1. Design and testing of a humanized porcine donor for xenotransplantation.
- Author
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Anand RP, Layer JV, Heja D, Hirose T, Lassiter G, Firl DJ, Paragas VB, Akkad A, Chhangawala S, Colvin RB, Ernst RJ, Esch N, Getchell K, Griffin AK, Guo X, Hall KC, Hamilton P, Kalekar LA, Kan Y, Karadagi A, Li F, Low SC, Matheson R, Nehring C, Otsuka R, Pandelakis M, Policastro RA, Pols R, Queiroz L, Rosales IA, Serkin WT, Stiede K, Tomosugi T, Xue Y, Zentner GE, Angeles-Albores D, Chris Chao J, Crabtree JN, Harken S, Hinkle N, Lemos T, Li M, Pantano L, Stevens D, Subedar OD, Tan X, Yin S, Anwar IJ, Aufhauser D, Capuano S, Kaufman DB, Knechtle SJ, Kwun J, Shanmuganayagam D, Markmann JF, Church GM, Curtis M, Kawai T, Youd ME, and Qin W
- Subjects
- Animals, Humans, Animals, Genetically Modified, Endothelial Cells immunology, Endothelial Cells metabolism, Polysaccharides deficiency, Transgenes genetics, Graft Rejection immunology, Graft Rejection prevention & control, Kidney Transplantation methods, Macaca fascicularis, Swine genetics, Transplantation, Heterologous methods
- Abstract
Recent human decedent model studies
1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts., (© 2023. The Author(s).)- Published
- 2023
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