De Ravin Suk See, Brault Julie
Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, U.S.A.
Emerg Top Life Sci. 2019 May 31;3(3):277-287. doi: 10.1042/ETLS20180157.
Primary immunodeficiency diseases (PIDs) encompass a range of diseases due to mutations in genes that are critical for immunity. Haploinsufficiency and gain-of-function mutations are more complex than simple loss-of-function mutations; in addition to increased susceptibility to infections, immune dysregulations like autoimmunity and hyperinflammation are common presentations. Hematopoietic stem cell (HSC) gene therapy, using integrating vectors, provides potential cure of disease, but genome-wide transgene insertions and the lack of physiological endogenous gene regulation may yet present problems, and not applicable in PIDs where immune regulation is paramount. Targeted genome editing addresses these concerns; we discuss some approaches of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas system applicable for gene therapy in PIDs. Preclinical repair of gene mutations and insertion of complementary DNA restore endogenous gene regulation and they have shown very promising data for clinical application. However, ongoing studies to characterize off-target genotoxicity, careful donor designs to ensure physiological expression, and maneuvers to optimize engraftment potential are critical to ensure successful application of this next-gen targeted HSC gene therapy.
原发性免疫缺陷病（PIDs）涵盖了一系列因对免疫至关重要的基因突变而导致的疾病。单倍剂量不足和功能获得性突变比简单的功能丧失性突变更为复杂；除了对感染的易感性增加外，免疫失调如自身免疫和过度炎症也是常见表现。使用整合载体的造血干细胞（HSC）基因疗法为疾病提供了潜在的治愈方法，但全基因组转基因插入以及缺乏生理性内源性基因调控可能仍然存在问题，并且不适用于免疫调节至关重要的原发性免疫缺陷病。靶向基因组编辑解决了这些问题；我们讨论了一些适用于原发性免疫缺陷病基因治疗的CRISPR（成簇规律间隔短回文重复序列）/Cas系统方法。基因突变的临床前修复和互补DNA的插入恢复了内源性基因调控，并且它们已经显示出非常有前景的临床应用数据。然而，正在进行的表征脱靶基因毒性的研究、精心设计供体以确保生理性表达以及优化植入潜力的策略对于确保这种下一代靶向造血干细胞基因治疗的成功应用至关重要。
