Recent advances in genome editing tools, especially novel developments in the clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases (CRISPR/Cas9)-derived editing machinery, have revolutionized not only basic science but, importantly, also the gene therapy field. Their flexibility and ability to introduce precise modifications in the genome to disrupt or correct genes or insert expression cassettes in safe harbors in the genome underline their potential applications as a medicine of the future to cure many genetic diseases. In this review, we give an overview of the recent progress made by French researchers in the field of therapeutic genome editing, while putting their work in the general context of advances made in the field. We focus on recent hematopoietic stem cell gene editing strategies for blood diseases affecting the red blood cells or blood coagulation as well as lysosomal storage diseases. We report on a genome editing-based therapy for muscular dystrophy and the potency of T cell gene editing to increase anticancer activity of chimeric antigen receptor T cells to combat cancer. We will also discuss technical obstacles and side effects such as unwanted editing activity that need to be surmounted on the way toward a clinical implementation of genome editing. We propose here improvements developed today, including by French researchers to overcome the editing-related genotoxicity and improve editing precision by the use of novel recombinant nuclease-based systems such as nickases, base editors, and prime editors. Finally, a solution is proposed to resolve the cellular toxicity induced by the systems employed for gene editing machinery delivery.

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基因治疗应用基因组编辑的最新进展：法国的观点

基因组编辑工具的最新进展，特别是与 Cas9 核酸酶 (CRISPR/Cas9) 衍生的编辑机制相关的成簇规则间隔短回文重复的新发展，不仅彻底改变了基础科学，而且更重要的是，也改变了基因治疗领域。它们在基因组中引入精确修饰以破坏或纠正基因或将表达盒插入基因组中的安全港的灵活性和能力强调了它们作为未来治疗许多遗传疾病的药物的潜在应用。在这篇综述中，我们概述了法国研究人员在治疗性基因组编辑领域取得的最新进展，同时将他们的工作置于该领域取得的进展的总体背景下。我们专注于最近的造血干细胞基因编辑策略，用于影响红细胞或血液凝固的血液疾病以及溶酶体贮积病。我们报告了一种基于基因组编辑的肌营养不良疗法，以及 T 细胞基因编辑提高嵌合抗原受体 T 细胞抗癌活性以对抗癌症的效力。我们还将讨论技术障碍和副作用，例如在基因组编辑的临床实施过程中需要克服的不需要的编辑活动。我们在这里提出了今天开发的改进，包括法国研究人员通过使用新型重组核酸酶系统（如切口酶、碱基编辑器和主编辑器）来克服与编辑相关的基因毒性并提高编辑精度。最后，