International Journal of Molecular Zoology 2024, Vol.14, No.4, 244-254 http://animalscipublisher.com/index.php/ijmz 244 Review and Progress Open Access Pathogen-Free Pigs for Safer Xenotransplantation: Advances and Challenges in Genetic Engineering Xiaofang Lin Tropical Animal Medicine Research Center, Hainan Institute of Tropical Agricultural Resources, Sanya, 572000, Hainan, China Corresponding email: xiaofang.lin@hitar.org International Journal of Molecular Zoology, 2024, Vol.14, No.4 doi: 10.5376/ijmz.2024.14.0022 Received: 18 Jun., 2024 Accepted: 29 Jul., 2024 Published: 21 Aug., 2024 Copyright © 2024 Lin, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Lin X.F., 2024, Pathogen-free pigs for safer xenotransplantation: advances and challenges in genetic engineering, International Journal of Molecular Zoology, 14(4): 244-254 (doi: 10.5376/ijmz.2024.14.0022) Abstract Xenotransplantation, the transplantation of organs and tissues between different species, holds significant promise for addressing the shortage of human organs available for transplantation. Pigs are considered ideal donors due to their physiological similarities to humans. However, the risk of zoonotic pathogen transmission poses a substantial barrier to their use. This systematic review explores the latest advances in genetic engineering techniques aimed at creating pathogen-free pigs for safer xenotransplantation. We examine the current state of gene-editing technologies, such as CRISPR-Cas9, and their application in eliminating endogenous retroviruses and other pathogens. Additionally, we discuss the challenges faced in achieving complete pathogen eradication, including off-target effects, genetic stability, and ethical considerations. By evaluating the progress and limitations in this field, we aim to provide insights into the future directions for research and the potential impact of pathogen-free pigs on the safety and efficacy of xenotransplantation. Keywords Xenotransplantation; Genetic engineering; Pathogen-free pigs; CRISPR-Cas9; Endogenous retroviruses 1 Introduction Xenotransplantation, the process of transplanting organs, tissues, or cells from one species to another, has emerged as a promising solution to the critical shortage of human organs available for transplantation. The demand for organ transplants far exceeds the supply, with thousands of patients dying each year while waiting for a suitable donor organ (Wolf et al., 2019; Sykes and Sachs, 2019). Xenotransplantation, particularly using pigs as organ donors, has emerged as a promising solution to the organ shortage crisis (Lin, 2024). Pigs have been identified as the preferred donor species due to their anatomical and physiological similarities to humans, as well as their compatible organ sizes (Wolf et al., 2019; Ali et al., 2023). Recent advancements in genetic engineering have further enhanced the potential of pigs as viable organ donors by addressing key challenges such as immune rejection and physiological incompatibilities (Yue et al., 2020; Xi et al., 2023). One of the major concerns in xenotransplantation is the risk of transmitting zoonotic pathogens from pigs to human recipients. Porcine endogenous retroviruses (PERVs) and other porcine viruses pose significant risks, as they can potentially infect human cells and compromise the safety of the transplant (Sykes and Sachs, 2019). To mitigate these risks, extensive efforts have been made to develop pathogen-free pigs through advanced genetic engineering techniques. For instance, the inactivation of PERVs using CRISPR-Cas9 technology has shown promising results in producing pigs that are free from these retroviruses (Yue et al., 2020). Additionally, the implementation of highly sensitive screening methods for detecting xenotransplantation-relevant viruses has further ensured the safety of using genetically modified pigs as organ donors (Denner, 2022). This perspective paper aims to provide a comprehensive overview of the advances and challenges in the field of genetic engineering for creating pathogen-free pigs for safer xenotransplantation. By reviewing recent developments and highlighting key findings from various studies, this paper seeks to underscore the significance of genetic modifications in enhancing the safety and efficacy of pig-to-human organ transplants. By achieving these objectives, this paper aims to contribute to the ongoing efforts to make xenotransplantation a viable and safe alternative for patients in need of life-saving organ transplants. The insights provided herein will be valuable for
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