Immunological Response In Cynomolgus Macaques To Porcine Alpha-1,3 Galactosyltransferase Knockout Viable Skin Xenotransplants-A Pre-Clinical Study

Background: Allogeneic skin recovered from human deceased donors (HDD) has been a mainstay interim treatment for severe burns, but unfortunately risk of infectious disease and availability limitations exist. Genetically engineered alpha-1,3 galactosyltransferase knockout (GalT-KO) porcine source animals for viable skin xenotransplants may provide a promising clinical alternative.Methods: Four cynomolgus macaque recipients received full-thickness surgical wounds to model the defects arising from excision of full-thickness burn injury and were treated with biologically active skin xenotransplants derived from GalT-KO, Designated Pathogen Free (DPF) miniature swine. Evaluations were conducted for safety, tolerability, and recipient immunological response.Results: All skin xenotransplants demonstrated prolonged survival, vascularity, and persistent dermal adhesion until the study endpoint at post-operative day 30. No adverse outcomes were observed during the study. Varying levels of epidermolysis coincided with histologic detection of CD4+ and CD8+ T cells, and other cellular infiltrates in the epidermis. Recipient sera IgM and IgG demonstrated significant antibody immune response to non-alpha-1,3-galactose porcine xenoantigens. Separately, specific wound healing mediators were quantified. Neither porcine cell migration nor PERV were detected in circulation or any visceral organs.Conclusions: These results provide a detailed analysis of vital skin xenotransplants utilizing a non-human primate model to predict the anticipated immunological response of human patients. The lack of adverse rejection even in the presence of elevated Ig indicates this is a prospective therapeutic option. The findings reported here directly supported regulatory clearance for a first-in-man, Phase I xenotransplantation clinical trial.