Research progress of splicing mutations in inherited retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Zhuoying , Tian Lu , Li Yang ,  Wang Yanling

Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;

Corresponding?author：

Wang Yanling, Email: wangyanling999@vip.sina.com

Keywords：

Inherited retinal diseases; Splicing mutations; Antisense oligonucleotide; Gene editing; CRISPR-Cas9; Review

DOI：

10.3760/cma.j.cn511434-202501020-00456

Video：

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Hereditary retinopathy (IRD) is a group of congenital retinal degenerative diseases caused by lesions in photoreceptor cells or retinal pigment epithelial cells. It has a high degree of genetic and clinical heterogeneity and is an important cause of incurable blindness in adolescents. Splicing variation is a special type of genetic variation caused by gene sequence mutations interfering with the normal RNA splicing process. It leads to abnormal rearrangement patterns of messenger ribonucleic acid during maturation, which is essentially different from the physiological isomers produced by normal selective splicing. IRD splicing variations mainly include classical site variations and deep intron site variations. Many breakthroughs have been made in targeted therapy for these variations. Antisense oligonucleotides, clustered regularly interspaced short palindromic repeats and associated protein 9 binding induced pluripotent stem cells, small molecule compounds, and spliceosome-mediated RNA trans-splicing techniques all show good application prospects. However, at present, related research is still in a fragmented state. A systematic review of splicing mutations and related treatment progress will provide important support for in-depth clarification of their pathogenic mechanisms and the development of effective therapies, bringing a glimmer of hope to such diseases that were once regarded as "incurable". Although there are still challenges such as low detection efficiency, poor treatment safety and individualized differences at present, with the continuous progress of molecular biology and gene therapy technology, it is gradually becoming possible to achieve precise diagnosis and radical individualized treatment of splicing mutation-related IRD, bringing hope to patients.

