The potential of genetically-engineered pigs in providing an alternative source of organs and cells for transplantation

Abstract

There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplantation of organs, cells, and corneas from a readily available animal species, such as the pig, and the transfusion of red blood cells from pigs into humans. However, to achieve these ends, major immunologic and other barriers have to be overcome. Considerable progress has been made in this respect by the genetic modification of pigs to protect their tissues from the primate immune response and to correct several molecular incompatibilities that exist between pig and primate. These have included knockout of genes responsible for the expression of major antigenic targets for primate natural anti-pig antibodies, insertion of human complement- and coagulation-regulatory transgenes, and knockdown of swine leukocyte antigens that stimulate the primate's adaptive immune response. As a result of these manipulations, the administration of novel immunosuppressive agents, and other innovations, pig hearts have now functioned in baboons for 6-8 months, pig islets have maintained normoglycemia in diabetic monkeys for > 1 year, and pig corneas have maintained transparency for several months. Clinical trials of pig islet transplantation are already in progress. Future developments will involve further genetic manipulations of the organ-source pig, with most of the genes that are likely to be beneficial already identified.

Future Economics of Liver Transplantation: A 20-Year Cost Modeling Forecast and the Prospect of Bioengineering Autologous Liver Grafts

“…These include: the use of marginal donors, an ill-defined group comprised of donors over the age of 60; donors with greater than 30% hypernatremia or macrosteatosis; donors with positive serologies for the hepatitis C or hepatitis B virus; donors with a cold ischemia time of greater than 12 hours; non-heart-beating donors; and grafts from split-livers or living-related donors [ 3 , 6 ]. Resuscitation of marginal quality donor organs using machine perfusion [ 7 ] and the production of pigs with genetic manipulations [ 8 ] has also been explored. Unfortunately, these alternative approaches have presented a variety of practical and logistic difficulties.…”

The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation

“…The initial production of GTKO animals was performed through a tedious process of homologous recombination; however, recent advances in gene editing have dramatically sped the pace of xenotransplantation research ( Table 1 ) [ 9 , 11 – 13 ] setting the stage for highly efficient and rapid porcine genetic modification. Recently, the role of genetically engineered pigs has been reviewed, and this role effectively negates the human anti-pig humoral response to the threshold where hyperacute rejection and AHXR are no longer expected [ 9 , 12 – 14 ]. In this climate of reduced humoral xenoantigenicity, an appraisal of pharmacologic strategies that will modulate the human cell-mediated response to porcine xenografts is increasingly relevant.…”

Magnetic Cell Labeling of Primary and Stem Cell-Derived Pig Hepatocytes for MRI-Based Cell Tracking of Hepatocyte Transplantation

“…Appropriate preclinical animal models, along with MRI techniques, would allow for the development and refinement of cell transplantation methodology prior to advancing to clinical trials. Swine models of liver disease are considered a reliable model for liver failure because the pig’s liver has a similar anatomy, physiology and size compared with the human liver [ 40 ]. This is particularly true for modeling newborn liver diseases caused by inborn metabolic disorders of a genetic basis.…”