Gene Therapy for Neovascular AMD

An update on ongoing clinical trials.


Anti-vascular endothelial growth factor (anti-VEGF) agents have revolutionized treatment for neovascular age-related macular degeneration (nAMD). Injections of VEGF-neutralizing proteins work to decrease fluid leakage, allow fluid reabsorption, and enhance visual acuity.1 Ranibizumab (Lucentis; Genentech), aflibercept (Eylea; Regeneron), and the recently approved brolucizumab (Beovu; Novartis) are indicated for the treatment of nAMD.

While intravitreal injections have been significant in preventing blindness in patients diagnosed with nAMD,2 the treatment burden faced by the aging population is evident due to frequent clinic visits. Thus, visual acuity gains in the real world are much lower than randomized clinical trials due to undertreatment. Our recently published SIERRA-AMD study also confirmed the decline in visual acuity in the real world over time in patients being treated for nAMD.3 New therapies and approaches are essential in addressing patients’ unmet needs and the limitations of current treatment methods.

Sustained delivery of anti-VEGF protein would facilitate better disease control in patients with nAMD and also decrease the number of clinic visits needed. One pathway that shows strong potential in managing current unmet needs in sustained delivery is gene therapy. Gene therapy functions by placing copies of a gene into cells, so to capacitate them in producing the needed proteins to treat a condition. The gene is delivered to the target cells using a modified virus, also known as a vector. The vector is specifically designed to deliver the gene only to its target cells. With regard to nAMD, once the gene is inserted within the DNA of an individual’s cells, the cells are able to produce anti-VEGF protein on their own. Gene therapy is a one-time treatment with the potential to generate long-lasting effects and eliminate the treatment burdens faced by patients receiving intravitreal injections by decreasing or eliminating the need for frequent injections.

Trials are ongoing of both RGX-314 and ADVM-022 investigating gene therapy for nAMD by producing anti-VEGF. In addition, HMR59 is a gene therapy developed by Hemera Biosciences that is being tested as an adjunct therapy to intravitreal anti-VEGF.


Developed by REGENXBIO, RGX-314 is a gene therapy trial targeting nAMD. It utilizes adeno-associated virus serotype 8 (AAV8) as its gene therapy vector. Research indicates AAV vectors provide long-term transgene expression.4 The RGX-314 AAV8 vector holds a gene encoding for a monoclonal antibody fragment, similar to ranibizumab, that binds to and neutralizes VEGF. The vector is preferentially taken up by retinal cells, leading to high levels of production of this monoclonal antibody fragment. Following a one-time subretinal administration, the long-standing and stable production of the anti-VEGF therapeutic protein has potential of reducing treatment burden of frequent intravitreal injections (Figure 1).

Figure 1. The RGX-314 gene therapy targeting neovascular AMD (REGENXBIO), designed to deliver an anti-VEGF Fab.

The current ongoing phase 1/2a, open-label, multiple-cohort, dose-escalation study is designed to evaluate the RGX-314 gene therapy product in subjects who have received prior treatment for nAMD. After patients met the inclusion and exclusion criteria and showed an anatomical response to ranibizumab injection, they underwent vitrectomy with subretinal delivery of a single dose of RGX-314. Patients received rescue anti-VEGF injections mainly based on discretion of the investigator to make sure they were not undertreated or if they met these criteria: increased, new, or persistent fluid; vision loss of 5 or more letters; or new ocular hemorrhage. In the primary study period (the first 26 weeks after administration), safety was the principal focus. At the end of the primary study period, subjects will be assessed for 104 weeks following the initial treatment. The RGX-314 trial has been fully recruited and is evaluating 5 distinct doses (3x109 genome copies [GC]/eye, 1x1010 GC/eye, 6x1010 GC/eye, 1.6 x1011 GC/eye, 2.5 x1011 GC/eye) in 42 subjects.

Recently reported results of the phase 1/2a trial showed that RGX-314 has been well tolerated at all dose levels. Further, there has been dose-dependent protein expression levels across all 5 cohorts, and 50% of subjects in cohort 3 remained free of anti-VEGF injections at 18 months. Cohort 4 and cohort 5 patients have also shown stable to improved vision and optical coherence tomography (OCT) on average. Seventy-five percent of patients in cohort 5 are injection-free at 5 to 6 months. The RGX-314 phase 2b clinical trial is planned to initiate in 2020.5,6


Developed by Adverum Biotechnologies, ADVM-022 is an intravitreal gene therapy for the treatment of nAMD (NCT03748784). The ADVM-022 therapy functions as a recombinant AAV-centered treatment, optimized for intravitreal administration and vigorous protein expression. ADVM-022 utilizes the AAV.7m8 capsid, carrying strong, ubiquitous expression cassette encoding for a codon-optimized cDNA of the anti-VEGF aflibercept protein.7 With a one-time administration, ADVM-022 shows potential in treating nAMD by delivering long-term expression of therapeutic levels of anti-VEGF protein (Figure 2).

