Results and possible prospects of genetic technology in ophthalmology (literature review). Part 2.
DOI:
https://doi.org/10.31288/oftalmolzh202124045Keywords:
small interfering RNAs, antisense nucleotides, CRISPR, gene therapy, retinaAbstract
The emergence of fundamentally novel technological solutions in the field of gene therapy today, the formation of the priority and the development of genetic technologies create serious prerequisites for the beginning of a new Fusion era in ophthalmology in the near future. This review, in its second part, presents the results of fundamental and clinical studies on the use of genetic therapeutic strategies – gene replacement, gene suppression, genomic editing using CRISPR / Cas9 technology which have been used in ophthalmology over the past several years.
References
1.Ali RR, Sarra GM, Stephens C, Alwis MD, Bainbridge JW, Munro PM, et al. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet. 2000;25(3):306‐10. https://doi.org/10.1038/77068
2.Vollrath D, Feng W, Duncan JL, Yasumura D, D'Cruz PM, Chappelow A, et al. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci USA. 2001;98(22):12584‐9. https://doi.org/10.1073/pnas.221364198
3.Smith AJ, Schlichtenbrede FC, Tschernutter M, Bainbridge JW, Thrasher AJ, Ali RR. AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther. 2003;8(2):188‐95. https://doi.org/10.1016/S1525-0016(03)00144-8
4.Tschernutter M, Schlichtenbrede FC, Howe S, Balaggan KS, Munro PM, Bainbridge JWB, et al. Long‐term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus‐mediated gene therapy. Gene Ther. 2005;12694-701. https://doi.org/10.1038/sj.gt.3302460
5.Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008;16(3):458‐465. https://doi.org/10.1038/sj.mt.6300389
6.Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, et al. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest. 2008;118(5):1955‐1964. https://doi.org/10.1172/JCI34316
7.Drenser KA, Timmers AM, Hauswirth WW, Lewin AS. Ribozyme-targeted destruction of RNA associated with autosomal-dominant retinitis pigmentosa 5. Invest Ophthalmol Vis Sci. 1998;39:681-9.
8.Lewin AS, Drenser KA, Hauswirth WW, Nishikawa S, Yasumura D, Flannery JG, LaVail MM. Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa 4. Nat Med. 1998;4:967-71. https://doi.org/10.1038/nm0898-967
9.O'Neill B, Millington-Ward S, O'Reilly M, Tuohy G, Kiang AS, Kenna PF, et al. Ribozyme-based therapeutic approaches for autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2000;41(10):2863‐2869.
10.Sullivan JM, Pietras KM, Shin BJ, Misasi JN. Hammerhead ribozymes designed to cleave all human rod opsin mRNAs which cause autosomal dominant retinitis pigmentosa 1. Mol Vis. 2002;8:102-13.
11.Gorbatyuk MS, Pang JJ, Thomas J Jr., Hauswirth WW, Lewin AS. Knockdown of wild-type mouse rhodopsin using an AAV vectored ribozyme as part of an RNA replacement approach. MolVis. 2005;11:648-56.
12.Gorbatyuk M, Justilien V, Liu J, Hauswirth WW, Lewin AS. Preservation of photoreceptor morphology and function in P23H rats using an allele independent ribozyme. Exp Eye Res. 2007;84(1):44‐52. https://doi.org/10.1016/j.exer.2006.08.014
13.Corydon TJ. Antiangiogenic Eye Gene Therapy. Human Gene Therapy. 2015;26(8):525-37. https://doi.org/10.1089/hum.2015.064
14.Garba AO, Mousa SA. Bevasiranib for the treatment of wet, age-related macular degeneration. Ophthalmol Eye Dis. 2010;2:75-83. https://doi.org/10.4137/OED.S4878
15.Guzman-Aranguez A, Loma P, Pintor J. Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy. Br J Pharmacol. 2013;170(4):730-47. https://doi.org/10.1111/bph.12330
16.Nguyen QD, Schachar RA, Nduaka CI, Sperling M, Klamerus KJ, Chi-Burris K, et al; MONET Clinical Study Group. Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study). Ophthalmology. 2012;119(9):1867-73. https://doi.org/10.1016/j.ophtha.2012.03.043
17.Chau VQ, Hu J, Gong X, Hulleman JD, Ufret-Vincenty RL, Rigo F, et al. Delivery of Antisense Oligonucleotides to the Cornea. Nucleic Acid Therapeutics. 2020; https://doi.org/10.1089/nat.2019.0838
18.Cideciyan AV, Jacobson SG, Drack AV, Ho AC, Charng J, Garafalo AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25(2):225-8. https://doi.org/10.1038/s41591-018-0295-0
