International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 155-166 http://medscipublisher.com/index.php/ijmms 155 Research Perspective Open Access CRISPR/Cas9 Technology in Xenotransplantation: Current Applications and Future Challenges Huixian Li, Jingqiang Wang Institute of Life Science, Jiyang College of Zhejiang A&F University, Zhuji, 311800, Zhejiang, China Corresponding author : jingqiang.wang@gmail.com International Journal of Molecular Medical Science, 2024, Vol.14, No.1 doi: 10.5376/ijmms.2024.14.0019 Received: 11 May, 2024 Accepted: 13 Jun., 2024 Published: 24 Jun., 2024 Copyright © 2024 Li and Wang, 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: Li H.X., and Wang J.Q., 2024, CRISPR/Cas9 technology in xenotransplantation: current applications and future challenges, International Journal of Molecular Medical Science, 14(3): 155-166 (doi: 10.5376/ijmms.2024.14.0019) Abstract Xenotransplantation has emerged as a promising solution to the severe shortage of human donor organs. The CRISPR/Cas9 technology, with its unprecedented precision and efficiency in gene editing, has revolutionized this field, making it possible to genetically modify donor animals to enhance compatibility and reduce immunogenicity. This study explores the current applications of CRISPR/Cas9 in xenotransplantation, highlighting significant advancements such as the knockout of genes producing xenogeneic antigens and the elimination of porcine endogenous retroviruses (PERVs) to prevent zoonotic disease transmission. Despite these achievements, challenges such as off-target effects, genetic mosaicism, and long-term organ survival rates still exist. The research also discusses emerging technologies and the integration of CRISPR/Cas9 with other biotechnological approaches, which have the potential to address these challenges and further advance the field. This study hopes to promote a broader understanding and acceptance of xenotransplantation as a life-saving medical intervention driven by innovations in CRISPR/Cas9 technology. Keywords CRISPR/Cas9; Xenotransplantation; Genetic modification; Immunological rejection; Gene editing 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 donor organs. This biotechnological approach seeks to alleviate the gap between the demand and supply of transplantable organs, which remains a significant challenge in modern medicine. By utilizing organs from genetically modified animals, particularly pigs, xenotransplantation holds the potential to save countless lives (Ryczek et al., 2021). Pigs are considered the most suitable donors due to their physiological similarities to humans and the feasibility of breeding them in large numbers. However, significant immunological and virological barriers have historically impeded the clinical application of pig-to-human xenotransplantation. The phylogenetic distance between pigs and humans leads to acute immune rejection, and the presence of porcine endogenous retroviruses (PERVs) poses a risk of cross-species viral transmission (Salomon, 2016; Niu et al., 2017; Ryczek et al., 2021). The advent of CRISPR/Cas9 technology has revolutionized genetic engineering by providing a precise, efficient, and scalable method for genome editing. Derived from a microbial adaptive immune system, CRISPR/Cas9 allows for targeted modifications of DNA sequences, enabling the insertion, deletion, or replacement of genes with unprecedented accuracy. This technology has been instrumental in advancing various fields, including biotechnology, medicine, and basic biological research (Hsu et al., 2014; Kararoudi et al., 2018). This breakthrough has opened new avenues in biomedical research, including the potential for developing genetically modified animals that are better suited for xenotransplantation. The ability to engineer donor animals with reduced immunogenicity and enhanced compatibility with human physiology represents a significant leap forward in the quest to make xenotransplantation a viable clinical option (Cowan et al., 2019). This study aims to provide a comprehensive overview of the current applications of CRISPR/Cas9 technology in the field of xenotransplantation. By examining the latest advancements and identifying ongoing challenges, it highlights the transformative potential of genetic engineering in overcoming obstacles associated with
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