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6.	Liu MM, Zack DJ. Alternative splicing and retinal degeneration[J]. Clin Genet, 2013, 84(2): 142-149. DOI: 10.1111/cge.12181.
7.	Khan M, Cornelis SS, Pozo-Valero MD, et al. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics[J]. Genet Med, 2020, 22(7): 1235-1246. DOI: 1235-46.10.1038/s41436-020-0787-4. DOI: 10.1038/s41436-020-0787-4.
8.	Love SL, Emerson JD, Koide K, et al. Pre-mRNA splicing-associated diseases and therapies[J]. RNA Biol, 2023, 20(1): 525-538. DOI: 10.1080/15476286.2023.2239601.
9.	El Marabti E, Malek J, Younis I. Minor intron splicing from basic science to disease[J/OL]. Int J Mol Sci, 2021, 22(11): 6062[2021-06-04]. https://pubmed.ncbi.nlm.nih.gov/34199764/. DOI: 10.3390/ijms22116062.
10.	Wilkinson ME, Charenton C, Nagai K. RNA splicing by the spliceosome[J]. Annu Rev Biochem, 2020, 89: 359-388. DOI: 10.1146/annurev-biochem-091719-064225.
11.	Aísa-Marín I, García-Arroyo R, Mirra S, et al. The alter retina: alternative splicing of retinal genes in health and disease[J/OL]. Int J Mol Sci, 2021, 22(4): 1855[2021-02-12]. https://pubmed.ncbi.nlm.nih.gov/33673358/. DOI: 10.3390/ijms22041855.
12.	Delmaghani S, El-Amraoui A. The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification[J]. Hum Genet, 2022, 141(3-4): 709-735. DOI: 10.1007/s00439-022-02448-7.
13.	Mansard L, Baux D, Vaché C, et al. The study of a 231 French patient cohort significantly extends the mutational spectrum of the two major usher genes MYO7A and USH2A[J/OL]. Int J Mol Sci, 2021, 22(24): 13294[2021-12-10]. https://pubmed.ncbi.nlm.nih.gov/34948090/. DOI: 10.3390/ijms222413294.
14.	De Angeli P, Spaag S, Shliaga S, et al. Single-guide RNA Cas9 and enhanced-deletion Cas9 rescue a recurrent USH2A-related splicing defect[J/OL]. Mol Ther Nucleic Acids, 2025, 36(2): 102523[2025-03-21]. https://pubmed.ncbi.nlm.nih.gov/40235854/. DOI: 10.1016/j.omtn.2025.102523.
15.	Tian L, Chen C, Song Y, et al. Phenotype-based genetic analysis reveals missing heritability of ABCA4-related retinopathy: deep intronic variants and copy number variations[J/OL]. Invest Ophthalmol Vis Sci, 2022, 63(6): 5[2022-06-01]. https://pubmed.ncbi.nlm.nih.gov/35657619/. DOI: 10.1167/iovs.63.6.5.
16.	Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to cep290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI: 10.1097/IAE.0000000000003133.
17.	Valkenburg D, van Cauwenbergh C, Lorenz B, et al. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c. 2991+1655A>G mutation in CEP290[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4384-4391. DOI: 10.1167/iovs.18-24817.
18.	Gagliardi M, Ashizawa AT. The Challenges and strategies of antisense oligonucleotide drug delivery[J/OL]. Biomedicines, 2021, 9(4): 433[2021-04-16]. https://pubmed.ncbi.nlm.nih.gov/33923688/. DOI: 10.3390/biomedicines9040433.
19.	Sang A, Zhuo S, Bochanis A, et al. Mechanisms of action of the US food and drug administration-approved antisense oligonucleotide drugs[J]. BioDrugs, 2024, 38(4): 511-526. DOI: 10.1007/s40259-024-00665-2.
20.	Kaltak M, de Bruijn P, Piccolo D, et al. Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c. 5461-10T>C[J]. Mol Ther Nucleic Acids, 2023, 31: 674-688. DOI: 10.1016/j.omtn.2023.02.020.
21.	Egli M, Manoharan M. Chemistry, structure and function of approved oligonucleotide therapeutics[J]. Nucleic Acids Res, 2023, 51(6): 2529-2573. DOI: 10.1093/nar/gkad067.
22.	Russell SR, Drack AV, Cideciyan AV, et al. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial[J]. Nat Med, 2022, 28(5): 1014-1021. DOI: 10.1038/s41591-022-01755-w.
23.	Dulla K, Aguila M, Lane A, et al. Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c. 2991+1655A>G LCA10 models[J]. Mol Ther Nucleic Acids, 2018, 12: 730-740. DOI: 10.1016/j.omtn.2018.07.010.
24.	Burnight ER, Giacalone JC, Cooke JA, et al. CRISPR-Cas9 genome engineering: treating inherited retinal degeneration[J]. Prog Retin Eye Res, 2018, 65: 28-49. DOI: 10.1016/j.preteyeres.2018.03.003.
25.	Wiley LA, Burnight ER, Kaalberg EE, et al. Assessment of adeno-associated virus serotype tropism in human retinal explants[J]. Hum Gene Ther, 2018, 29(4): 424-436. DOI: 10.1089/hum.2017.179.
26.	Meng X, Jia R, Zhao X, et al. In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment[J/OL]. Nat Commun, 2024, 15(1): 3773[2024-05-06]. https://pubmed.ncbi.nlm.nih.gov/38710738/. DOI: 10.1038/s41467-024-48092-9.
27.	Ajiro M, Awaya T, Kim YJ, et al. Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia[J/OL]. Nat Commun, 2021, 112(1): 4507[2021-07-23]. https://pubmed.ncbi.nlm.nih.gov/34301951/. DOI: 10.1038/s41467-021-24705-5.
28.	Nishio H, Niba ETE, Saito T, et al. Spinal muscular atrophy: the past, present, and future of diagnosis and treatment[J/OL]. Int J Mol Sci, 2023, 24(15): 11939[2023-07-26]. https://pubmed.ncbi.nlm.nih.gov/37569314/. DOI: 10.3390/ijms241511939.
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30.	Doi A, Delaney C, Tanner D, et al. RNA exon editing: Splicing the way to treat human diseases[J/OL]. Mol Ther Nucleic Acids, 2024, 35(3): 102311[2024-08-16]. https://pubmed.ncbi.nlm.nih.gov/39281698/. DOI: 10.1016/j.omtn.2024.102311.
31.	Berger A, Maire S, Gaillard MC, et al. mRNA trans-splicing in gene therapy for genetic diseases[J]. Wiley Interdiscip Rev RNA, 2016, 7(4): 487-498. DOI: 10.1002/wrna.1347.
32.	Dooley SJ, McDougald DS, Fisher KJ, et al. Spliceosome-mediated pre-mRNA trans-splicing can repair CEP290 mRNA[J]. Mol Ther Nucleic Acids, 2018, 12: 294-308. DOI: 10.1016/j.omtn.2018.05.014.
33.	Kolesnik VV, Nurtdinov RF, Oloruntimehin ES, et al. Optimization strategies and advances in the research and development of AAV-based gene therapy to deliver large transgenes[J/OL]. Clin Transl Med, 2024, 14(3): e1607[2024-03-01]. https://pubmed.ncbi.nlm.nih.gov/38488469/. DOI: 10.1002/ctm2.1607.

