Miniature Pig’s Kidneys: Solution to Organ Shortage?

Article by: Emil Koch, on 24 October 2023, at 12:48 CEST

Image by gpointstudio on Freepik

As of 24 October, in the US, almost 104,000 organ transplants are missing, and in 2018, over 150,000 were lacking in Europe. A new study suggests genetically modified miniature pigs could help solve the problem.

Xenotransplantation is called the technique they applied, an artificial method of creating an animal-human chimera. For that, the researchers humanized the Yucatan miniature pig breed by inserting seven human transgenes and three glycans with or without retroviral inactivation (RI). The authors explain that they chose the Yucatan miniature pig because its organs resemble human organs (Anand et al., 2023). Of particular interest are the cell-surface antigens that would lead to incompatibility between primates and pigs - the three glycan antigens α-Gal, Neu5Gc, and Sd(a) expressed by porcine cells. When exposed to primate serum, glycan antigens are recognized by primate antibodies, and antibody-mediated rejection (AMR) is performed (Robson et al., 1999). In other words, the primate and human immune system would suspiciously eye and then reject the transplanted organ from pigs.

The good news is that the pig, edited in 69 genes, disrupted the dangerous genes for glycan synthesis genes, inserted seven human transgenes, and inactivated retrovirus genes found in the pig genome by CRISPR-Cas-9 editing. Findings confirm the effectiveness of putting human transgenes in pigs to reduce the likelihood of autoimmune reactions upon transplantation. In fact, while monkeys with kidneys from pigs with knocked-out sugar groups and transgenes survived up to 758 days, they only lived up to 24 days without. Importantly, the transgenes CD46 and CD55 were able to block antibodies and mitigate the complement system that would promote inflammation and attack foreign cells. In addition, the scientists conclude that D46 and CD55 proteins regulate complement activity when expressed on porcine kidney endothelial cells.

Recently, doctors at NYU Langone Health have accomplished the transplantation of a genetically modified pig kidney functioning within a human recipient's body. In a breakthrough, carboxyl alpha-gal has been pinpointed as the factor responsible for rapid antibody-mediated rejection of pig organs in humans. A pig kidney with a single-gene knockout, devoid of carboxyl alpha-gal, managed to evade immediate rejection and effectively for a record 32 days within a brain-dead human recipient. This discovery underscores the effectiveness of genetically modified pigs, even when altering a single gene, in aiding the recovery of human patients.

In a different study at the University of Alabama at Birmingham's Heersink School of Medicine, genetically modified pig kidneys have been transplanted in a human patient declared brain-dead. Remarkably, together with drugs that prevented the patient's immune system from rejecting the organs, the pig kidneys have produced urine and filtered waste, specifically high creatine levels dropped. This is another promising step in animal organ utilization.

In September 2023, the University of Maryland Medical Center achieved a significant milestone by conducting its second pig heart transplant, following the groundbreaking surgery in 2022. This life-saving procedure was performed on a patient in the advanced stages of cardiovascular disease who was considered ineligible for a traditional heart transplant. These recent advancements in the field signify a promising step forward, suggesting that xenotransplantation may soon become a viable option for large-scale implementation.

Nonetheless, there may be individuals who raise valid concerns regarding animal welfare, especially considering the intelligence of pigs as a species. Consequently, it is of utmost importance to ensure that the welfare requirements of these animals are consistently met throughout their lives, enabling them to express their natural behaviors and undergo subsequent surgery without experiencing pain.

In conclusion, as ongoing research continues to demonstrate promise through larger sample sizes and addresses ethical concerns, this innovative technique has the potential to revolutionize the field of organ transplantation in kidneys, hearts, and beyond, significantly reducing the agonizing wait times for patients in need.

References:

Anand, R., Layer, J. V., Héja, D., Hirose, T., Lassiter, G., Firl, D. J., Paragas, V., Akkad, A., Chhangawala, S., Colvin, R. B., Ernst, R. J., Van Esch, N. E. B. a. M., Getchell, K., Griffin, A., Guo, X., Hall, K., Hamilton, P., Kalekar, L. A., Kan, Y., . . . Qin, W. (2023). Design and testing of a humanized porcine donor for xenotransplantation. Nature, 622(7982), 393–401. https://doi.org/10.1038/s41586-023-06594-4.

Locke, J. E., Kumar, V., Anderson, D. J., & Porrett, P. M. (2023). Normal graft function after Pig-to-Human kidney xenotransplant. JAMA Surgery, 158(10), 1106. https://doi.org/10.1001/jamasurg.2023.2774.

NYU Langone News (2023, September 14). Two-Month study of pig kidney xenotransplantation gives new hope to the future of the organ supply. https://nyulangone.org/news/two-month-study-pig-kidney-xenotransplantation-gives-new-hope-future-organ-supply. Accessed on 10/24/2023.

Robson, S. C., Esch, J. S. A., & Bach, F. H. (1999). Factors in xenograft rejection. Annals of the New York Academy of Sciences, 875(1), 261–276. https://doi.org/10.1111/j.1749-6632.1999.tb08509.x.