Design and testing of a humanized porcine donor for xenotransplantation

Ranjith P. Anand, Jacob V. Layer, David Heja, Takayuki Hirose, Grace Lassiter, Daniel J. Firl, Violette B. Paragas, Adam Akkad, Sagar Chhangawala, Robert B. Colvin, Russell J. Ernst, Nicholas Esch, Kristen Getchell, Alexandra K. Griffin, Xiaoyun Guo, Katherine C. Hall, Paula Hamilton, Lokesh A. Kalekar, Yinan Kan, Ahmad Karadagi, Feng Li, Susan C. Low, Rudy Matheson, Claudia Nehring, Ryo Otsuka, Matthew Pandelakis, Robert A. Policastro, Rebecca Pols, Luis Queiroz, Ivy A. Rosales, William T. Serkin, Kathryn Stiede, Toshihide Tomosugi, Yongqiang Xue, Gabriel E. Zentner, David Angeles-Albores, J. Chris Chao, Juliet N. Crabtree, Sierra Harken, Nicole Hinkle, Tania Lemos, Mailin Li, Lorena Pantano, Denise Stevens, Omar D. Subedar, Xiaoqing Tan, Shiyi Yin, Imran J. Anwar, David Aufhauser, Saverio Capuano, Dixon B. Kaufman, Stuart J. Knechtle, Jean Kwun, Dhanansayan Shanmuganayagam, James F. Markmann, George M. Church, Mike Curtis, Tatsuo Kawai, Michele E. Youd () and Wenning Qin ()
Additional contact information
Ranjith P. Anand: eGenesis
Jacob V. Layer: eGenesis
David Heja: eGenesis
Takayuki Hirose: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Grace Lassiter: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Daniel J. Firl: eGenesis
Violette B. Paragas: eGenesis
Adam Akkad: eGenesis
Sagar Chhangawala: eGenesis
Robert B. Colvin: Massachusetts General Hospital, Harvard Medical School
Russell J. Ernst: eGenesis
Nicholas Esch: eGenesis
Kristen Getchell: eGenesis
Alexandra K. Griffin: eGenesis
Xiaoyun Guo: eGenesis
Katherine C. Hall: eGenesis
Paula Hamilton: eGenesis
Lokesh A. Kalekar: eGenesis
Yinan Kan: eGenesis
Ahmad Karadagi: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Feng Li: eGenesis
Susan C. Low: eGenesis
Rudy Matheson: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Claudia Nehring: eGenesis
Ryo Otsuka: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Matthew Pandelakis: eGenesis
Robert A. Policastro: eGenesis
Rebecca Pols: eGenesis
Luis Queiroz: eGenesis
Ivy A. Rosales: Massachusetts General Hospital, Harvard Medical School
William T. Serkin: eGenesis
Kathryn Stiede: eGenesis
Toshihide Tomosugi: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Yongqiang Xue: eGenesis
Gabriel E. Zentner: eGenesis
David Angeles-Albores: eGenesis
J. Chris Chao: eGenesis
Juliet N. Crabtree: eGenesis
Sierra Harken: eGenesis
Nicole Hinkle: eGenesis
Tania Lemos: eGenesis
Mailin Li: eGenesis
Lorena Pantano: eGenesis
Denise Stevens: eGenesis
Omar D. Subedar: eGenesis
Xiaoqing Tan: eGenesis
Shiyi Yin: eGenesis
Imran J. Anwar: Duke University Medical Center
David Aufhauser: University of Wisconsin
Saverio Capuano: Wisconsin National Primate Research Center
Dixon B. Kaufman: University of Wisconsin
Stuart J. Knechtle: Duke University Medical Center
Jean Kwun: Duke University Medical Center
Dhanansayan Shanmuganayagam: University of Wisconsin
James F. Markmann: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
George M. Church: Harvard Medical School
Mike Curtis: eGenesis
Tatsuo Kawai: Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School
Michele E. Youd: eGenesis
Wenning Qin: eGenesis

Nature, 2023, vol. 622, issue 7982, 393-401

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06594-4

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