Development of artificial transcription factors and their applications in cell reprograming, genetic screen, and disease treatment.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.029
Yetong Sang, Lingjie Xu, Zehua Bao
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Abstract

Gene dysregulations are associated with many human diseases, such as cancers and hereditary diseases. Artificial transcription factors (ATFs) are synthetic molecular tools to regulate the expression of disease-associated genes, which is of great significance in basic biological research and biomedical applications. Recent advances in the engineering of ATFs for regulating endogenous gene expression provide an expanded set of tools for understanding and treating diseases. However, the potential immunogenicity, large size, inefficient delivery, and off-target effects persist as obstacles for ATFs to be developed into therapeutics. Moreover, the activation of an endogenous gene following ATF activity lacks durability. In this review, we first describe the functional components of ATFs, including DNA-binding domains, transcriptional effector domains, and control switches. We then highlight examples of applications of ATFs, including cell reprogramming and differentiation, pathogenic gene screening, and disease treatment. Finally, we analyze and summarize major challenges for the clinical translation of ATFs and propose potential strategies to improve these useful molecular tools.

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人工转录因子:技术开发及在细胞重编程、基因筛选和疾病治疗中的应用。
基因失调与许多人类疾病(如癌症和遗传性疾病)有关。人工转录因子(ATFs)是调节疾病相关基因表达的合成分子工具,在基础生物学研究和生物医学应用中具有重要意义。最近,用于调节内源基因表达的 ATFs 工程技术取得了进展,为了解和治疗疾病提供了更多的工具。然而,ATFs 的潜在免疫原性、体积大、传递效率低和脱靶效应等问题仍然是其开发成治疗药物的障碍。此外,ATF 活性对内源性基因的激活缺乏持久性。在这篇综述中,我们首先介绍了 ATF 的功能成分,包括 DNA 结合域、转录效应域和控制开关。然后,我们重点介绍 ATF 的应用实例,包括细胞重编程和分化、致病基因筛选和疾病治疗。最后,我们分析并总结了 ATFs 临床转化所面临的主要挑战,并提出了改进这些有用分子工具的潜在策略。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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