Max Farley

Background: Inherited retinal diseases (IRDs), including Stargardt disease, X-linked retinitis pigmentosa (XLRP), and Leber congenital amaurosis (LCA), are genetic disorders that lead to progressive vision loss due to photoreceptor and retinal pigment epithelium dysfunction^1-3. With limited conventional treatment options, gene therapy has emerged as a targeted approach to correct or compensate for genetic defects. The retina presents an ideal site for gene therapy due to its accessibility and immune privileged environment². Despite promising advances, knowledge gaps persist regarding efficacy, delivery optimization, and adverse effects in outcomes.

Methods: Initial literature review consisted of PubMed searches for “inherited retinal diseases”, such as “(inherited retinal diseases) AND (pathophysiology)” and “(inherited retinal diseases) AND (gene therapy)”. Information derived from these sources led to more targeted searches including keywords such as “Stargardt disease”, “Leber congenital amaurosis”, “retinitis pigmentosa”, “CRISPR-Cas9”, and “ABCA4”, focusing on clinical and preclinical studies from 2020 to 2025.

Results: Preclinical and early-stage clinical trials indicate gene therapy has the potential to slow or reverse vision loss in IRDs. Most studies focus on the treatment of monogenic IRDs, with a vast variety of delivery methods explored. In animal models, ECO/pRHO-ABCA4 nanoparticles demonstrated efficacy in delivering ABCA4 for Stargardt disease⁴. Furthermore, CRISPR/Cas9 genome editing reduced photoreceptor degeneration in XLRP². In clinical trials, a dose escalation study for a subretinal viral gene therapy treating LCA led to improvements in vision at higher doses⁵. Similarly, another study described improvements in retinal sensitivity and visual acuity following a single, subretinal injection of viral gene therapy in XLRP patients⁶. There is only one FDA approved gene therapy for an IRD, Luxturna, and it has shown efficacy in improving retinal light sensitivity over the course of years, particularly in LCA pediatric patients⁷. Across studies, reported adverse events were generally mild to moderate.

Conclusions: Gene therapy offers transformative potential for IRD treatment by addressing root genetic causes. While current preclinical and clinical studies demonstrate promising outcomes, efficacy is difficult to assess, as most human studies are designed primarily to evaluate safety at this point. Future directions include advancing to phase 3 clinical trials for select therapies, refining delivery, and conducting longitudinal studies to investigate long term outcomes.

Works Cited:

1. Kim BM, Song HS, Kim JY, et al. Functional characterization of ABCA4 genetic variants related to Stargardt disease. Sci Rep. 2022;12(1):22282. Published 2022 Dec 24. doi:10.1038/s41598-022-26912-6
2. Hu S, Du J, Chen N, et al. In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. 2020;61(4):31. doi:10.1167/iovs.61.4.31
3. Jacobson SG, Cideciyan AV, Sumaroka A, et al. Leber Congenital Amaurosis Due to GUCY2D Mutations: Longitudinal Analysis of Retinal Structure and Visual Function. Int J Mol Sci. 2021;22(4):2031. Published 2021 Feb 18. doi:10.3390/ijms22042031
4. Sun D, Schur RM, Sears AE, et al. Non-viral Gene Therapy for Stargardt Disease with ECO/pRHO-ABCA4 Self-Assembled Nanoparticles. Mol Ther. 2020;28(1):293-303. doi:10.1016/j.ymthe.2019.09.010
5. 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. Lancet. 2024;404(10456):962-970. doi:10.1016/S0140-6736(24)01447-8
6. von Krusenstiern L, Liu J, Liao E, et al. Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations. JAMA Ophthalmol. 2023;141(3):275-283. doi:10.1001/jamaophthalmol.2022.6254
7. Fischer MD, Simonelli F, Sahni J, et al. Real-World Safety and Effectiveness of Voretigene Neparvovec: Results up to 2 Years from the Prospective, Registry-Based PERCEIVE Study. Biomolecules. 2024;14(1):122. Published 2024 Jan 17. doi:10.3390/biom14010122