Current Updates, Recent Trends and Future Directions of Gene Therapy on Various Eye Disorders

Saeed Ur Rehman; Umar Javed; Ammara Saleem; Moazzam Saleem; Usman Hameed; Khadija Muzaffar; Tajammal Raza; Rabia Ijaz; Fiza Ali

doi:10.70749/ijbr.v3i1.524

Authors

Saeed Ur Rehman School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Punjab, Pakistan.
Umar Javed Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, Pakistan.
Ammara Saleem Department of Biochemistry, Quaid-e-Azam University Islamabad, Pakistan.
Moazzam Saleem Institute of Genetics, Heinrich-Heine -Universität Düsseldorf, Germany.
Usman Hameed Department of Biochemistry, Quaid-e-Azam University Islamabad, Pakistan.
Khadija Muzaffar School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Punjab, Pakistan.
Tajammal Raza Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Punjab, Pakistan.
Rabia Ijaz Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland.
Fiza Ali School of Biological Sciences, University of the Punjab, Lahore, Punjab, Pakistan.

DOI:

https://doi.org/10.70749/ijbr.v3i1.524

Keywords:

Gene Therapy, Eye Disorders, Ocular Diseases, Retinal Gene Therapy, Corneal Gene Therapy, CRISPR-Cas9 in Ophthalmology, Inherited Retinal Diseases (IRDs), Leber Congenital Amaurosis (LCA), Age-related Macular Degeneration (AMD).

Abstract

Gene therapy has emerged as a novel strategy in the treatment of eye problems, bringing fresh hope for illnesses previously believed to be untreatable. Recent developments in molecular biology and genetic engineering have enabled the creation of tailored medicines that address the fundamental genetic causes of ocular illnesses rather than just treating symptoms. Gene therapy interventions are showing promise in treating conditions including diabetic retinopathy, age-related macular degeneration, and hereditary retinal dystrophies. The area has undergone a revolution because of methods like CRISPR-Cas9 gene editing and adeno-associated viral (AAV) vectors, which enable precise delivery and change of genetic material within the protected and limited environment of the eye. Patients receiving these treatments have shown notable increases in visual acuity and retinal structural repair in clinical studies. Furthermore, in order to overcome obstacles like immunogenicity and limited payload capacity, next-generation delivery systems like nanoparticles and non-viral vectors are emerging, which could increase the potential of gene therapy. Although the field is still developing quickly, ethical concerns, high expenses, and the requirement for long-term safety assessments are still major problems. This review highlights the latest developments in gene therapy for eye disorders, discussing key breakthroughs, ongoing clinical trials, and future directions to achieve widespread accessibility and efficacy in treating ocular diseases.

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References

Amador, C., Shah, R., Ghiam, S., Kramerov, A. A., & Ljubimov, A. V. (2022). Gene Therapy in the Anterior Eye Segment. Current Gene Therapy, 22(2), 104–131. https://doi.org/10.2174/1566523221666210423084233

Apte, R. S. (2018). Gene therapy for retinal degeneration. Cell, 173(1), 5. https://www.cell.com/action/showCitFormats?doi=10.1016%2Fj.cell.2018.03.021&pii=S0092-8674%2818%2930301-5

Arsenijevic, Y., Berger, A., Udry, F., & Kostic, C. (2022). Lentiviral Vectors for Ocular Gene Therapy. Pharmaceutics, 14(8), 1605. https://doi.org/10.3390/pharmaceutics14081605

Collin, J., Queen, R., Zerti, D., Dorgau, B., Hussain, R., Coxhead, J., ... & Lako, M. (2019). Deconstructing retinal organoids: single cell RNA-Seq reveals the cellular components of human pluripotent stem cell-derived retina. Stem Cells, 37(5), 593-598. https://doi.org/10.1002/stem.2963

Cubillo, L. T., Gurdal, M., & Zeugolis, D. I. (2024). Corneal fibrosis: From in vitro models to current and upcoming drug and gene medicines. Advanced Drug Delivery Reviews, 209, 115317–115317. https://doi.org/10.1016/j.addr.2024.115317

den Hollander, A. I., Roepman, R., Koenekoop, R. K., & Cremers, F. P. M. (2008). Leber congenital amaurosis: Genes, proteins and disease mechanisms. Progress in Retinal and Eye Research, 27(4), 391–419. https://doi.org/10.1016/j.preteyeres.2008.05.003

Ding, Y., Zhou, G., & Hu, W. (2024). Epigenetic regulation of TGF-β pathway and its role in radiation response. International Journal of Radiation Biology, 100(6), 834–848. https://doi.org/10.1080/09553002.2024.2327395

Fernández, C. R. (2020). Can Gene Therapy Become? The Cure For Blindness? Labiotech. Eu, Labiotech UG, 13.

Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M., & Abedi, M. R. (2018). Gene therapy clinical trials worldwide to 2017: An update. The Journal of Gene Medicine, 20(5), e3015. https://doi.org/10.1002/jgm.3015

Glenisson, W., Castronovo, V., & Waltregny, D. (2007). Histone deacetylase 4 is required for TGFβ1-induced myofibroblastic differentiation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1773(10), 1572–1582. https://doi.org/10.1016/j.bbamcr.2007.05.016

Gupta, S., Rodier, J. T., Sharma, A., Giuliano, E. A., Sinha, P. R., Hesemann, N. P., Ghosh, A., & Mohan, R. R. (2017). Targeted AAV5-Smad7 gene therapy inhibits corneal scarring in vivo. PLOS ONE, 12(3), e0172928. https://doi.org/10.1371/journal.pone.0172928

Huang, L., Xiao, X., Li, S., Jia, X., Wang, P., Guo, X., & Zhang, Q. (2012). CRX variants in cone–rod dystrophy and mutation overview. Biochemical and Biophysical Research Communications, 426(4), 498–503. https://doi.org/10.1016/j.bbrc.2012.08.110

Hudecek, M., & Ivics, Z. (2018). Non-viral therapeutic cell engineering with the Sleeping Beauty transposon system. Current Opinion in Genetics & Development, 52, 100–108. https://doi.org/10.1016/j.gde.2018.06.003

Hudecek, M., Zsuzsanna Izsvák, Johnen, S., Renner, M., Thumann, G., & Zoltán Ivics. (2017). Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side. Critical Reviews in Biochemistry and Molecular Biology, 52(4), 355–380. https://doi.org/10.1080/10409238.2017.1304354

Ibrahim, M. T., Alarcon-Martinez, T., Lopez, I., Fajardo, N., Chiang, J., & Koenekoop, R. K. (2018). A complete, homozygous CRX deletion causing nullizygosity is a new genetic mechanism for Leber congenital amaurosis. Scientific Reports, 8(1), 1-6. https://doi.org/10.1038/s41598-018-22704-z

Ji, P., Li, Y., Wang, Z., Jia, S., Jiang, X., Chen, H., & Wang, Q. (2024). Advances in precision gene editing for liver fibrosis: From technology to therapeutic applications. Biomedicine & Pharmacotherapy, 177, 117003. https://doi.org/10.1016/j.biopha.2024.117003

Kruczek, K., & Swaroop, A. (2020). Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies. Stem Cells, 38(10), 1206-1215. https://doi.org/10.1002/stem.3239

Kruczek, K., Qu, Z., Gentry, J., Fadl, B. R., Gieser, L., Hiriyanna, S., Batz, Z., Samant, M., Samanta, A., Chu, C. J., Campello, L., Brooks, B. P., Wu, Z., & Swaroop, A. (2021). Gene therapy of dominant CRX-leber congenital amaurosis using patient stem cell-derived retinal Organoids. Stem Cell Reports, 16(2), 252-263. https://doi.org/10.1016/j.stemcr.2020.12.018

Liu, M. M., Tuo, J., & Chan, C. (2010). Gene therapy for ocular diseases. British Journal of Ophthalmology, 95(5), 604-612. https://doi.org/10.1136/bjo.2009.174912

Marlo, T. L., Giuliano, E. A., Tripathi, R., Sharma, A., & Mohan, R. R. (2017). Altering equine corneal fibroblast differentiation through Smad gene transfer. Veterinary Ophthalmology, 21(2), 132-139. https://doi.org/10.1111/vop.12485

