N‐glycolylneuraminic acid knockout reduces erythrocyte sequestration and thromboxane elaboration in an ex vivo pig‐to‐human xenoperfusion model

Cimeno, Arielle; Hassanein, Wessam; French, Beth M.; Powell, Jessica M.; Burdorf, Lars; Goloubeva, Olga; Cheng, Xiangfei; Parsell, Dawn; Ramsoondar, Jagdeece; Kuravi, Kasinath; Vaught, Todd D.; Uluer, Mehmet C.; Redding, Emily; O’Neill, Natalie A.; Laird, Christopher; Hershfeld, Alena; Tatarov, Ivan; Thomas, Kathryn; Ayares, David; Azimzadeh, Agnes M.; Pierson, Richard N.; Barth, Rolf N.; LaMattina, John C.

doi:10.1111/xen.12339

Cited by 21 publications

(43 citation statements)

References 37 publications

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“…Springer reported that NWNHPs do not express Neu5Gc antigens . Ex vivo pig organ perfusion models with human blood have been used to investigate the effect of anti‐Neu5Gc antibodies . However, the significance of expression of Neu5Gc in pigs has not been studied in vivo, as all OWNHPs express Neu5Gc.…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

Shaikh

Iwase

et al. 2019

Xenotransplantation

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Background: Old World non-human primates (OWNHPs) are used for preclinical pigto-NHP studies. However, like pigs, OWNHPs express Neu5Gc, and therefore do not develop natural anti-Neu5Gc antibodies. New World NHPs (NWNHPs) have been reported not to express Neu5Gc. We investigated the potential of NWNHPs in xenotransplantation research. Methods:We investigated expression of Gal, Neu5Gc, and Sd a antigens on RBCs and PBMCs from humans, selected OWNHPs, and capuchin monkeys (a NWNHP). Serum anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. Binding of primate serum IgM and IgG to pig RBCs was measured by flow cytometry.

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Section: Discussionmentioning

confidence: 99%

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

Shaikh

Iwase

et al. 2019

Xenotransplantation

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“…This disproportionate rise in AST compared to ALT has been noted before 14 . The reason for this is unknown but could be due in part to elevated levels of hemolysis in the 2-gene and 3-gene groups 13 .…”

Section: Discussionmentioning

confidence: 99%

Synthetic liver function is detectable in transgenic porcine livers perfused with human blood

Cimeno

French

Powell

et al. 2017

Xenotransplantation

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In addition to immune barriers, molecular incompatibilities between species are predicted to limit pig liver survival in primate xenotransplantation models. Assessment and measurement of synthetic function of genetically modified porcine livers after ex vivo perfusion with human blood have not previously been described. Eight porcine livers from α1,3-galactosyl transferase knockout and human membrane cofactor (GalTKO.hCD46), six livers from GalTKO.hCD46 and N-glycolylneuraminic acid knockout (GalTKO.hCD46.Neu5GcKO), and six livers from GalTKO.hCD46 with humanized decay-accelerating factor (hCD55), endothelial protein C receptor (hEPCR), tissue factor pathway inhibitor (hTFPI), and integrin-associated protein (hCD47) (GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47) pigs were perfused with human blood under physiologic conditions. Timed blood samples were tested for liver enzymes and for pig-specific albumin production via Western blot. Porcine albumin levels increased with time in all experiments. By densitometry, GalTKO.hCD46.Neu5GcKO livers had the highest albumin levels, measured both as total produced, and when controlled for perfusion duration, compared to GalTKO.hCD46 (P = .068) and GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47 livers (P = .04). Porcine livers perfused with human blood demonstrated the synthetic ability to produce albumin in all cases. GalTKO.hCD46.Neu5GcKO pig livers demonstrated the most robust albumin production. This suggests that the Neu5GcKO phenotype provides a protective effect on the graft due to decreased human antibody recognition and graft injury.

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“…The enzymes responsible for other xenoantigens, such as CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase critical for Neu5Gc biosynthesis) and B4GALNT2 (beta 1,4 N-acetylgalactosaminyltran sferase), have been identified as sources of porcine-specific epitopes bound by antibodies found in human serum. In each case, the deletion of the gene responsible for creating the specific glycan leads to greatly decreased recognition of porcine cells by antibodies in human serum, and reduction in complement-mediated destruction [38,39].…”

Section: Gene Knockoutmentioning

confidence: 99%

Genome Engineering for Xenotransplantation

Stevens¹

2020

Genetic Engineering - A Glimpse of Techniques and Applications

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Xenotransplantation, the transfer of cells, tissues or organs between species, has the potential to overcome the critical need for organs to treat patients. One major barrier in the widespread application of xenotransplantation in the clinic is the overwhelming rejection response that occurs when non-human organs encounter the human immune system. Recent progress in developing new and better genome engineering tools now allows the genetic engineering of genes and pathways in non-human animals to overcome the human rejection response and provide an unlimited supply of rejection-free organs. In this review, the benefits and drawbacks of various genome engineering protocols, and examples of their application in xenotransplantation, are discussed.

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N‐glycolylneuraminic acid knockout reduces erythrocyte sequestration and thromboxane elaboration in an ex vivo pig‐to‐human xenoperfusion model

Abstract: The lack of Neu5Gc expression attenuated erythrocyte loss but did not prevent profound early onset thrombocytopenia or platelet activation, although TXB2 levels were decreased in the presence of Neu5GcKO.

Cited by 21 publications

References 37 publications

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

Synthetic liver function is detectable in transgenic porcine livers perfused with human blood

Genome Engineering for Xenotransplantation

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