clinical topic updates

Gene Therapy and Future Directions for Neovascular Age-Related Macular Degeneration

by Peter K. Kaiser, MD


Gene therapy has the potential to transform the treatment of neovascular age-related macular degeneration (nAMD) and many other retinal diseases. Research is rapidly advancing, with multiple delivery techniques and targets being explored in clinical trials.

Expert Commentary

Peter K. Kaiser, MD

Chaney Family Endowed Chair in Ophthalmology Research
Professor of Ophthalmology
Cleveland Clinic Lerner College of Medicine
Staff, Vitreoretinal Department
Cleveland Clinic Cole Eye Institute
Cleveland, OH

“With gene therapy, multiple injections are not required, except for possible rescue injections following the first treatment. Ideally, the therapeutic protein continues to be expressed for life, and the protein levels in the eye do not diminish substantially over time.”

Peter K. Kaiser, MD

An unmet need in nAMD is treatment durability. We would like to achieve the efficacy of anti-VEGF therapy without the frequent intraocular injections. Real-world outcomes in patients with nAMD are often not as good as the outcomes that are reported in clinical trials, which may be a reflection of less frequent injections and a less rigorous follow-up schedule in the real world as compared with the fairly strict, fixed schedule that is utilized in clinical trials. While gene therapy has potential applications in a variety of ocular diseases, including inherited retinal degeneration, in nAMD, the primary goals of gene therapy are to address this treatment burden, the need for frequent injections, and the discrepancy in outcomes between real-world conditions and clinical trials. 

In the case of nAMD, instead of requiring frequent injections to deliver the treatment, gene therapy involves essentially inserting an anti-VEGF gene, which is normally not present, to direct the patient’s own cells in the eye to produce the anti-VEGF protein. Companies are making genes that look very similar to ranibizumab or aflibercept. With gene therapy, multiple injections are not required, except for possible rescue injections following the first treatment. Ideally, the therapeutic protein continues to be expressed for life, and the protein levels in the eye do not diminish substantially over time.

There are several different ways to introduce a gene into the cells, the most common of which is a viral vector. We use a virus that has been made to be replication deficient; it delivers DNA for an anti-VEGF protein into the cells but cannot replicate or produce viral particles after it does its job. Another method that is being investigated preclinically is electroporation, which employs electrical microcurrents to allow for the delivery of DNA into the cell nucleus.

There are also several different viral gene therapy delivery techniques that are being studied in patients with nAMD. One technique involves surgery to inject the viral vector into the subretinal space to transfect the retinal pigment epithelium. Although this is the most complicated approach because it requires surgery, it is also one of the most effective approaches. The body is very good at killing viruses and has an immune reaction to any viral infection, including viruses that are associated with gene therapy. However, when you inject them directly into the subretinal space using this surgical technique, the risk of producing an immune response is reduced because the subretinal space is immune privileged.

The easier approach in the clinic is to do a straight intravitreal injection of the virus. The problem with an intravitreal injection, however, is that it provides a greater opportunity for the immune system to attack and neutralize the virus and therefore carries a greater risk of inflammation. We have to watch for intraocular inflammation with many of these intravitreal gene therapies. In addition, transfection rates are somewhat lower than those with subretinal injections such that higher doses may be required, which could also raise the risk of inflammation.

Suprachoroidal delivery (also sometimes referred to as the Goldilocks approach), where the virus is injected into the suprachoroidal space, is a delivery technique that is currently being evaluated in several clinical studies. This may be an ideal approach because it can be performed in the office setting, there is less immune activation with a suprachoroidal vs an intravitreal injection, and it provides a nice rate of transfection of the retinal pigment epithelial cells. 

Any therapeutic protein could theoretically be developed into a gene therapy, and so, as other targets are developed for nAMD, they might become future candidates for gene therapy. Faricimab targets both the TIE2 receptor and the VEGF receptor, and it appears to add longevity and some increased drying capability in diabetic macular edema. So, theoretically, an ANG2 inhibitor could be developed as a gene therapy. 4D Molecular Therapeutics has a gene therapy program that is trying to block VEGFA, VEGFB, and VEGFC to have a pan-VEGF blockade, if you will. That is already in clinical testing. 


Campochiaro PA. Gene therapy for neovascular AMG. Section XV: gene- and cell-based therapies. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL. 4D-150 in patients with neovascular (wet) age-related macular degeneration. Updated October 20, 2011. Accessed May 17, 2023.

de 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;105(2):151-157. doi:10.1136/bjophthalmol-2020-316195

Duncan JL, Pierce EA, Laster AM, et al; The Foundation Fighting Blindness Scientific Advisory Board. Inherited retinal degenerations: current landscape and knowledge gaps. Transl Vis Sci Technol. 2018;7(4):6. doi:10.1167/tvst.7.4.6

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

Kirkner RM. 2023: the year of geographic atrophy. Retina Specialist. February 14, 2023. Accessed May 17, 2023.

Latella MC, Di Salvo MT, Cocchiarella F, et al. In vivo editing of the human mutant Rhodopsin gene by electroporation of plasmid-based CRISPR/Cas9 in the mouse retina. Mol Ther Nucleic Acids. 2016;5(11):e389. doi:10.1038/mtna.2016.92

Maguire AM, Russell S, Chung DC, et al. Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years. Ophthalmology. 2021;128(10):1460-1468. doi:10.1016/j.ophtha.2021.03.031

Tan CS, Ngo WK, Chay IW, Ting DS, Sadda SR. Neovascular age-related macular degeneration (nAMD): a review of emerging treatment options. Clin Ophthalmol. 2022;16:917-933. doi:10.2147/OPTH.S231913

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