Physiological basis for xenotransplantation from genetically modified pigs to humans

Abstract

The collective efforts of scientists over multiple decades have led to advancements in molecular and cellular biology-based technologies including genetic engineering and animal cloning, that are now being harnessed to enhance the suitability of pig organs for xenotransplantation into humans. Using organs sourced from pigs with multiple gene deletions and human transgene insertions, investigators have overcome formidable immunological and physiological barriers in pig-to-non-human primate (NHP) xenotransplantation and achieved prolonged pig xenograft survival. These studies informed the design of Revivicor's (Revivicor Inc, Blacksburg, VA) genetically engineered pig with 10 genetic modifications (10 GE) (including the inactivation of 4 endogenous porcine genes and insertion of 6 human transgenes) whose hearts and kidneys have now been studied in preclinical human xenotransplantation models using brain-dead recipients. Additionally, the first two clinical cases of pig-to-human heart xenotransplantation were recently performed using hearts from this 10 GE pig at the University of Maryland. While this review focuses on xenotransplantation of hearts and kidneys, multiple organs, tissues, and cell-types from genetically engineered pigs will provide much-needed therapeutic interventions in the future.