Gene therapy for hereditary retinal diseases: hopes and challenges_Chinese Journal of Ocular Fundus Diseases

Authors：

 Lu Fang , Ren Chengda

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

Lu Fang, Email: lufang@wchscu.cn

Keywords：

Inherited retinal diseases; Gene therapy; Genome editing; Editorial

DOI：

10.3760/cma.j.cn511434-20250714-00312

Video：

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Hereditary retinal diseases (IRD) are a type of blinding eye disease with high genetic heterogeneity. In recent years, the rapid development of gene therapy technology has provided new possibilities for the treatment of IRD. Among them, recombinant adeno-associated virus (rAAV) has become the most concerned gene delivery vector at present due to its low immunogenicity, long-term stable transgenic expression and good retinal targeting. Raav-based gene replacement therapies have demonstrated good safety and efficacy in multiple clinical trials. For instance, the Luxturna^® therapy for RPE65 gene mutation-related retinopathy has been successfully applied in clinical practice. However, the packaging capacity limitation of rAAV makes it difficult to deliver larger pathogenic genes, such as USH2A or ABCA4, etc. In addition, some IRD require precise gene modification rather than simple gene supplementation. To overcome these limitations, researchers are exploring a variety of strategies, including the splitting and delivery of biadeno-associated viral vectors, CRISPR/Cas9 gene editing technology, and the development of novel engineered capsids. Future research should focus on optimizing the safety and delivery efficiency of gene editing tools, establishing a more complete preclinical evaluation system, and further enhancing the tissue specificity of vectors. The breakthroughs in these technologies will promote the application of gene therapy in a wider range of IRD.

Citation： Lu Fang, Ren Chengda. Gene therapy for hereditary retinal diseases: hopes and challenges. Chinese Journal of Ocular Fundus Diseases, 2025, 41(7): 489-491. doi: 10.3760/cma.j.cn511434-20250714-00312 Copy

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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. Schneider N, Sundaresan Y, Gopalakrishnan P, et al. Inherited retinal diseases: linking genes, disease-causing variants, and relevant therapeutic modalities[J/OL]. Prog Retin Eye Res, 2022, 101029[2021-11-25]. https://pubmed.ncbi.nlm.nih.gov/34839010/. DOI: 10.1016/j.preteyeres.2021.101029.
3. Wang JH, Gessler DJ, Zhan W, et al. Adeno-associated virus as a delivery vector for gene therapy of human diseases[J/OL]. Signal Transduct Target Ther, 2024, 9(1): 78[2024-04-03]. https://pubmed.ncbi.nlm.nih.gov/38565561/. DOI: 10.1038/s41392-024-01780-w.
4. Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR[J]. Nat Med, 2020, 26(3): 354-359. DOI: 10.1038/s41591-020-0763-1.
5. Michaelides M, Laich Y, Wong SC, et al. Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study[J]. Lancet, 2025, 405(10479): 648-657. DOI: 10.1016/S0140-6736(24)02812-5.
6. Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study[J]. Lancet, 2024, 404(10456): 962-970. DOI: 10.1016/S0140-6736(24)01447-8.
7. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis[J]. N Engl J Med, 2015, 372(20): 1887-1897. DOI: 10.1056/NEJMoa1414221.
8. Shalem O, Sanjana NE, Hartenian E, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells[J]. Science, 2014, 343(6166): 84-87. DOI: 10.1126/science.1247005.
9. Komor AC, Kim YB, Packer MS, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage[J]. Nature, 2016, 533(7603): 420-424. DOI: 10.1038/nature17946.
10. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage[J]. Nature, 2017, 551(7681): 464-471. DOI: 10.1038/nature24644.
11. Anzalone AV, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double-strand breaks or donor DNA[J]. Nature, 2019, 576(7785): 149-157. DOI: 10.1038/s41586-019-1711-4.
12. Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290-associated retinal degeneration[J]. N Engl J Med, 2024, 390(21): 1972-1984. DOI: 10.1056/NEJMoa2309915.
13. Geilenkeuser J, Armbrust N, Steinmaßl E, et al. Engineered nucleocytosolic vehicles for loading of programmable editors[J]. Cell, 2025, 188(10): 2637-2655. DOI: 10.1016/j.cell.2025.03.015.
14. An M, Raguram A, Du SW, et al. Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo[J]. Nat Biotechnol, 2024, 42(10): 1526-1537. DOI: 10.1038/s41587-023-02078-y.
15. Hołubowicz R, Du SW, Felgner J, et al. Safer and efficient base editing and prime editing via ribonucleoproteins delivered through optimized lipid-nanoparticle formulations[J]. Nat Biomed Eng, 2025, 9(1): 57-78. DOI: 10.1038/s41551-024-01296-2.
16. Herrera-Barrera M, Ryals RC, Gautam M, et al. Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates[J/OL]. Sci Adv, 2023, 9(2): eadd4623[2023-01-13]. https://pubmed.ncbi.nlm.nih.gov/36630502/. DOI: 10.1126/sciadv.add4623.
17. Musunuru K, Grandinette SA, Wang X, et al. Patient-specific in vivo gene editing to treat a rare genetic disease[J]. N Engl J Med, 2025, 392(22): 2235-2243. DOI: 10.1056/NEJMoa2504747.

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Gene therapy for hereditary retinal diseases: hopes and challenges

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