Gene-edited Pigs for Xenotransplantation

The critical shortage of human organs for allotransplantation has led to intensive research on xenotransplantation, with the pig being the species of choice as an organ source. However, wild-type pig organs undergo rapid hyperacute rejection (HAR) when transplanted into non-human primates (NHP), due the existence of preformed anti-pig antibodies expressed in the recipient. In NHP, these antibodies are directed to galactose-α1,3-galactose (Gal) and SDa. Humans express antibodies to both of these antigens, but also to N-glycolylneuraminic acid (Neu5Gc), and are thus anticipated to elicit a similar response. Hyperacute rejection stems from the binding of preformed antibodies to xenoantigens on the pig vascular endothelium, followed by complement-mediated endothelial lysis, interstitial hemorrhage, and necrosis.