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      Recent advances in genetically modified large-animal models of human diseases


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          Large-animal models show greater advantages than rodents in recapitulating human genetic diseases, primarily because of their higher similarity to humans in terms of anatomy, physiology and genetics. Notably, as genome-editing technologies have rapidly improved, particularly transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR-associated protein 9) systems, their application in biomedical research has accelerated. A variety of genetically modified large-animal models, including non-human primates, pigs, dogs, bovines and sheep, have been produced to recapitulate human inherited disorders, thus providing novel biological and translational insights. Here, we review recent progress in the generation of large-animal models over the past 5 years and summarize their use in studying human genetic diseases, focusing on the nervous system, cardiovascular and metabolic systems, the immune system, xenotransplantation, the reproductive system and embryonic development.

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          Most cited references136

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          Genome engineering using the CRISPR-Cas9 system.

          Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks.
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            Inflammation and metabolic disorders.

            Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
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              Base editing: precision chemistry on the genome and transcriptome of living cells

              RNA-guided programmable nucleases from CRISPR systems generate precise breaks in DNA or RNA at specified positions. In cells, this activity can lead to changes in DNA sequence or RNA transcript abundance. Base editing is a newer genome editing approach that uses components from CRISPR systems together with other enzymes to directly install point mutations into cellular DNA or RNA without making double-stranded DNA breaks (DSBs). DNA base editors comprise a catalytically disabled nuclease fused to a nucleobase deaminase enzyme and, in some cases, a DNA glycosylase inhibitor. RNA base editors achieve analogous changes using components that target RNA. Base editors directly convert one base or base pair into another, enabling the efficient installation of point mutations in non-dividing cells without generating excess undesired editing byproducts. In this Review, we summarize base editing strategies to generate specific and precise point mutations in genomic DNA and RNA, highlight recent developments that expand the scope, specificity, precision, and in vivo delivery of base editors, and discuss limitations and future directions of base editing for research and therapeutic applications.

                Author and article information

                BIO Integration
                Compuscript (Ireland )
                December 2022
                29 November 2022
                : 3
                : 4
                : 161-171
                [1] 1Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
                [2] 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
                [3] 3Center for Reproductive Genetics and Reproductive Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
                [4] 4Guangzhou Laboratory, Guangzhou, Guangdong, China
                Author notes
                *Correspondence to: Chunwei Cao, E-mail: caochw5@ 123456mail.sysu.edu.cn
                Copyright © 2022 The Authors

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See https://bio-integration.org/copyright-and-permissions/

                Self URI (journal-page): https://bio-integration.org/
                Review Article

                Medicine,Molecular medicine,Radiology & Imaging,Biotechnology,Pharmacology & Pharmaceutical medicine,Microscopy & Imaging
                large animal models,translational medicine,human inherited diseases,TALEN,CRISPR/Cas9


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