19.Collin RW, Garanto A. Applications of antisense oligonucleotides for the treatment of inherited retinal diseases. Curr Opin Ophthalmol. 2017;28(3):260-6. https://doi.org/10.1097/ICU.0000000000000363
20.Gerard X, Garanto A, Rozet JM, Collin R.W. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies. Adv Exp Med Biol. 2016;854:517‐24. https://doi.org/10.1007/978-3-319-17121-0_69
21.Hu J, Rong Z, Gong X, Zhou Z, Sharma VK, Xing C, et al. Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy. Hum Mol Genet. 2018;27(6):1015-26. https://doi.org/10.1093/hmg/ddy018
22.Hu J, Shen X, Rigo F, Prakash TP, Mootha VV, Corey DR. Duplex RNAs and ss-siRNAs Block RNA Foci Associated with Fuchs' Endothelial Corneal Dystrophy. Nucleic Acid Ther. 2019;29(2):73‐81. https://doi.org/10.1089/nat.2018.0764
23.Moore SM, Skowronska-Krawczyk D, Chao DL. Emerging Concepts for RNA Therapeutics for Inherited Retinal Disease. Adv Exp Med Biol. 2019;1185:85‐89. https://doi.org/10.1007/978-3-030-27378-1_14
24.Rocha EM, Nominato LF, Reinach PS. Re: Cursiefen et al.: Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. Ophthalmology. 2015;122(5):e28. https://doi.org/10.1016/j.ophtha.2014.10.017
25.Sangermano R, Garanto A, Khan M, Runhart EH, Bauwens M, Bax NM, et al. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. Genet Med. 2019;21(8):1751-60. https://doi.org/10.1038/s41436-018-0414-9
26.Yang G, Fu Y, Zhang L, Lu X, Li Q. miR106b regulates retinoblastoma Y79 cells through Runx3. Oncol Rep. 2017;38(5):3039-43. https://doi.org/10.3892/or.2017.5931
27.Zarouchlioti C, Sanchez-Pintado B, Hafford Tear NJ, et al. Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity. Am J Hum Genet. 2018;102(4):528-39. https://doi.org/10.1016/j.ajhg.2018.02.010
28.Cursiefen C, Viaud E, Bock F, Geudelin B, Ferry A, Kadlecová P, Lévy M, et al. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. Ophthalmology. 2014;121(9):1683‐92. https://doi.org/10.1016/j.ophtha.2014.03.038
29.Lorenz K, Scheller Y, Bell K, Grus F, Ponto KA, Bock F, et al. A prospective, randomised, placebo-controlled, double-masked, three-armed, multicentre phase II/III trial for the Study of a Topical Treatment of Ischaemic Central Retinal Vein Occlusion to Prevent Neovascular Glaucoma - the STRONG study: study protocol for a randomised controlled trial. Trials. 2017;18(1):128. https://doi.org/10.1186/s13063-017-1861-3
30.Pfeiffer N, Voykov B, Renieri G, Bell K, Richter P, Weigel M, et al. First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery. PLoS One. 2017;12(11):e0188899. https://doi.org/10.1371/journal.pone.0188899
31.Naert T, Colpaert R, Van Nieuwenhuysen T, Dimitrakopoulou D, Leoen J, Haustraete J, et al. CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis. Sci Rep. 2016;6:35264. https://doi.org/10.1038/srep35264
32.Wu WH, Tsai YT, Justus S, Lee TT, Zhang L, Lin CS, et al. CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa. Mol Ther. 2016;24(8):1388-94. https://doi.org/10.1038/mt.2016.107
33.Bakondi B, Lv W, Lu B, Jones MK, Tsai Y, Kim KJ, et al. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa. Mol Ther. 2016;24(3):556‐63. https://doi.org/10.1038/mt.2015.220
34.Burnight ER, Giacalone JC, Cooke JA, Thompson JR, Bohrer LR, Chirco KR, et al. CRISPR-Cas9 genome engineering: Treating inherited retinal degeneration. Prog Retin Eye Res. 2018;65:28‐49. https://doi.org/10.1016/j.preteyeres.2018.03.003
35.Huang KC, Wang ML, Chen SJ, Kuo JC, Wang WJ, Nhi Nguyen PN, et al. Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis. Stem Cell Reports. 2019;13(5):906-23. https://doi.org/10.1016/j.stemcr.2019.09.010
36.Kim EK, Kim S, Maeng YS. Generation of TGFBI knockout ABCG2+/ABCB5+ double-positive limbal epithelial stem cells by CRISPR/Cas9-mediated genome editing. PLoS One. 2019;14(2):e0211864. https://doi.org/10.1371/journal.pone.0211864
37.Kim K, Park SW, Kim JH, Lee SH, Kim D, Koo T, et al. Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Genome Res. 2017;27(3):419‐426. https://doi.org/10.1101/gr.219089.116
38.Peddle CF, MacLaren RE The Application of CRISPR/Cas9 for the Treatment of Retinal Diseases. Yale J Biol Med. 2017;90(4):533‐41.