1. Hu ML, Edwards TL, O'Hare F, et al. Gene therapy for inherited retinal diseases: progress and possibilities[J]. Clin Exp Optom, 2021, 104(4): 444-454. DOI: 10.1080/08164622.2021.1880863.
2. Hanany M, Shalom S, Ben-Yosef T, et al. Comparison of worldwide disease prevalence and genetic prevalence of inherited retinal diseases and variant interpretation considerations[J/OL]. Cold Spring Harb Perspect Med, 2024, 14(2): a041277[2024-02-01]. https://pubmed.ncbi.nlm.nih.gov/37460155/. DOI: 10.1101/cshperspect.a041277.
3. Georgiou M, Fujinami K, Michaelides M. Inherited retinal diseases. DOI: Therapeutics, clinical trials and end points-a review[J]. Clin Exp Ophthalmol, 2021, 49(3): 270-288. DOI: 10.1111/ceo.13917.
4. Ben-Yosef T. Inherited retinal diseases[J/OL]. Int J Mol Sci, 2022, 23(21): 13467[2022-11-03]. https://pubmed.ncbi.nlm.nih.gov/36362249/. DOI: 10.3390/ijms232113467.
5. Georgiou M, Robson AG, Fujinami K, et al. Phenotyping and genotyping inherited retinal diseases: molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes[J/OL]. Prog Retin Eye Res, 2024, 100: 101244[2024-01-24]. https://pubmed.ncbi.nlm.nih.gov/38278208/. DOI: 10.1016/j.preteyeres.2024.101244.
6. Liu MM, Zack DJ. Alternative splicing and retinal degeneration[J]. Clin Genet, 2013, 84(2): 142-149. DOI: 10.1111/cge.12181.
7. Khan M, Cornelis SS, Pozo-Valero MD, et al. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics[J]. Genet Med, 2020, 22(7): 1235-1246. DOI: 1235-46.10.1038/s41436-020-0787-4. DOI: 10.1038/s41436-020-0787-4.
8. Love SL, Emerson JD, Koide K, et al. Pre-mRNA splicing-associated diseases and therapies[J]. RNA Biol, 2023, 20(1): 525-538. DOI: 10.1080/15476286.2023.2239601.
9. El Marabti E, Malek J, Younis I. Minor intron splicing from basic science to disease[J/OL]. Int J Mol Sci, 2021, 22(11): 6062[2021-06-04]. https://pubmed.ncbi.nlm.nih.gov/34199764/. DOI: 10.3390/ijms22116062.
10. Wilkinson ME, Charenton C, Nagai K. RNA splicing by the spliceosome[J]. Annu Rev Biochem, 2020, 89: 359-388. DOI: 10.1146/annurev-biochem-091719-064225.
11. Aísa-Marín I, García-Arroyo R, Mirra S, et al. The alter retina: alternative splicing of retinal genes in health and disease[J/OL]. Int J Mol Sci, 2021, 22(4): 1855[2021-02-12]. https://pubmed.ncbi.nlm.nih.gov/33673358/. DOI: 10.3390/ijms22041855.
12. Delmaghani S, El-Amraoui A. The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification[J]. Hum Genet, 2022, 141(3-4): 709-735. DOI: 10.1007/s00439-022-02448-7.
13. Mansard L, Baux D, Vaché C, et al. The study of a 231 French patient cohort significantly extends the mutational spectrum of the two major usher genes MYO7A and USH2A[J/OL]. Int J Mol Sci, 2021, 22(24): 13294[2021-12-10]. https://pubmed.ncbi.nlm.nih.gov/34948090/. DOI: 10.3390/ijms222413294.
14. De Angeli P, Spaag S, Shliaga S, et al. Single-guide RNA Cas9 and enhanced-deletion Cas9 rescue a recurrent USH2A-related splicing defect[J/OL]. Mol Ther Nucleic Acids, 2025, 36(2): 102523[2025-03-21]. https://pubmed.ncbi.nlm.nih.gov/40235854/. DOI: 10.1016/j.omtn.2025.102523.
15. Tian L, Chen C, Song Y, et al. Phenotype-based genetic analysis reveals missing heritability of ABCA4-related retinopathy: deep intronic variants and copy number variations[J/OL]. Invest Ophthalmol Vis Sci, 2022, 63(6): 5[2022-06-01]. https://pubmed.ncbi.nlm.nih.gov/35657619/. DOI: 10.1167/iovs.63.6.5.
16. Leroy BP, Birch DG, Duncan JL, et al. Leber congenital amaurosis due to cep290 mutations-severe vision impairment with a high unmet medical need: a review[J]. Retina, 2021, 41(5): 898-907. DOI: 10.1097/IAE.0000000000003133.
