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Xenogeneic transplantation and tolerance in the era of CRISPR-Cas9

Cowan, Peter J.a,b; Hawthorne, Wayne J.c,d; Nottle, Mark B.e

Current Opinion in Organ Transplantation: February 2019 - Volume 24 - Issue 1 - p 5–11
doi: 10.1097/MOT.0000000000000589
TRANSPLANT IMMUNOLOGY: REJECTION, TOLERANCE AND HISTOCOMPATIBILITY: Edited by Paolo Cravedi
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Purpose of review The use of genetically modified donor pigs has been integral to recent major advances in xenograft survival in preclinical nonhuman primate models. CRISPR-Cas9 gene editing technology has dramatically accelerated the development of multimodified pigs. This review examines the current and projected impact of CRISPR-Cas9-mediated donor modification on preventing rejection and potentially promoting tolerance of porcine xenografts.

Recent findings CRISPR-Cas9 has been used to engineer several genetic modifications relevant to xenotransplantation into pigs, including glycosyltransferase knockouts (GGTA1, CMAH, β4GALNT2, A3GALT2 and combinations thereof), other knockouts (SLA-I, ULBP1, PERV and GHR), and one knock-in (anti-CD2 monoclonal antibody transgene knocked into GGTA1). Although the use of these pigs as donors in preclinical nonhuman primate models has been limited to a single study to date, in-vitro analysis of their cells has provided invaluable information. For example, deletion of three of the glycosyltransferases progressively decreased the binding and cytotoxicity of preexisting immunoglobulin G and immunoglobulin M in human sera, suggesting that this ‘triple-KO’ pig could be a platform for clinical xenotransplantation.

Summary CRISPR-Cas9 enables the rapid generation of gene-edited pigs containing multiple tailored genetic modifications that are anticipated to have a positive impact on the efficacy and safety of pig-to-human xenotransplantation.

aImmunology Research Centre, St Vincent's Hospital (Melbourne)

bDepartment of Medicine, University of Melbourne, Melbourne, Victoria

cDepartment of Surgery, Westmead Clinical School, University of Sydney, Westmead Hospital

dThe Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales

eRobinson Research Institute & Adelaide School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

Correspondence to Peter J. Cowan, Professor, Immunology Research Centre, St Vincent's Hospital Melbourne, PO Box 2900, Fitzroy 3065, Victoria, Australia. Tel: +61 3 9231 3144; fax: +61 3 9231 3151; e-mail: peter.cowan@svha.org.au.

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