The desirable donor pig to eliminate all xenoreactive antigens

Abstract

The humoral barrier has been the limiting factor in moving xenotransplantation towards the clinic. Improvements in somatic cell nuclear transfer and genome editing, particularly CRISPR‐Cas9, have made it possible to create pigs with multiple glycan xenoantigen deletions for the purposes of reducing xenoreactive antibody binding to the xenografted organ. Recent studies have also considered the aetiology and existence of antibodies directed at the swine leucocyte antigen (SLA) complex, and potential genetic engineering strategies to avoid these antibodies. Evaluation of xenoreactive antibody binding is very important for the advancement of xenotransplantation, because if patients do not have any detectable xenoreactive antibody, then it is reasonable to expect that cellular rejection and not antibody‐mediated rejection (AMR) will be the next hurdle to clinical application.

Xenotransplantation literature update, July/August 2019

“…Reactivity is variable among donors, and the question of whether we can avoid genetic engineering by screening porcine donors and conduct similar studies to Hundrieser et al's analysis continue to be present within Ladowski et al's commentary. Current understanding would provide support for approaching the xenotransplant from both angles, and Ladowski et al discuss the option of screening clinical trial candidates for xenoreactivity and the care to be taken for positive antibody crossmatching. Cooper et al go further in their commentary suggesting that in addition to GGTA1, CMAH, and B4GALNT2 triple‐knockout pigs, additional genetic modification to knock in human genes including CD46, CD55, CD47, human hemeoxygenase‐1, thrombomodulin, and endothelial cell protein C receptors, for a total of nine genetic modifications, will be successful in xenotransplantation.…”

“…Through identifying porcine carbohydrate‐based antigens and strategic elimination by genetic engineering, the donor pig becomes more human‐like than ever before. Knockout of GGTA1, CMAH, and B4GALNT2 porcine genes has been particularly effective in reducing human anti‐pig immune responses . Reactivity is variable among donors, and the question of whether we can avoid genetic engineering by screening porcine donors and conduct similar studies to Hundrieser et al's analysis continue to be present within Ladowski et al's commentary.…”

“…Knockout of GGTA1, CMAH, and B4GALNT2 porcine genes has been particularly effective in reducing human anti‐pig immune responses . Reactivity is variable among donors, and the question of whether we can avoid genetic engineering by screening porcine donors and conduct similar studies to Hundrieser et al's analysis continue to be present within Ladowski et al's commentary. Current understanding would provide support for approaching the xenotransplant from both angles, and Ladowski et al discuss the option of screening clinical trial candidates for xenoreactivity and the care to be taken for positive antibody crossmatching.…”

“…In the push to perfection, Ladowski et al's commentary titled, “The desirable donor pig to eliminate all xenoreactive antigens” hit the mark as genetic engineering with CRISPR/Cas9 systems has allowed for efficient multi‐knockout porcine models. Through identifying porcine carbohydrate‐based antigens and strategic elimination by genetic engineering, the donor pig becomes more human‐like than ever before.…”

“…In the previous issue of Xenotransplantation, Zhou et al provided an updated review of the complement system in xenograft rejection; Hundrieser et al discuss how porcine and human MHC‐II polymorphisms influence donor reactivity; Ladowski et al seek to eliminate all donor xenoantigens; Cooper et al review a 9 gene alteration of porcine donors for clinical xenotransplantation; Zhou et al present a strategy to monitor xenograft rejection with porcine cDNA biomarkers; Zafar et al provide further research into reducing porcine islet immunoreactivity; Li et al studied the cold storage of porcine hepatocyte spheroids; Iizuka et al deep dive into porcine C‐peptide pharmacokinetics; and, finally, Zheng et al, Zhao et al, and Yoon et al provide updates in corneal xenotransplantation.…”