LIVER TRANSPLANTATION: WILL XENOTRANSPLANTATION BE THE ANSWER TO THE DONOR ORGAN SHORTAGE?

Since the first report of a successful liver transplant in 1968, access to this operation has dramatically improved. In 2018, 8,250 patients underwent liver transplantation in the United States. Despite this remarkable advance, a persistent shortage of donor organs remains the primary obstacle to optimal utilization of this life-saving operation. Over the past two decades, transplant professionals have pursued two broad strategies to overcome this roadblock: increasing the number of donor organs and decreasing the number of patients requiring transplantation through advances in medical interventions. Despite these efforts, more than 13,500 patients remained on liver transplant waiting lists at the end of 2018. Almost 1,200 died while waiting, and 1,350 were removed from wait lists because they had become too sick to survive the operation. Clearly, a dramatic new approach to the donor organ shortage is needed. One effort, first attempted by surgeons in the 1960s, was to utilize donor organs from other species (xenotransplantation). The major obstacle to xenotransplantation acceptance has been the fear of transmitting new infectious diseases from animals to humans. As the twentieth century came to a close, national moratoria on xenotransplantation ended both research and clinical activities in this field. The recent discoveries that modern gene-editing techniques can be used to eliminate the retrovirus that is ubiquitous in pigs and that retrovirus-free pigs can be cloned has reopened the possibility that xenotransplantation may be a potentially game-changing approach to eliminating the donor shortage for liver and other solid organ transplant recipients. In response to these advances, the FDA has released comprehensive industry guidelines regarding all aspects of xenotransplantation. This release has resulted in numerous preclinical studies in which organs from genetically modified pigs are transplanted into various nonhuman primates (NHPs). Use of a variety of gene-editing and immunosuppressive techniques has greatly increased the survival of recipient animals in the past few years. Survival of NHP renal transplant recipients has been extended to 435 days, functional cardiac transplant recipients to 195 days, and liver transplant recipients to 29 days. Current research studies using various gene modification strategies combined with newer immunosuppressive protocols are attempting to further extend the survival of these experimental animals. These encouraging results have raised the possibility that clinical xenotransplantation in humans is just beyond the horizon. The most likely candidates for initial clinical studies probably will be kidney transplant recipients who are difficult to crossmatch for human organs, neonates with severe congenital heart disease, and liver transplant candidates with acute liver failure.