Journal of Vaccine Research 2024, Vol.14, No.3, 120-134 http://medscipublisher.com/index.php/jvr 121 2 Background on Genetically Modified Pig Organs 2.1 Rationale for using pigs in xenotransplantation Pigs are considered ideal donors for xenotransplantation due to their anatomical and physiological similarities to humans. The size and function of pig organs are comparable to those of human organs, making them suitable for transplantation purposes. Additionally, pigs have a relatively short gestation period and produce large litters, which ensures a sustainable and scalable source of donor organs (Lei et al., 2022). This characteristic is crucial in addressing the severe shortage of human donor organs. Moreover, pigs can be raised in controlled environments, minimizing the risk of zoonotic infections that could potentially complicate transplantation outcomes. This controlled breeding allows for better health monitoring and management of the donor animals, ensuring that they are free from specific pathogens that could be harmful to human recipients (Pan et al., 2019). The similarity in blood pressure, heart rate, and organ function between pigs and humans further supports the use of pigs in xenotransplantation. The ethical considerations also favor pigs over non-human primates. While non-human primates are biologically closer to humans, their use raises significant ethical concerns. Pigs, on the other hand, are already extensively used in agriculture and medical research, making their use in xenotransplantation more ethically acceptable and less controversial (Cooper et al., 2019). 2.2 Overview of genetic modifications for improving organ compatibility Genetic modifications are essential for overcoming the immunological barriers that typically cause rejection of pig organs when transplanted into humans. One of the primary targets for genetic modification is the α 1,3-galactosyltransferase (GGTA1) gene, which is responsible for producing the Gal antigen. This antigen is a major cause of hyperacute rejection in xenotransplantation. By knocking out the GGTA1 gene, the expression of the Gal antigen is eliminated, significantly reducing the risk of hyperacute rejection (Petersen et al., 2016). In addition to knocking out problematic genes, genetic engineering has introduced human genes into pigs to enhance the compatibility of pig organs with the human immune system. For instance, the expression of human complement regulatory proteins such as CD46, CD55, and CD59 helps protect the transplanted organ from immune attack by inhibiting the complement cascade, which is part of the immune response that leads to organ rejection (Lei et al., 2022). Further modifications include the introduction of anti-inflammatory and anti-coagulation genes to address other immune and physiological barriers. The expression of human thrombomodulin and endothelial cell protein C receptor in pigs helps prevent coagulation issues that can arise after transplantation, improving the overall success rates of xenotransplantation (Fischer et al., 2016). 2.3 Current status and advancements in pig organ transplantation research The field of pig organ xenotransplantation has seen significant advancements in recent years, with genetically modified pigs showing promising results in preclinical studies. For example, triple-gene modified pigs, which lack major xenoantigens and express multiple human regulatory proteins, have demonstrated improved survival rates and function in non-human primate models. These pigs are bred to express human complement and coagulation regulatory proteins, reducing both hyperacute and acute vascular rejection (Cooper et al., 2019). Recent research has also focused on refining genetic modifications to address remaining challenges such as chronic rejection and long-term graft function. For instance, new techniques like CRISPR/Cas9 are being used to make precise and efficient genetic edits, further improving the compatibility and function of pig organs for transplantation into humans (Kararoudi et al., 2018). Moreover, the first clinical trials involving pig-to-human xenotransplantation are on the horizon, with studies showing that kidneys from genetically modified pigs can function effectively in brain-dead human recipients for extended periods without signs of hyperacute rejection (Montgomery et al., 2022). These advancements represent a significant step forward in making xenotransplantation a viable solution to the organ shortage crisis.
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