The role of genetically engineered pigs in xenotransplantation research

Abstract

There is a critical shortage in the number of deceased human organs that become available for purposes of clinical transplantation. This problem might be resolved by the transplantation or organs from pigs genetically-engineered to protect them from the human immune response. The pathobiological barriers to successful pig organ transplantation in primates include activation of the innate and adaptive immune systems, coagulation dysregulation, and inflammation. Genetic engineering of the pig as an organ source has increased the survival of the transplanted pig heart, kidney, islet and corneal graft in nonhuman primates (NHP) from minutes to months or occasionally years. Genetic engineering may also contribute to any physiological barriers that might be identified as well as to reducing the risks of transfer of a potentially infectious micro-organism with the organ. There are now an estimated 40 or more genetic alterations that have been carried out in pigs, with some pigs expressing 5 or 6 manipulations. With the new technology now available, it will become increasingly common for a pig to express even more genetic manipulations, and these could be tested in the pig-to-NHP models to assess their efficacy and benefit. It is therefore likely that clinical trials of pig kidney, heart, and islet transplantation will become feasible in the near future.

Ultrastructure of apoptotic T lymphocytes and thymicepithelial cells in early postnatal pig thymus

“…This makes the pig more advantageous than other experimental animals for various purposes such as studying specific disease models, xenotransplantation, and usage as a large animal model for educational and research purposes. Moreover, it is clear that results obtained from pig-oriented studies have higher applicability and reliability for humans compared with other animal models (3).…”

Xenotransplantation of pig chondrocytes: therapeutic potential and barriers for cartilage repair

“…Based on the transplantation of cells, tissues and organs across different species, it has the potential to overcome the severe shortage of human cells, tissues and organs for clinical transplantation . Its applicability has gained feasibility with the recent advancements made in the field of animal genetic engineering (Estrada et al, 2015;Yang et al, 2015;Cooper et al, 2016;Niemann and Petersen, 2016). Xenotransplantation offers an unlimited supply of cells that can be obtained under very high quality standards .…”

“…Humans produce abundant natural anti-Gal antibodies because they lack a functional α1,3-GT and as a result do not express Gal residues. Notably, HAR has been precluded by eliminating Gal from pig tissues by homologous recombination and nuclear transfer/cloning technology, as well as by expression of human complement regulatory proteins (Costa Vallés and Máñez Mendiluce, 2012;McGregor et al, 2012;Cooper et al, 2016). Now, the genetically-modified pig organs transplanted into non-human primate models succumb to AHXR within weeks to months.…”

“…The activation of T cells during xenograft rejection is mediated through the T cell receptor (TCR) and co-stimulatory signals conserved across species, involving both direct R Sommaggio et al Barriers to chondrocyte xenotransplantation and indirect pathways (Griesemer et al, 2014;Vadori and Cozzi, 2015;Higginbotham et al, 2015). The various immunosuppressive protocols currently available or in advanced development are considered sufficient to control the T-cell immune response against the xenograft (Cooper et al, 2016). In fact, the cellular mechanisms that lead to rejection of cellular grafts are probably very similar and have been successfully controlled in some experiments resulting in long-term survival (i.e.…”

Substituição gênica ortotópica de porco para humano baseada em CRISPR/Cas9 e recombinases para xenotransplante

“…While non-human primates are genetically closer to human, there are many limitations to use them as adequate source of organs for transplantation, such as ethical concerns and difficulty in breeding, including other factors summarized on Table 1 (32,33). Pig was then chosen to be the animal for xenotransplantation, because it has an unlimited availability, rapid growth to human size, and lower risk for zoonosis.…”