Research targets gene therapy for exudative AMD patients


Two anti-VEGF gene therapies are being investigated in clinical trials of patients with exudative age-related macular degeneration. Initial efficacy and safety results are encouraging.


Anti-VEGF gene therapy for exudative age-related macular degeneration (AMD) has transformative potential for reducing treatment burden and improving patient outcomes, according to Szilárd Kiss, MD.

Two investigational anti-VEGF gene therapies are currently being investigated in clinical trials-RGX-314 (Regenxbio) and ADVM-022 (Adverum). Dr. Kiss described the two technologies and reviewed some preliminary clinical trial results that support their promise for providing sustained benefit with a single injection.

“Considering the treatment burden of anti-VEGF therapy for other ocular diseases, we can imagine that exudative AMD is just the first indication that will be targeted for anti-VEGF gene therapy,” said Dr. Kiss, chief, Retina Service, associate professor of ophthalmology, and associate dean at Weill Cornell Medical College, New York, NY.

RGX-314 delivers a gene for an anti-VEGF fab protein that is similar to ranibizumab. It uses adeno-associated virus-8 (AAV8) as a vector and is administered in the operating room as a subretinal injection.

“AAV is the most common viral vector carrier used for gene therapy. Different AAV serotypes have different tissue selectivity,” Dr. Kiss explained. “AAV8 is a wild type AAV that has the propensity for greater transfection of retinal cells compared with AAV2 following subretinal gene therapy delivery.” 

Dose-excalating design

The phase I study of RGX-314 has a dose-escalating design and is enrolling previously treated patients requiring frequent injections for exudative AMD.

Results have been reported for 42 subjects enrolled across five cohorts who completed at least six months of follow-up, which is the primary endpoint.

On average, the patients had been diagnosed 56 months previously and had received an average of 33 anti-VEGF injections (9.6/year). Mean baseline BCVA was 55.7 ETDRS letters and mean OCT-measured central retinal thickness (CRT) was 399 μm.

The treatment has been well-tolerated in all dose cohorts. Most adverse events have been rated mild in severity, and there have been no serious drug-related adverse events.

“Fifteen serious adverse events were recorded in nine subjects and there were two deaths, but none were related to the treatment,” Dr. Kiss said.

There has been no observed clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation exceeding that expected following routine vitrectomy. Two ocular procedure-related serious adverse events occurred, including a peripheral retinal detachment that was repaired and a case of endophthalmitis following collection of an aqueous humor sample.

In the fourth dose cohort, which included 12 patients, BCVA remained stable through six months and mean CRT improved. Five (42%) patients were injection-free through the six months, requiring no rescue anti-VEGF therapy.

The fifth dose cohort includes 12 patients who have five to six months of available follow-up. This group also had stable BCVA and improved CRT, and nine of the patients (75%) remained injection-free.

“Standardization, automation, and surgeon skill are critical for the success and safety of subretinal gene therapy,” Dr. Kiss noted. “Surgeons need extensive training that begins in the wet lab and then moves into a virtual reality environment.”

ADVM-022 is an AAV vector encoding aflibercept. It uses a novel AAV.7m8 capsid for gene delivery, which is an engineered vector optimized for strong retinal transfection following in-office intravitreal injection. 

OPTIC trial

OPTIC, the phase I clinical trial investigating ADVM-022 in exudative AMD, is evaluating two dose levels of the gene therapy. Eligible subjects must demonstrate a meaningful response to anti-VEGF therapy and are receiving an injection of aflibercept seven to 14 days prior to ADVM-022 injection.

Data from median follow-up of eight months was available for six patients enrolled in OPTIC. This first cohort had received an average of 6.2 anti-VEGF injections in the eight months prior to study screening and a mean of 35.3 injections since being diagnosed with exudative AMD.

There were some other interesting findings, and patients were requiring few, if any, injections. Dr. Kiss pointed out that one patient had received 109 previous injections.

“Of the 52 rescue injection opportunities during the eight-month follow-up period, zero rescue injections were needed in any of the first six subjects,” he said.

In this small group there have been no serious adverse events nor any adverse events meeting criteria for dose-limiting toxicity.

According to the research, there were 19 ocular adverse events potentially related to the investigational agent, of which 14 were mild and five rated as moderate in severity.

Mild anterior inflammation and vitreous cells were the most common adverse events, and all were well controlled with topical corticosteroids. The research team reported that there were no cases of vasculitis, retinitis, or choroiditis.

Evaluations for efficacy showed BCVA remained stable and CRT improved while all patients remained injection-free.

Retinal gene therapy

Gene therapy approaches represent three basic categories, the choice of which depends on the underlying pathology. Both RGX-314 and ADVM-022 are gene augmentation approaches as they are designed to deliver a gene for a functioning protein that is not naturally produced.

Gene augmentation can also be utilized to replace a non-functioning gene, as represented by voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) the FDA-approved gene therapy that replaces the non-functioning RPE65 gene in those patients with biallelic RPE65 mutation-associated retinal dystrophy.

As another approach, gene therapy can aim to edit existing genes. This approach is applicable to diseases caused by a single-nucleotide, gain-of-function/dominant-negative mutation. Or, in the case of pathologies caused by a dominant mutation, gene therapy can be designed to inactivate the causative gene.


Szilárd Kiss, MD
This article was adapted from Dr. Kiss’ presentation at the 2019 meeting of the American Academy of Ophthalmology. Dr. Kiss is a consultant to RegenxBio and Spark Therapeutics and is a consultant and equity owner in Adverum.

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