Double knockout pigs deficient in N-glycolylneuraminic acid and Galactose α-1,3-Galactose reduce the humoral barrier to xenotransplantation

Andrew J. Lutz, Ping Li, Jose L. Estrada, Richard A. Sidner, Ray K. Chihara, Susan M. Downey, Christopher Burlak, Zheng Yu Wang, Luz M. Reyes, Bess Ivary, Fuqin Yin, Ross L. Blankenship, Leela L. Paris, A. Joseph Tector

Research output: Contribution to journalArticle

177 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)27-35
Number of pages9
JournalXenotransplantation
Volume20
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • humoral
  • Neu5Gc
  • pig
  • xenotransplantation
  • zinc-finger nuclease

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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