Gene Supplementation Therapy: Redefining “Incurable” In Ophthalmology Sector

Authored by: Armaan Vaswani

Art by: Ava Shi

Diabetic Retinopathy (DR), a complication of diabetes that poorly affects the light sensitive retina in the back of the eye, is one of the leading causes of vision loss worldwide [1]. Genetic eye diseases, which are genetically heterogeneous, affect 1 in 1,000 people [2]. The rapid progression and technical factors of both conditions once led researchers to believe they were incurable. 

While inherited eye disorders and DR were both thought to be incurable, gene supplementation therapy, a treatment method involving the replacement of a defective gene with a functional one, has been designed to slow the progression and eventually restore vision in individuals with those diseases [3]. Recent gene supplementation treatments such as ADVM-022, for DR, and RGX-314, for age-related macular degeneration (another extremely prevalent ocular disease), have shown promise in both clinical and preclinical models [4]. 

Gene supplementation therapy for ocular diseases is an advancement that has been around for several years now–the first gene therapy drug that was approved by the FDA in 2017, Luxterna, was intended to treat inherited retinal disorders [5]. Mouse models were established with 25%, 50%, and 70% rod loss and treated with Luxterna [6]. The early and middle stage models saw restoration in vision close to wild-type levels, marking Luxterna’s ability to slow disease progression and restore vision. Its success since that has paved the way for other gene therapy reagents aimed at restoring sight and halting the progression of other diseases. 

While Luxterna achieved significant initial success, challenges arose when delivering Luxterna to patients and when altering technology for treatment of other diseases. Luxterna is an adeno-associated virus (AAV) vector—a small, manmade virus that is used to deliver genes—that delivers the functional version of the RPE65 gene to the genome [7]. While the system is considered both safe and versatile, no other AAV gene therapy for ocular diseases, including DR, is considered ready for clinical applications [8]. The persistence of these adaptation challenges have led to exploration of other delivery methods, including CRISPR genome editing, or capsid engineering [8]. Despite AAVs being the most extensively studied and technology, gaining multiple clinical approvals, they rely on invasive administration methods such as subretinal injections [9]. 

The vast challenges that exist with altering technology for new therapies and the many complications that arise with the current delivery methods of Luxterna create a variety of issues that need to be addressed before gene supplement therapy can continue advancing [10]. Despite the challenges, Luxterna’s AAV platform has been adapted for a variety of purposes. While initially focused on a specific retinal disease, Luxterna now serves as the blueprint for a variety of other retinal diseases such as choroideremia and Stargardt disease [7]. Additionally, Luxterna now has the potential to be modified for diseases outside of the retina, from other parts of the eye all the way down to the base of the spine [11]. 

Overall, the development of gene therapy, specifically AAVs, for ocular diseases shows a lot of promise and potential within the healthcare field. While a variety of issues need to be evaluated, including ethical concerns regarding the availability and economical barriers behind this treatment and alternative treatments need to be evaluated, gene supplementation therapy is one of the most vital advancements for the ophthalmology field in the current age, redefining the word incurable.

References

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2. Méjécase, C., Kozak, I., & Moosajee, M. (2020). The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 184(3), 762–772. https://doi.org/10.1002/ajmg.c.31824

3. Hushmandi, K., Lam, H. Y., Wong, W. M., Tan, W., Daryabari, S.-H., Reiter, R. J., Farahani, N., & Kumar, A. P. (2025). Gene therapy for age-related macular degeneration: A promising frontier in vision preservation. Cell Communication and Signaling, 23(1), 233. https://doi.org/10.1186/s12964-025-02246-4

4. Leroy, B. P., Fischer, M. D., Flannery, J. G., MacLaren, R. E., Dalkara, D., Scholl, H. P. N., Chung, D. C., Spera, C., Viriato, D., & Banhazi, J. (2023). Gene Therapy for Inherited Retinal Disease: Long-Term Durability of Effect. Ophthalmic Research, 66(1), 179–196. https://doi.org/10.1159/000526317

5. Bennett, J., & Maguire, A. M. (2023). Lessons Learned from the Development of the First FDA-Approved Gene Therapy Drug, Voretigene Neparvovec-rzyl. Cold Spring Harbor Perspectives in Medicine, 13(5), a041307. https://doi.org/10.1101/cshperspect.a041307

6. Scalabrino, M. L., Thapa, M., Wang, T., Sampath, A. P., Chen, J., & Field, G. D. (2023). Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa. bioRxiv: The Preprint Server for Biology, 2023.04.07.536035. https://doi.org/10.1101/2023.04.07.536035

7. Ferreira, M., Marques, J. P., Raimundo, M., Quental, H., & Castelo-Branco, M. (2025). Improvements induced by retinal gene therapy with voretigene neparvovec depend on visual cortical hemispheric dominance mechanisms. Communications Medicine, 5(1), 107. https://doi.org/10.1038/s43856-025-00820-y

8. Biber, J., Gandor, C., Becirovic, E., & Michalakis, S. (2025). Retina-directed gene therapy: Achievements and remaining challenges. Pharmacology & Therapeutics, 271, 108862. https://doi.org/10.1016/j.pharmthera.2025.108862

9. Siontas, O., & Ahn, S. (2024). Challenges in AAV-Based Retinal Gene Therapies and the Role of Magnetic Nanoparticle Platforms. Journal of Clinical Medicine, 13(23), 7385. https://doi.org/10.3390/jcm13237385

10. Jain, R., & Daigavane, S. (2024). Advances and Challenges in Gene Therapy for Inherited Retinal Dystrophies: A Comprehensive Review. Cureus, 16(9), e69895. https://doi.org/10.7759/cureus.69895

11. Hinsch, V. G., Boye, S. L., & Boye, S. E. (2025). A Comprehensive Review of Clinically Applied Adeno-Associated Virus-Based Gene Therapies for Ocular Disease. Human Gene Therapy, 36(19–20), 1301–1320.https://doi.org/10.1089/hum.2024.252