Research progress of <i>CRISPR</i> gene editing technology in the treatment of inherited retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Yang Chongchao ^1,2 , Cui Kaixuan ^1,2 ,  Zhang Guoming ^1,2

1. The First Clinical Medical College of Jinan University, Guangzhou 510630, China;
2. Shenzhen Eye Hospital/Shenzhen Eye Research Center, Southern Medical University, Shenzhen 518040, China;

Corresponding author：

Zhang Guoming, Email: zhangguoming@sz-eyes.com

Keywords：

CRISPR; Gene therapy; Inherited retinal diseases; Adeno-associated virus; Review

DOI：

10.3760/cma.j.cn511434-20250805-00334

Video：

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Abstract Full text Figures/Tables Video References Cited by

In recent years, with the rapid development of gene editing technologies, research on the application of the clustered regularly interspaced short palindromic repeats (CRISPR) system in inherited retinal diseases (IRD) has become increasingly in-depth. Many IRD, such as retinitis pigmentosa, Leber congenital amaurosis, and Stargardt disease, are characterized by clearly defined pathogenic gene mutations, making them ideal targets for gene therapy. Owing to its high efficiency, strong specificity, and programmability, CRISPR technology offers a novel approach for the precise treatment of these conditions. This review summarizes recent progress in the application of CRISPR in IRD therapy, with a focus on target gene selection, optimization of editing tools and delivery systems, in vitro and in vivo validation, and early clinical investigations. In addition, current challenges, including off target effects, immune responses, and limitations in editing and delivery efficiency, are discussed. With continuous improvements in editing platforms and delivery strategies, CRISPR holds great promise for personalized treatment of IRD and may further accelerate the clinical application of precision medicine in ophthalmology.