Maslankova, J., Vecurkovska, I., Rabajdova, M., Katuchova, J., Kicka, M., Gayova, M., & Katuch, V. (2022). Regulation of transforming growth factor-β signaling as a therapeutic approach to treating colorectal cancer. World Journal of Gastroenterology, 28(33), 4744-4761. https://doi.org/10.3748/wjg.v28.i33.4744

Mitton, K. P., Swain, P. K., Chen, S., Xu, S., Zack, D. J., & Swaroop, A. (2000). The leucine zipper of NRL interacts with the CRX Homeodomain. Journal of Biological Chemistry, 275(38), 29794-29799. https://doi.org/10.1074/jbc.m003658200

Mohan, R. R., Martin, L. M., & Sinha, N. R. (2021). Novel insights into gene therapy in the cornea. Experimental Eye Research, 202, 108361. https://doi.org/10.1016/j.exer.2020.108361

Oliva, M., Schottman, T., & Gulati, M. (2012). Turning the tide of corneal blindness. Indian Journal of Ophthalmology, 60(5), 423. https://doi.org/10.4103/0301-4738.100540

Prado, D. A., Acosta-Acero, M., & Maldonado, R. S. (2020). Gene therapy beyond luxturna: A new horizon of the treatment for inherited retinal disease. Current Opinion in Ophthalmology, 31(3), 147-154. https://doi.org/10.1097/icu.0000000000000660

Rivolta, C., Berson, E. L., & Dryja, T. P. (2001). Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Human Mutation, 18(6), 488-498. https://doi.org/10.1002/humu.1226

Roger, J. E., Hiriyanna, A., Gotoh, N., Hao, H., Cheng, D. F., Ratnapriya, R., Kautzmann, M. I., Chang, B., & Swaroop, A. (2014). OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness. Journal of Clinical Investigation, 124(2), 631-643. https://doi.org/10.1172/jci72722

Samiy, N. (2014). Gene therapy for retinal diseases. Journal of Ophthalmic and Vision Research, 9(4), 506. https://doi.org/10.4103/2008-322x.150831

Sengillo, J. D., Justus, S., Tsai, Y., Cabral, T., & Tsang, S. H. (2016). Gene and cell‐based therapies for inherited retinal disorders: An update. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 172(4), 349-366. https://doi.org/10.1002/ajmg.c.31534

Swaroop, A. (1999). Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Human Molecular Genetics, 8(2), 299–305. https://doi.org/10.1093/hmg/8.2.299

Swaroop, A. (1999). Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: Direct evidence for the involvement of CRX in the development of photoreceptor function. Human Molecular Genetics, 8(2), 299-305. https://doi.org/10.1093/hmg/8.2.299

Tran, N. M., Zhang, A., Zhang, X., Huecker, J. B., Hennig, A. K., & Chen, S. (2014). Mechanistically distinct mouse models for CRX-associated retinopathy. PLoS Genetics, 10(2), e1004111. https://doi.org/10.1371/journal.pgen.1004111

Trinity College Dublin. (2020, November 26). Scientists develop new gene therapy for eye disease. ScienceDaily. www.sciencedaily.com/releases/2020/11/201126085921.htm

Van Grunsven, L. A., Verstappen, G., Huylebroeck, D., & Verschueren, K. (2005). Smads and chromatin modulation. Cytokine & Growth Factor Reviews, 16(4-5), 495-512. https://doi.org/10.1016/j.cytogfr.2005.05.006

Veleri, S., Lazar, C. H., Chang, B., Sieving, P. A., Banin, E., & Swaroop, A. (2015). Biology and therapy of inherited retinal degenerative disease: Insights from mouse models. Disease Models & Mechanisms, 8(2), 109-129. https://doi.org/10.1242/dmm.017913

Yu, W., & Wu, Z. (2021). Ocular delivery of CRISPR/Cas genome editing components for treatment of eye diseases. Advanced Drug Delivery Reviews, 168, 181-195. https://doi.org/10.1016/j.addr.2020.06.011

Zhang, T., Wang, X., Wang, Z., Lou, D., Fang, Q., Hu, Y., Zhao, W., Zhang, L., Wu, L., & Tan, W. (2020). Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomedicine & Pharmacotherapy, 129, 110287. https://doi.org/10.1016/j.biopha.2020.110287