Disease Modeling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore, 138673, Singapore.
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
J Mol Med (Berl). 2020 May;98(5):615-632. doi: 10.1007/s00109-020-01893-z. Epub 2020 Mar 20.
The rapid advancement of genome editing technologies has opened up new possibilities in the field of medicine. Nuclease-based techniques such as the CRISPR/Cas9 system are now used to target genetically linked disorders that were previously hard-to-treat. The CRISPR/Cas9 gene editing approach wields several advantages over its contemporary editing systems, notably in the ease of component design, implementation and the option of multiplex genome editing. While results from the early phase clinical trials have been encouraging, the small patient population recruited into these trials hinders a conclusive assessment on the safety aspects of the CRISPR/Cas9 therapy. Potential safety concerns include the lack of fidelity in the CRISPR/Cas9 system which may lead to unintended DNA modifications at non-targeted gene loci. This review focuses modifications to the CRISPR/Cas9 components that can mitigate off-target effects in in vitro and preclinical models and its translatability to gene therapy in patient populations.
基因编辑技术的快速发展为医学领域开辟了新的可能性。基于核酸酶的技术，如 CRISPR/Cas9 系统，现在被用于靶向以前难以治疗的与基因相关的疾病。与当代编辑系统相比，CRISPR/Cas9 基因编辑方法具有多个优势，特别是在组件设计、实施的简便性以及多基因编辑的选择方面。虽然早期临床试验的结果令人鼓舞，但这些试验招募的患者人数较少，这阻碍了对 CRISPR/Cas9 治疗安全性方面的明确评估。潜在的安全问题包括 CRISPR/Cas9 系统缺乏保真度，这可能导致非靶向基因座的非预期 DNA 修饰。本综述重点介绍了可以减轻体外和临床前模型中脱靶效应的 CRISPR/Cas9 组件的修饰，以及其在患者群体中的基因治疗中的可转化性。
