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The application and progression of CRISPR/Cas9 technology in ophthalmological diseases

Abstract

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) system is an adaptive immune defence system that has gradually evolved in bacteria and archaea to combat invading viruses and exogenous DNA. Advances in technology have enabled researchers to enhance their understanding of the immune process in vivo and its potential for use in genome editing. Thus far, applications of CRISPR/Cas9 genome editing technology in ophthalmology have included gene therapy for corneal dystrophy, glaucoma, congenital cataract, Leber’s congenital amaurosis, retinitis pigmentosa, Usher syndrome, fundus neovascular disease, proliferative vitreoretinopathy, retinoblastoma and other eye diseases. Additionally, the combination of CRISPR/Cas9 genome editing technology with adeno-associated virus vector and inducible pluripotent stem cells provides further therapeutic avenues for the treatment of eye diseases. Nonetheless, many challenges remain in the development of clinically feasible retinal genome editing therapy. This review discusses the development, as well as mechanism of CRISPR/Cas9 and its applications and challenges in gene therapy for eye diseases.

摘要

CRISPR/CRISPR相关核酸酶 (Cas) 系统是一种在细菌和古细菌中逐渐进化, 以对抗入侵病毒和外源性DNA的适应性免疫防御系统。基因编辑技术的发展使研究人员更深刻地认识到了生物体内的免疫过程及将该系统应用于基因组编辑的巨大潜力。迄今为止, CRISPR/Cas9基因组编辑技术在眼科的应用已涵盖了角膜营养不良、青光眼、先天性白内障、Leber先天性黑朦、视网膜色素变性、Usher综合征、眼底新生血管疾病、增生性玻璃体视网膜病变、视网膜母细胞瘤等疾病的基因治疗。此外, CRISPR/Cas9基因组编辑技术和腺相关病毒载体以及诱导型多能干细胞的结合, 为眼科疾病提供了进一步的治疗途径。

尽管如此, 临床上开展可行的视网膜基因组编辑治疗仍然存在许多挑战。本综述讨论了CRISPR/Cas9技术的发展历程、作用机制及其在眼科疾病基因治疗中的应用和挑战。

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Fig. 1: Schematic representation of the Clustered-regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated (Cas) 9 system.
Fig. 2: Schematic representation of a double-stranded break (DSB; blue dotted line), which can be repaired through nonhomologous end-joining (NHEJ), homology-directed repair (HDR) or microhomology-mediated end joining (MMEJ) pathways.
Fig. 3: The protocol for genome editing in the retina includes in vivo and ex vivo approaches.

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Funding

This work was supported by grants from the Natural Science Foundation of China (82101162), the Joint Construction Program of Henan Medical Science and Technology Research Plan (LHGJ20200067) and the Basic Research Project of Henan Eye Hospital (22JCQN011 and 20JCZD001).

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XMH, ZMS, and BBZ conceived and drafted the review outline. XMH wrote the paper. ZMS, BBZ, XLL, ML, YGW, HDD, JMZ, YMW, KKG, and PL provided critical review of the paper.

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Correspondence to Zongming Song.

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Hu, X., Zhang, B., Li, X. et al. The application and progression of CRISPR/Cas9 technology in ophthalmological diseases. Eye (2022). https://doi.org/10.1038/s41433-022-02169-1

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