Lin Yingqi, Li Jun, Li Caijuan, Tu Zhuchi, Li Shihua, Li Xiao-Jiang, Yan Sen
Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
Front Cell Dev Biol. 2022 May 17;10:919155. doi: 10.3389/fcell.2022.919155. eCollection 2022.
The foundation for investigating the mechanisms of human diseases is the establishment of animal models, which are also widely used in agricultural industry, pharmaceutical applications, and clinical research. However, small animals such as rodents, which have been extensively used to create disease models, do not often fully mimic the key pathological changes and/or important symptoms of human disease. As a result, there is an emerging need to establish suitable large animal models that can recapitulate important phenotypes of human diseases for investigating pathogenesis and developing effective therapeutics. However, traditional genetic modification technologies used in establishing small animal models are difficultly applied for generating large animal models of human diseases. This difficulty has been overcome to a great extent by the recent development of gene editing technology, especially the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). In this review, we focus on the applications of CRISPR/Cas9 system to establishment of large animal models, including nonhuman primates, pigs, sheep, goats and dogs, for investigating disease pathogenesis and treatment. We also discuss the limitations of large animal models and possible solutions according to our current knowledge. Finally, we sum up the applications of the novel genome editing tool Base Editors (BEs) and its great potential for gene editing in large animals.
研究人类疾病机制的基础是建立动物模型，动物模型在农业、制药应用和临床研究中也有广泛应用。然而，诸如啮齿动物等已被广泛用于创建疾病模型的小型动物，往往不能完全模拟人类疾病的关键病理变化和/或重要症状。因此，迫切需要建立合适的大型动物模型，以重现人类疾病的重要表型，用于研究发病机制和开发有效的治疗方法。然而，用于建立小型动物模型的传统基因改造技术很难应用于创建人类疾病的大型动物模型。基因编辑技术的最新发展，尤其是成簇规律间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9），在很大程度上克服了这一困难。在这篇综述中，我们重点关注CRISPR/Cas9系统在建立大型动物模型中的应用，包括非人灵长类动物、猪、绵羊、山羊和狗，用于研究疾病发病机制和治疗。我们还根据目前的知识讨论了大型动物模型的局限性和可能的解决方案。最后，我们总结了新型基因组编辑工具碱基编辑器（BEs）的应用及其在大型动物基因编辑中的巨大潜力。