17. Valkenburg D, van Cauwenbergh C, Lorenz B, et al. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c. 2991+1655A>G mutation in CEP290[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4384-4391. DOI: 10.1167/iovs.18-24817.
18. Gagliardi M, Ashizawa AT. The Challenges and strategies of antisense oligonucleotide drug delivery[J/OL]. Biomedicines, 2021, 9(4): 433[2021-04-16]. https://pubmed.ncbi.nlm.nih.gov/33923688/. DOI: 10.3390/biomedicines9040433.
19. Sang A, Zhuo S, Bochanis A, et al. Mechanisms of action of the US food and drug administration-approved antisense oligonucleotide drugs[J]. BioDrugs, 2024, 38(4): 511-526. DOI: 10.1007/s40259-024-00665-2.
20. Kaltak M, de Bruijn P, Piccolo D, et al. Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c. 5461-10T>C[J]. Mol Ther Nucleic Acids, 2023, 31: 674-688. DOI: 10.1016/j.omtn.2023.02.020.
21. Egli M, Manoharan M. Chemistry, structure and function of approved oligonucleotide therapeutics[J]. Nucleic Acids Res, 2023, 51(6): 2529-2573. DOI: 10.1093/nar/gkad067.
22. Russell SR, Drack AV, Cideciyan AV, et al. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial[J]. Nat Med, 2022, 28(5): 1014-1021. DOI: 10.1038/s41591-022-01755-w.
23. Dulla K, Aguila M, Lane A, et al. Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c. 2991+1655A>G LCA10 models[J]. Mol Ther Nucleic Acids, 2018, 12: 730-740. DOI: 10.1016/j.omtn.2018.07.010.
24. Burnight ER, Giacalone JC, Cooke JA, et al. CRISPR-Cas9 genome engineering: treating inherited retinal degeneration[J]. Prog Retin Eye Res, 2018, 65: 28-49. DOI: 10.1016/j.preteyeres.2018.03.003.
25. Wiley LA, Burnight ER, Kaalberg EE, et al. Assessment of adeno-associated virus serotype tropism in human retinal explants[J]. Hum Gene Ther, 2018, 29(4): 424-436. DOI: 10.1089/hum.2017.179.
26. Meng X, Jia R, Zhao X, et al. In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment[J/OL]. Nat Commun, 2024, 15(1): 3773[2024-05-06]. https://pubmed.ncbi.nlm.nih.gov/38710738/. DOI: 10.1038/s41467-024-48092-9.
27. Ajiro M, Awaya T, Kim YJ, et al. Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia[J/OL]. Nat Commun, 2021, 112(1): 4507[2021-07-23]. https://pubmed.ncbi.nlm.nih.gov/34301951/. DOI: 10.1038/s41467-021-24705-5.
28. Nishio H, Niba ETE, Saito T, et al. Spinal muscular atrophy: the past, present, and future of diagnosis and treatment[J/OL]. Int J Mol Sci, 2023, 24(15): 11939[2023-07-26]. https://pubmed.ncbi.nlm.nih.gov/37569314/. DOI: 10.3390/ijms241511939.
29. Yeo CJJ, Tizzano EF, Darras BT. Challenges and opportunities in spinal muscular atrophy therapeutics[J/OL]. Lancet Neurol, 2024, 23(3): e7[2024-02-01]. https://pubmed.ncbi.nlm.nih.gov/38267192/. DOI: 10.1016/S1474-4422(24)00050-4.
30. Doi A, Delaney C, Tanner D, et al. RNA exon editing: Splicing the way to treat human diseases[J/OL]. Mol Ther Nucleic Acids, 2024, 35(3): 102311[2024-08-16]. https://pubmed.ncbi.nlm.nih.gov/39281698/. DOI: 10.1016/j.omtn.2024.102311.
31. Berger A, Maire S, Gaillard MC, et al. mRNA trans-splicing in gene therapy for genetic diseases[J]. Wiley Interdiscip Rev RNA, 2016, 7(4): 487-498. DOI: 10.1002/wrna.1347.
32. Dooley SJ, McDougald DS, Fisher KJ, et al. Spliceosome-mediated pre-mRNA trans-splicing can repair CEP290 mRNA[J]. Mol Ther Nucleic Acids, 2018, 12: 294-308. DOI: 10.1016/j.omtn.2018.05.014.
33. Kolesnik VV, Nurtdinov RF, Oloruntimehin ES, et al. Optimization strategies and advances in the research and development of AAV-based gene therapy to deliver large transgenes[J/OL]. Clin Transl Med, 2024, 14(3): e1607[2024-03-01]. https://pubmed.ncbi.nlm.nih.gov/38488469/. DOI: 10.1002/ctm2.1607.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesResearch progress of splicing mutations in inherited retinal diseases

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