39.Ruan GX, Barry E, Yu D, Lukason M, Cheng SH, Scaria A. CRISPR/Cas9-Mediated Genome Editing as a Therapeutic Approach for Leber Congenital Amaurosis 10. Mol Ther. 2017;25(2):331‐41. https://doi.org/10.1016/j.ymthe.2016.12.006
40.Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim EJ, et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 2016;540(7631):144‐9. https://doi.org/10.1038/nature20565
41.Taketani Y, Kitamoto K, Sakisaka T, Kimakura M, Toyono T, Yamagami S, et al. Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair. Sci Rep. 2017;7(1):16713. https://doi.org/10.1038/s41598-017-16308-2
42.Xu CL, Park KS, Tsang SH. CRISPR/Cas9 genome surgery for retinal diseases. Drug Discov Today Technol. 2018;28:23‐32. https://doi.org/10.1016/j.ddtec.2018.05.001
43.Yu W, Mookherjee S, Chaitankar V, Suja Hiriyanna, Kim J-W, Brooks M, Ataeijannati Y, et al. Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun. 2017;8:14716. https://doi.org/10.1038/ncomms14716
44.Zhu J, Ming C, Fu X, Duan Y, Hoang DA, Rutgard J, Zhang R, et al. Gene and mutation independent therapy via CRISPR-Cas9 mediated cellular reprogramming in rod photoreceptors. Cell Res. 2017;27:830-3. https://doi.org/10.1038/cr.2017.57
45.Chung SH, Mollhoff IN, Nguyen U, Nguyen A, Stucka N, Tieu E, et al. Factors Impacting Efficacy of AAV-Mediated CRISPR-Based Genome Editing for Treatment of Choroidal Neovascularization. Mol Ther Methods Clin Dev. 2020;17:409‐17. https://doi.org/10.1016/j.omtm.2020.01.006
46.Huang X, Zhou G, Wu W, Duan Y, Ma G, Song J, et al. Genome editing abrogates angiogenesis in vivo. Nat Commun. 2017;8(1):112. https://doi.org/10.1038/s41467-017-00140-3
47.Yiu G, Tieu E, Nguyen AT, Wong B, Smit-McBride Z. Genomic Disruption of VEGF-A Expression in Human Retinal Pigment Epithelial Cells Using CRISPR-Cas9 Endonuclease. Invest Ophthalmol Vis Sci. 2016;57(13):5490-7. https://doi.org/10.1167/iovs.16-20296
48.Lightfoot JD, Fuller KK. CRISPR/Cas9-Mediated Gene Replacement in the Fungal Keratitis Pathogen Fusarium solani var. petroliphilum. Microorganisms. 2019;7(10):457. https://doi.org/10.3390/microorganisms7100457
49.Yang TC, Chang CY, Yarmishyn AA, Mao YS, Yang YP, Wang ML, et al. Carboxylated nanodiamond-mediated CRISPR-Cas9 delivery of human retinoschisis mutation into human iPSCs and mouse retina. Acta Biomater. 2020;101:484-94. https://doi.org/10.1016/j.actbio.2019.10.037
50.Li F, Hung SSC, Mohd Khalid MKN, Wang J-H, Chrysostomou V, Wong VHY, et al. Utility of Self-Destructing CRISPR/Cas Constructs for Targeted Gene Editing in the Retina. Hum Gene Ther. 2019;30(11):1349‐60. https://doi.org/10.1089/hum.2019.021
51.Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk AG, Mahajan VB. Unexpected mutations after CRISPR-Cas9 editing in vivo. Nat Methods. 2017;14(6):547‐48. https://doi.org/10.1038/nmeth.4293
52.Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576(7785):149-57. https://doi.org/10.1038/s41586-019-1711-4
53.Hernandez M, Recalde S, Garcia-Garcia L, Bezunartea J, Miskey C, Johnen S, Diarra S, et al. Preclinical Evaluation of a Cell-Based Gene Therapy Using the Sleeping Beauty Transposon System in Choroidal Neovascularization. Mol Ther Methods Clin Dev. 2019;15:403-17. https://doi.org/10.1016/j.omtm.2019.10.013
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Н. А. Гаврилова, О. Е. Тищенко, А. В. Зиновьева

This work is licensed under a Creative Commons Attribution 4.0 International License.
This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) that allows users to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author as long as they cite the source.
COPYRIGHT NOTICE
Authors who publish in this journal agree to the following terms:
- Authors hold copyright immediately after publication of their works and retain publishing rights without any restrictions.
- The copyright commencement date complies the publication date of the issue, where the article is included in.
DEPOSIT POLICY
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) during the editorial process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work with an acknowledgement of its initial publication in this journal.
- Post-print (post-refereeing manuscript version) and publisher's PDF-version self-archiving is allowed.
- Archiving the pre-print (pre-refereeing manuscript version) not allowed.