Figure 2. The mechanism of the ADVM-022 gene therapy (Adverum Biotechnologies), which aims to treat neovascular AMD by delivering long-term expression of therapeutic levels of anti-VEGF protein.

OPTIC is a phase 1 ongoing open-label, multicenter, dose-ranging study that is currently evaluating 2 specific dose levels (6x1011 vector genomes [vg] and 2x1011 vg) of ADVM-022. Neovascular AMD patients who were previously treated with frequent anti-VEGF injections are being enrolled in the study. After patients met the inclusion and exclusion criteria and showed an anatomical response to aflibercept injection, they received an intravitreal injection of a single dose of ADVM-022. Six subjects each in cohorts 1 and 2 have been recruited. Key objectives of the study are to evaluate safety and efficacy of ADVM-022 at weeks 24, 52, and 104. Patients will receive rescue aflibercept if any of the following criteria are met: (1) loss of ≥10 letters in BCVA from baseline due to intraretinal or subretinal fluid observed by SD-OCT; (2) increase in central subfield thickness >75 μm from baseline as assessed by SD-OCT; or (3) presence of vision-threatening hemorrhage due to macular degeneration. The data from 6 subjects in cohort 1 were recently presented.8 At the median follow-up of 34 weeks, ADVM-022 was safe and well tolerated and showed consistent and sustained anatomic improvements in OCT and stable best-corrected visual acuity. There were zero rescue injections. There were 19 ocular events (14 mild adverse events and 5 moderate adverse events) potentially related to ADVM-022. Episodes of intraocular inflammation were successfully treated with topical steroids. Enrollment is ongoing for cohorts 3 and 4 with a prophylactic topical steroid regimen to address intraocular inflammation.


HMR59 (AAVCAGsCD59) is an AAV2 gene therapy developed by Hemera Biosciences and designed as an intravitreal injection that directly blocks membrane attack complex (MAC), the final step of the complement cascade. In targeting MAC, the upstream complement cascade is left intact to perform its normal activities. The transgene product of AAVCAGsCD59, soluble CD59 (sCD59), mimics natural protein-bound CD59 and prevents C9 from incorporating into the forming MAC composed of complement factors C5b, C6, C7, and C8 (Figure 3). In preclinical testing, AAVCAGsCD59 injected in the vitreous of mice 14 days prior to laser CNV reduced CNV formation by ~60% and MAC formation by ~70%.9

Figure 3. The HMR59 gene therapy (Hemera Biosciences) aims to increase the ability of retinal cells to make a soluble form of CD59.

Intravitreal AAVCAGsCD59 is being tested in naïve nAMD patients as an adjunct therapy to intravitreal anti-VEGF. Patients return monthly with retreatment based on recurrence of fluid on OCT, a decrease in visual acuity, presence of new subretinal hemorrhage, or based on the clinical expertise of the treating physician. To date, AAVCAGsCD59 has been administered in 24 eyes at a dose of 3.56x1011 vg and 1.07x1012 vg. The study is ongoing, but early results demonstrate a reduction in anti-VEGF burden with patients receiving approximately 2 additional anti-VEGF injections with a mean follow-up of 9.2 months. Three eyes have had mild ocular inflammation. No ocular or systemic SAEs attributed to AAVCAGsCD59 have occurred.


Gene therapy appears to be an innovative treatment option in the management of nAMD by addressing the unmet needs posed by the current intravitreal treatments. Gene therapy has the potential to achieve significant visual acuity gains in the real world by eliminating or reducing the need for frequent injections. Clinical trials of RGX-314, ADVM-022, and AAVCAGsCD50 are ongoing to evaluate long-term safety and efficacy of gene therapy in patients with nAMD. RP


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  2. Smith AG, Kaiser PK. Emerging treatments for wet age-related macular degeneration. Expert Opin Emerg Drugs. 2014;19(1):157-164.
  3. Khanani AM, Skelly A, Bezlyak V, Griner R, Torres LR, Sagkriotis A. SIERRA-AMD: a retrospective, real-world evidence study of patients with neovascular age-related macular degeneration in the United States. Ophthalmol Retina. 2019. [Epub ahead of print]
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  5. REGENXBIO. REGENXBIO Reports second quarter 2019 financial and operating results and additional positive interim phase I/IIa trial update for RGX-314 for the treatment of wet AMD. Press release. August 7, 2019. Available at: . Accessed December 13, 2019.
  6. Heier J, Campochiaro P, Ho A, et al. Results of cohorts 1-5 for the RGX-314 phase I/IIa study of gene therapy for neovascular wAMD. Presented at: Retina Subspecialty Day, American Academy of Ophthalmology; October 11, 2019; San Francisco, California.
  7. Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Mol Ther. 2018;27(1):118-129.
  8. Kiss S. 24-week results of phase 1 study of intravitreal gene therapy with ADVM-022 for neovascular AMD (OPTIC trial). Presented at: Retina Subspecialty Day, American Academy of Ophthalmology; October 11, 2019; San Francisco, California.
  9. Cashman SM, Ramo K, Kumar-Singh, R. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS One. 2011;6(4):e19078.

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by REGENXBIO.