Design and testing of a humanized porcine donor for xenotransplantation

Anand, Ranjith P. and Layer, Jacob V. and Heja, David and Hirose, Takayuki and Lassiter, Grace and Firl, Daniel J. and Paragas, Violette B. and Akkad, Adam and Chhangawala, Sagar and Colvin, Robert B. and Ernst, Russell J. and Esch, Nicholas and Getchell, Kristen and Griffin, Alexandra K. and Guo, Xiaoyun and Hall, Katherine C. and Hamilton, Paula and Kalekar, Lokesh A. and Kan, Yinan and Karadagi, Ahmad and Li, Feng and Low, Susan C. and Matheson, Rudy and Nehring, Claudia and Otsuka, Ryo and Pandelakis, Matthew and Policastro, Robert A. and Pols, Rebecca and Queiroz, Luis and Rosales, Ivy A. and Serkin, William T. and Stiede, Kathryn and Tomosugi, Toshihide and Xue, Yongqiang and Zentner, Gabriel E. and Angeles-Albores, David and Chris Chao, J. and Crabtree, Juliet N. and Harken, Sierra and Hinkle, Nicole and Lemos, Tania and Li, Mailin and Pantano, Lorena and Stevens, Denise and Subedar, Omar D. and Tan, Xiaoqing and Yin, Shiyi and Anwar, Imran J. and Aufhauser, David and Capuano, Saverio and Kaufman, Dixon B. and Knechtle, Stuart J. and Kwun, Jean and Shanmuganayagam, Dhanansayan and Markmann, James F. and Church, George M. and Curtis, Mike and Kawai, Tatsuo and Youd, Michele E. and Qin, Wenning (2023) Design and testing of a humanized porcine donor for xenotransplantation. Nature, 622 (7982). pp. 393-401. ISSN 0028-0836

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Abstract

Recent human decedent model studies1,2 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.

Item Type: Article
Subjects: Science Global Plos > Multidisciplinary
Depositing User: Unnamed user with email support@science.globalplos.com
Date Deposited: 10 Nov 2023 06:23
Last Modified: 10 Nov 2023 06:23
URI: http://ebooks.manu2sent.com/id/eprint/2079

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