When will gene therapy be ready for patients with age-related macular degeneration?

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in elderly populations worldwide, that will affect almost 290 million individuals by 2040 and is projected to increase significantly due to aging demographics.¹ Advanced AMD is classified into atrophic and exudative (neovascular) forms. While the hallmark of the former is the presence of geographic atrophy, the central feature of the latter is the presence of macular neovascularisation (MNV), leading to rapid central vision loss. The growth of MNV is primarily driven by a perturbation of VEGF, confirmed by the dramatic improvements observed in patients with neovascular AMD (nAMD) treated with anti-VEGF agents, which are now the gold standard treatment for nAMD. Anti-VEGF therapy revolutionised AMD treatment by effectively inhibiting MNV progression.² Drugs such as ranibizumab, aflibercept and bevacizumab target VEGF, reducing vascular permeability and suppressing abnormal blood vessel growth. They have been used for almost 2 decades in the treatment of nAMD.

However, the necessity for frequent intravitreal injections (often monthly or bimonthly) places a significant burden on both healthcare systems and patients.³ Furthermore, non-adherence to the treatment regimen often results in suboptimal visual outcomes, with long-term therapy associated with atrophy of the retinal pigment epithelium (RPE). And last, but not least, not all patients respond adequately to anti-VEGF therapy in the first place. All the above arguments highlight the need for more durable and effective alternatives to the current standard of care.

Current approaches to gene therapy for AMD treatment

In this context, gene therapy provides a potential “one-and-done” treatment approach by introducing genetic material into retinal cells.⁴ Gene therapy uses viral and non-viral vectors to deliver therapeutic genes, in order to offer a prolonged efficacy and to reduce the need for repeated interventions.

Adeno-associated viruses (AAVs) are the most commonly used vectors due to their low immunogenicity and ability to transduce non-dividing cells: AAV2, AAV8, and AAV9 have demonstrated efficacy in retinal gene delivery.⁵ In AMD in particular, gene therapy would allow a continuous expression of anti-VEGF proteins to inhibit MNV in nAMD, but also a modulation of complement pathways in geographic atrophy.

The approaches currently being explored for AMD treatment include:

• Anti-VEGF gene therapy: Genes encoding anti-VEGF proteins such as sFLT-1, aflibercept- and ranibizumab-like proteins have been inserted into AAV vectors to ensure sustained VEGF suppression. Examples include ADVM-022 and RGX-314.⁶
• Complement inhibitors: Given the role of complement dysregulation in AMD, gene therapies targeting complement factor H (CFH) and I (CFI) have been in development.⁷
• Angiogenesis inhibitors beyond VEGF: RetinoStat expresses endostatin and angiostatin, two angiogenesis inhibitors, to modulate MNV development.⁸

Promising trials and drugs under development

Gene therapy may be delivered in several ways, either through intravitreal injection, which offers a minimally invasive route, but also through subretinal injection, which has the advantage of directly targeting the RPE and photoreceptor cells, therfore ensuring high transduction efficiency.

Nevertheless, this delivery route requires vitrectomy. Suprachoroidal injection is a novel, less invasive delivery route of gene therapy.

Several clinical trials for AMD have shown promising results:

• RGX-314 (Regenxbio): An AAV8-based gene therapy expressing a ranibizumab-like protein, currently in phase 3 trials, demonstrating sustained VEGF suppression with reduced treatment burden.4 Seven clinical trials are currently studying RGX-314 gene therapy’s safety and effectiveness in the treatment of nAMD. In 2023, Regenxbio announced that RGX-314 was well tolerated in 46 patients; there were five serious adverse events but none were deemed related to the gene therapy. Moreover, for the 30 patients in the high-dose cohorts at 6 months post treatment, anti-VEGF Fab protein concentrations in the eye were similar between patients.9 Patients treated in both high-dose cohorts showed stable or improved visual acuity and a decrease in the central retinal thickness, together with an important decrease in anti- VEGF treatment burden.^4,9,10
• ADVM-022 (Adverum Biotechnologies): An AAV.7m8 vector delivering aflibercept, showing long-term VEGF inhibition in early trials. Cells transduced by this virus would be expected to synthesise aflibercept, potentially indefinitely, doing away with the need for ongoing intravitreal injections.¹⁰
• RetinoStat (Oxford BioMedica): A lentiviral vector expressing angiostatin and endostatin, completed phase 1 trials with sustained transgene expression.⁸

Navigating challenges of the current landscape

Despite significant progress, several challenges remain for AMD gene therapy, such as immune response and inflammation, the delivery route, its safety in the long-term and the cost of the therapy. We know that AAV-mediated gene therapy can elicit immune responses, necessitating immunosuppressive strategies.⁴ Sustained gene expression may have potential off-target effects, and these patients need to be carefully monitored.⁶ Finally, gene therapies are expensive to develop and produce, raising concerns about widespread availability. Future directions involve gene-editing approaches such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats, CRISPR-associated protein 9) to precisely modify AMD-associated genetic variants, as well as combination therapies that integrate gene and cell-based strategies for enhanced neuroprotection and retinal repair.

Gene therapy presents a revolutionary approach to the management of AMD by providing sustained therapeutic effects with reduced treatment burden. Advances in vector design, gene targets and delivery methods continue to improve its feasibility and efficacy. While challenges remain, ongoing clinical trials and technological innovations hold the promise of transforming AMD treatment paradigms in the near future.

References

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116.

2. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin®) for neovascular agerelated macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335. doi:10.3928/1542- 8877-20050701-14

3. Krüger Falk M, Kemp H, Sørensen TL. Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. Am J Ophthalmol. 2013;155:89-95.

4. Guimaraes TAC, Georgiou M, Bainbridge JWB, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol. 2021 Feb;105(2):151-157. doi: 10.1136/ bjophthalmol-2020-316195.

5. Lukashev AN, Zamyatnin AA. Viral Vectors for gene therapy: current state and clinical perspectives. Biochem (Mosc). 2016;81(7):700–708. doi:10.1134/S0006297916070063

6. Trincão-Marques J, Ayton LN, et al. Gene and cell therapy for age-related macular degeneration: a review. Surv Ophthalmol. 2024;69(5):665-676. doi: 10.1016/j.survophthal.2024.05.002.

7. Dreismann AK, McClements ME, Barnard AR, et al. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021;28(5):265-276. doi:10.1038/ s41434-021-00239-9

8. Campochiaro PA, Lauer AK, Sohn EH, et al. Lentiviral vector gene transfer of endostatin/angiostatin for macular degeneration (GEM) study. Hum Gene Ther. 2023;28(1):99.doi:10.1089/ hum.2016.117

9. REGENXBIO presents interim data from phase II bridging study evaluating the clinical performance of RGX-314 using the NAVXpress^TM manufacturing platform process. News release. Regenxbio Inc. February 11, 2023. Accessed March 24, 2025. https:// regenxbio.gcs-web.com/news-releases/ news-release-details/regenxbio-presentsinterim-data-phase-ii-bridging-study.

10. Khanani AM, Thomas MJ, Aziz AA, et al. Review of gene therapies for age-related macular degeneration. Eye (Basingstoke). 2022;36(2):303-311. doi:10.1038/s41433-021-01842-1

Alexandra Miere, MD, PhD | E: alexandramiere@gmail. com

Miere is an associate professor of ophthalmology, Université Paris-Est Créteil, France. She is also an honorary research fellow in medical retina at Moorfields Eye Hospital, London.