotransplantation: Current problems and recent progress

Zhang

Yang

et al. 2019

Xenotransplantation

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Pig liver xenotransplantation appears to be more perplexing when compared to heart or kidney xenotransplantation, even though great progress has been achieved. The relevant molecular mechanisms involved in xenogeneic rejection, including coagulopathy, and particularly thrombocytopenia, are complex, and need to be systematically investigated. The deletion of expression of Gal antigens in the liver graft highlights the injurious impact of nonGal antigens, which continue to induce humoral rejection. Innate immunity, particularly mediated by macrophages and natural killer cells, interplays with inflammation and coagulation disorders. Kupffer cells and liver sinusoidal endothelial cells (LSECs) together mediate leukocyte, erythrocyte, and platelet sequestration and phagocytosis, which can be exacerbated by increased cytokine production, cell desialylation, and interspecies incompatibilities. The coagulation cascade is activated by release of tissue factor which can be dependent or independent of the xenoreactive immune response. Depletion of endothelial anticoagulants and anti-platelet capacity amplify coagulation activation, and interspecies incompatibilities of coagulation-regulatory proteins facilitate dysregulation. LSECs involved in platelet phagocytosis and transcytosis, coupled with hepatocyte-mediated degradation, are responsible for thrombocytopenia. Adaptive immunity could also be problematic in long-term liver graft survival. Currently, relevant evidence and study results of various genetic modifications to the pig donor need to be fully determined, with the aim of identifying the ideal transgene combination for pig liver xenotransplantation. We believe that clinical trials of pig liver xenotransplantation should initially be considered as a bridge to allotransplantation. K E Y W O R D Scoagulation dysregulation, genetically engineered, liver, pig, xenotransplantation

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Section: Transplantation Absence Of Expression Of Neu5gc (In Cmah-komentioning

confidence: 99%

A review of pig liver xenotransplantation: Current problems and recent progress

Zhang

Yang

et al. 2019

Xenotransplantation

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“…Data in this respect are limited, but current evidence supports the likelihood that relatively good function can be obtained by a pig liver graft, including parameters of coagulation. 53 The current major problem is the rapid development of thrombocytopenia, 54 which will need a solution by further genetic engineering of the source pig 3,55 before any clinical trial can be contemplated.…”

Section: Liver Xenotransplantationmentioning

confidence: 99%

Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation

et al. 2017

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Several groups have reported extended survival of genetically-engineered pig organs in nonhuman primates, varying from almost 10 months for life-supporting kidney grafts and >2 years for nonlife-supporting heart grafts to less than 1 month for life-supporting liver and lung grafts. We have attempted to define groups of patients who may not have an option to wait for an allograft. These include kidney, heart, and lung candidates who are highly-allosensitized. In addition, some kidney candidates (who have previously lost at least 2 allografts from rapid recurrence of native kidney disease) have a high risk of further recurrence and will not be offered a repeat allotransplant. Patients with complex congenital heart disease, who may have undergone previous palliative surgical procedures, may be unsuitable for ventricular assist device implantation. Patients dying of fulminant hepatic failure, for whom no alternative therapy is available, may be candidates for a pig liver, even if only as a bridge until an allograft becomes available. When the results of pig organ xenotransplantation in nonhuman primates suggest a realistic potential for success of a pilot clinical trial, highly-selected patients should be offered participation.

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“…Today, research groups can produce multiple gene knock-out or knock-in pigs using CRISPR technology [87–94], which can also be used to delete PERV expression [74,95]. Genetically-modified pigs using CRIPSR technology have been used in several important studies relating to antibody binding [96–98] and coagulation dysfunction [99,100]. There are now more than 26 genetically-engineered pigs for xenotransplantation research (Table 2).…”

Section: Introductionmentioning

confidence: 99%

Xenotransplantation

Ekser

Li²,

Cooper³

2017

Current Opinion in Organ Transplantation

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Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

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Silencing Porcine CMAH and GGTA1 Genes Significantly Reduces Xenogeneic Consumption of Human Platelets by Porcine Livers

Cited by 37 publications

References 26 publications

A review of pig liver xenotransplantation: Current problems and recent progress

A review of pig liver xenotransplantation: Current problems and recent progress

Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation

Xenotransplantation

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