During the National Kidney Foundation’s (NKF) Spring Clinical Meetings (11–15 April, Austin, USA), researchers from Massachusetts General Hospital (Boston, USA) will present new data highlighting long-term outcomes for cynomolgus macaques transplanted with kidney xenografts from porcine donors harbouring genetic modifications as part of a new study..
In the study, kidney xenografts from porcine donors, modified to remove three major carbohydrate xenoantigens, called “triple knockout” (TKO) and express up to seven human transgenes, were evaluated in a non-human primate transplant model. The genetic modifications were intended to address cross-species molecular incompatibilities that lead to organ rejection, a major hurdle in the field of xenotransplantation. Xenografts from donors with TKO and human transgenes demonstrated prolonged survival compared to those with TKO alone, with one graft surviving over two years post-transplant.
“The two-year transplant survival outcome is a highly encouraging finding and represents a significant milestone for the xenotransplantation field,” said Toshihide Tomosugi, research fellow in surgery at Massachusetts General Hospital. “This groundbreaking study brings us one step closer to clinical testing of a gene-edited porcine renal graft in humans, potentially offering a much-needed approach to supply human compatible organs to alleviate the organ shortage and also providing an alternative therapeutic option for end-stage kidney disease (ESKD).”
It is estimated that 37 million Americans have kidney disease (also known as chronic kidney disease) and about 90,000 of these individuals are waitlisted for a kidney transplant. About 25,000 of those waiting for a kidney received one this year, one-third of which came from living donors. The average wait time for a kidney transplant is three to seven years. The use of genome engineering in xenotransplantation has the potential, says a press release “to meaningfully transform the treatment of chronic kidney disease (CKD) by providing a transplant earlier in the disease process and possibly ending waitlist mortality altogether”.
Porcine cells devoid of the three major carbohydrate xenoantigens of α-Gal, Neu5Gc, and Sda (otherwise known as TKO) have been shown to exhibit markedly decreased binding of naturally occurring anti-porcine antibodies in vitro. However, this study demonstrated that a TKO strategy alone is still insufficient to enable longer-term xenotransplantation survival.
Outlining several highlights from the study, the press release notes that the porcine donors used in this study were produced by eGenesis. Donors with three different sets of genetic modifications were evaluated – TKO, TKO with six human transgenes, and TKO with seven human transgenes. Certain donors were also edited to inactivate porcine endogenous retroviruses.
The combination of human transgenes with TKO was found to be beneficial in prolonging graft survival relative to TKO alone. Recipients were pre-selected for low levels of naturally occurring anti-porcine antibodies. No correlation between anti-porcine antibody levels and xenograft survival was observed, suggesting recipients were within an acceptable threshold for pre-transplant antibody levels. The immunosuppression regimen included T and B cell depletion, followed by weekly administration of anti-CD154 antibody and daily mycophenolate mofetil. A short course of corticosteroid and tacrolimus was also administered. Mechanisms of graft rejection, meanwhile, varied with duration of survival.