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1. Biber J, Gandor C, Becirovic E, et al. Retina-directed gene therapy: Achievements and remaining challenges[J/OL]. Pharmacol Ther, 2025, 271: 108862[2025-04-21]. https://pubmed.ncbi.nlm.nih.gov/40268248/. DOI: 10.1016/j.pharmthera.2025.108862.
2. Willett K, Bennett J. Immunology of AAV-mediated gene transfer in the eye[J/OL]. Front Immunol, 2013, 4: 261[2013-08-30]. https://pubmed.ncbi.nlm.nih.gov/24009613/. DOI: 10.3389/fimmu.2013.00261.
3. Di Carlo E, Sorrentino C. State of the art CRISPR-based strategies for cancer diagnostics and treatment[J/OL]. Biomark Res, 2024, 12(1): 156[2024-12-18]. https://pubmed.ncbi.nlm.nih.gov/39696697/. DOI: 10.1186/s40364-024-00701-x.
4. Xu W, Zhang S, Qin H, et al. From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine[J/OL]. J Transl Med, 2024, 22(1): 1133[2024-12-20]. https://pubmed.ncbi.nlm.nih.gov/39707395/. DOI: 10.1186/s12967-024-05957-3.
5. Cai R, Lv R, Shi X, et al. CRISPR/dCas9 tools: epigenetic mechanism and application in gene transcriptional regulation[J/OL]. Int J Mol Sci, 2023, 24(19): 14865[2023-10-03]. https://pubmed.ncbi.nlm.nih.gov/37834313/. DOI: 10.3390/ijms241914865.
6. Bakondi B, Lv W, Lu B, et al. In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa[J]. Mol Ther, 2016, 24(3): 556-563. DOI: 10.1038/mt.2015.220.
7. Patrizi C, Llado M, Benati D, et al. Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model[J]. Am J Hum Genet, 2021, 108(2): 295-308. DOI: 10.1016/j.ajhg.2021.01.006.
8. Giannelli SG, Luoni M, Castoldi V, et al. Cas9/sgRNA selective targeting of the P23H Rhodopsin mutant allele for treating retinitis pigmentosa by intravitreal AAV9. PHP. B-based delivery[J]. Hum Mol Genet, 2018, 27(5): 761-779. DOI: 10.1093/hmg/ddx438.
9. Liu X, Qiao J, Jia R, et al. Allele-specific gene-editing approach for vision loss restoration in RHO-associated retinitis pigmentosa[J/OL]. Elife, 2023, 12: e84065[2023-06-05]. https://pubmed.ncbi.nlm.nih.gov/37272616/. DOI: 10.7554/eLife.84065.
10. Sun X, Liang C, Chen Y, et al. Knockout and replacement gene surgery to treat rhodopsin-mediated autosomal dominant retinitis pigmentosa[J]. Hum Gene Ther, 2024, 35(5-6): 151-162. DOI: 10.1089/hum.2023.201.
11. Du W, Li J, Tang X, et al. CRISPR/SaCas9-based gene editing rescues photoreceptor degeneration throughout a rhodopsin-associated autosomal dominant retinitis pigmentosa mouse model[J]. Exp Biol Med (Maywood), 2023, 248(20): 1818-1828. DOI: 10.1177/15353702231199069.
12. Burnight ER, Wiley LA, Mullin NK, et al. CRISPRi-mediated treatment of dominant rhodopsin-associated retinitis pigmentosa[J]. CRISPRJ, 2023, 6(6): 502-513. DOI: 10.1089/crispr.2023.0039.
13. Yan Z, Yao Y, Li L, et al. Treatment of autosomal dominant retinitis pigmentosa caused by RHO-P23H mutation with high-fidelity Cas13X in mice[J]. Mol Ther Nucleic Acids, 2023, 33: 750-761. DOI: 10.1016/j.omtn.2023.08.002.
14. Diakatou M, Dubois G, Erkilic N, et al. Allele-specific knockout by CRISPR/Cas to treat autosomal dominant retinitis pigmentosa caused by the G56R mutation in NR2E3[J/OL]. Int J Mol Sci, 2021, 22(5): 2607[2024-03-05]. https://pubmed.ncbi.nlm.nih.gov/33807610/. DOI: 10.3390/ijms22052607.
15. Cai Y, Cheng T, Yao Y, et al. In vivo genome editing rescues photoreceptor degeneration via a Cas9/RecA-mediated homology-directed repair pathway[J/OL]. Sci Adv, 2019, 5(4): eaav3335[2019-04-17]. https://pubmed.ncbi.nlm.nih.gov/31001583/. DOI: 10.1126/sciadv.aav3335.
16. Tsai YT, Da Costa BL, Nolan ND, et al. Prime editing for the installation and correction of mutations causing inherited retinal disease: a brief methodology[J]. Methods Mol Biol, 2023, 2560: 313-331. DOI: 10.1007/978-1-0716-2651-1_29.
17. Fu Y, He X, Ma L, et al. In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa[J/OL]. Nat Commun, 2025, 16(1): 2394[2025-03-10]. https://pubmed.ncbi.nlm.nih.gov/40064881/. DOI: 10.1038/s41467-025-57628-6.
18. Wang Q, Xu X, Chen S, et al. dCasMINI-mediated therapy rescues photoreceptors degeneration in a mouse model of retinitis pigmentosa[J/OL]. Sci Adv, 2024, 10(51): eadn7540[2024-12-20]. https://pubmed.ncbi.nlm.nih.gov/39693439/. DOI: 10.1126/sciadv.adn7540.
19. Suzuki K, Tsunekawa Y, Hernandez-Benitez R, et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration[J]. Nature, 2016, 540(7631): 144-149. DOI: 10.1038/nature20565.
20. Puertas-Neyra K, Coco-Martin RM, Hernandez-Rodriguez LA, et al. Clinical exome analysis and targeted gene repair of the c. 1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes[J/OL]. Stem Cell Res Ther, 2024, 15(1): 192[2024-07-02]. https://pubmed.ncbi.nlm.nih.gov/38956727/. DOI: 10.1186/s13287-024-03804-2.
21. Du SW, Newby GA, Salom D, et al. In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice[J/OL]. Proc Natl Acad Sci USA, 2024, 121(48): e2416827121[2024-11-18]. https://pubmed.ncbi.nlm.nih.gov/39556729/. DOI: 10.1073/pnas.2416827121.
22. Deng WL, Gao ML, Lei XL, et al. Gene correction reverses ciliopathy and photoreceptor loss in iPSC-derived retinal organoids from retinitis pigmentosa patients[J]. Stem Cell Reports, 2018, 10(4): 1267-1281. DOI: 10.1016/j.stemcr.2018.02.003.
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Chinese Journal of Ocular Fundus Diseases

Latest ArticlesResearch progress of CRISPR gene editing technology in the treatment of inherited retinal diseases

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