Double knockout pigs deficient in N ‐glycolylneuraminic acid and G alactose α‐1,3‐ G alactose reduce the humoral barrier to xenotransplantation
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BACKGROUND: Clinical xenotransplantation is not possible because humans possess antibodies that recognize antigens on the surface of pig cells. Galα-1,3-Gal (Gal) and N-glycolylneuraminic acid (Neu5Gc) are two known xenoantigens. METHODS: We report the homozygous disruption of the α1, 3-galactosyltransferase (GGTA1) and the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) genes in liver-derived female pig cells using zinc-finger nucleases (ZFNs). Somatic cell nuclear transfer (SCNT) was used to produce healthy cloned piglets from the genetically modified liver cells. Antibody-binding and antibody-mediated complement-dependent cytotoxicity assays were used to examine the immunoreactivity of pig cells deficient in Neu5Gc and Gal. RESULTS: This approach enabled rapid production of a pig strain deficient in multiple genes without extensive breeding protocols. Immune recognition studies showed that pigs lacking both CMAH and GGTA1 gene activities reduce the humoral barrier to xenotransplantation, further than pigs lacking only GGTA1. CONCLUSIONS: This technology will accelerate the development of pigs for xenotransplantation research.
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Regulatory issues, complexity, time-consuming process, and high costs are among the main barriers that need to be addressed in these methods.
“However, regulatory issues, complexity, time-consuming process, and high costs are among the main barriers that need to be addressed in these methods [133, 185].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [133]
The Introduction describes limitations of traditional genetic-engineering tools and complex breeding programs; the Discussion calls standard knockout methods tedious and says ZFN accelerated production. These passages support complexity and a time-consuming process in this setting, but do not identify high costs or regulatory issues as barriers. Page numbers are not supplied for these passages. (LLM, conf=0.85)
Experimental — accuracy not yet measuredXenogeneic sialic acids are one of the leading non-α-gal antigens, participating in the rejection of xenografts.
“Xenogeneic sialic acids are one of the leading non-α-gal antigens, participating in the rejection of xenografts [133–135].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [133]
Exposing cells of GT-CMAH knockout pigs (which lack expression of α-gal and Neu5Gc epitopes) to human serum demonstrates fewer antigen-antibody reactions.
“Exposing cells of GT-CMAH knockout pigs (which lack expression of α-gal and Neu5Gc epitopes) to human serum demonstrates fewer antigen-antibody reactions [133, 134].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [133]
α-Gal and the nonhuman sialic acid Neu5Gc represent the major xenoantigens that must be bypassed for xenotransplantation into humans, and α-Gal- and Neu5Gc-double null pigs have recently been generated.
“glycans like ɑ -Gal and the nonhuman sialic acid Neu5Gc represent the major xenoantigens that must be bypassed, to pursue the goal of xeno- (pig organ) transplantation into humans. In pursuit of this dif fi cult goal, ɑ -Galand Neu5Gc-double null pigs have recently been generated (980 -983).”
From Biological roles of glycans (2017) · cites this paper as [980]
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- Authors
- Lutz, A. J., Li, P., Estrada, J. L., Sidner, R. A., Chihara, R. K., Downey, S. M., Burlak, C., Wang, Z., Reyes, L. M., Ivary, B., Yin, F., Blankenship, R. L., Paris, L. L., & Tector, A. J.
- Affiliations
- Indiana University Indianapolis (US)
- Corresponding author
- Tector, A. Joseph
- ORCID
- Venue
- Xenotransplantation
- Publisher
- Wiley
- Published
- 2013-01
- Volume
- 20
- Issue
- 1
- Pages
- 27-35
- ISSN
- 0908-665X (ISSN-L)
- 1399-3089
- OpenAlex
- W1979411388
- Cited by
- 294
- References
- 16
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 18 · 2023: 19 · 2022: 17 · 2021: 10 · 2020: 24 · 2019: 29 · 2018: 16 · 2017: 22 · 2016: 33 · 2015: 32 · 2014: 31 · 2013: 15
- FWCI
- 36.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Xenotransplantation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Langley Research Center
- National Center for Research Resources (C06RR010601, C06RR10601-01)
- Topics
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- N-glycolylneuraminic acid, galactose-alpha-1,3-galactose, xenoantigens, GGTA1, CMAH, knockout pigs, somatic cell nuclear transfer, zinc finger nucleases, humoral immune response, genetically modified pigs
- MeSH terms
- Animals, Antibodies, Heterophile, Antibody-Dependent Cell Cytotoxicity, Base Sequence, Cells, Cultured, Disaccharides, DNA, Female, Galactosyltransferases, Humans, Mixed Function Oxygenases, Leukocytes, Mononuclear, Neuraminic Acids, Transplantation, Heterologous, Antigens, Heterophile, Sus scrofa, Gene Knockout Techniques
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