The time has come for gene therapy to treat retinal disease, AMD


With the first ocular gene therapy approved in the United States, Szilard Kiss, MD, points out that the gene therapy era for retinal disease has arrived, “and hopefully it will arrive for age-related macular degeneration.”

By Michelle Dalton, ELS;Reviewed by S. Kiss, MD

Coming off the heels of the first ocular gene therapy approved in the United States, Szilard Kiss, MD, pointed out that the gene therapy era for retinal disease has arrived, “and hopefully it will arrive for age-related macular degeneration (AMD).”

When clinicians and researchers think about gene therapy, it is not just one product, but four different factors, said Dr. Kiss, assistant professor of ophthalmology; director of clinical research, Weill Cornell Medical College, New York. Considerations include the virus used (or if a virus will be used for delivery), and what is actually being delivered.

“We need to consider if we’re delivering anti-vascular endothelial growth factor (anti-VEGF) aflibercept or anti-VEGF ranibizumab or a gene therapy to treat a rare disorder?” Dr. Kiss said. “How are you delivering that in terms of formulation? Where in the retina–either intravitreal or subretinal space–are you delivering your gene therapy vector?”

Monogenetic disorders (such as Leber’s congenital amaurosis) readily lend themselves to gene therapy, Dr. Kiss believes.

“It’s amazing that we can cure blindness in young children,” Dr. Kiss said. “But what would be even more amazing is if we could somehow alleviate the 6 million injections we’re doing every year for things like diabetes and macular degeneration.”

Gene therapy itself is “not a new concept,” with 3 phase I clinical trials for AMD having been completed. Those studies did not move to phase II “for a variety of reasons,” Dr. Kiss cited. “But what they did show is that subretinal delivery in wet AMD is safe and feasible.”



Delivery methods

There are advantages to the subretinal space compared to an intravitreal injection in gene therapy, Dr. Kiss said.

For instance, subretinal delivery allows for the best expression, meaning broader coverage and a higher protein expression. Subretinal delivery does appear to be safe, as has been shown in several neovascular AMD trials, Dr. Kiss said.

“It would be great if we could do this intravitreally in our offices,” he added. “However, pre-existing antibodies present in 70% of patients may prevent that”–noting the technique is more invasive than injections and requires a surgical procedure.

Moreover, there is “up to 1,000-fold less expression when you give gene therapy via an intravitreal injection,” Dr. Kiss said. “That’s been shown in non-human primates.”

Dr. Kiss explained that is due to limited transduction–intravitreal injection only transduces cells in the fovea due to the internal limiting membrane that acts as a barrier for further dissemination.

Pre-existing adeno-associated viral vector (AAV) neutralizing antibodies may neutralize any gene therapy being delivered via intravitreal injection, Dr. Kiss said.

“Those pre-existing neutralizing antibodies may block transduction and limit therapeutic usefulness,” he added. “This is true even if you’re delivering the best molecule.”



AAV vectors

Dr. Kiss said researchers have not yet had success with a gene therapy trial for AMD, but that may have been a result of the molecules chosen or the vectors used to deliver the therapy.

“It’s possible the AAV2 vector is not the most optimal vector to be used for gene therapy,” Dr. Kiss said.

Dr. Kiss detailed some of these issues by talking about a recently published study that used AAV2-soluble FLT.1 The study by Heier et al represented the first clinical trial to test intravitreous injection of AAV2-sFLT01 for the treatment of AMD.

The trial’s primary goal was to assess safety. A secondary goal was to assess anti-permeability activity, which required withholding anti-VEGF injections, but only if visual potential was not compromised.

“In this phase I, dose-escalating trial, subjects were treated but subjects that had antibodies did not have any protein expression,” Dr. Kiss said. “In those subjects where there were no antibodies, some protein expression was seen. Clinical efficacy was variable.”

RegenXBio is using a proprietary technology in vector AAV8-NAV that delivers (essentially) something akin to ranibizumab, Dr. Kiss said.

“When you deliver AAV8 to the subretinal space, there is more transfection than if you deliver AAV2,” Dr. Kiss said. “There is more of the molecule in the vitreous–up to 1,000-fold to 2,000-fold higher with an AAV8 vector than can be achieved with a subretinal delivery with an AAV2 vector.”

(Editor’s note: RegenXBio has completed dosing in its third cohort of 6 patients. Topline data readout is expected in late 2018.)



Current trials

Dr. Kiss said that overcoming limitations of gene therapy trials may be as simple as developing or manufacturing a virus that can be delivered intravitreally that can transect the retina.

Adverum has accomplished that with AAC.7m8, Dr. Kiss said. This vector can be delivered via an intravitreal injection and has an apparent higher expression compared to AAV2 and other traditional vectors.

In 2016, the company presented preclinical data from ADVM-022 (AAV.7m8-aflibercept) and ADVM-032 (AAV.7m8-ranibizumab) for the treatment of neovascular AMD. Administered through a single, intravitreal injection, ADVM-022 and ADVM-032 demonstrated compelling proof-of-concept of these vectors’ anti-angiogenic effect, which was comparable to the standard-of-care anti-VEGF therapies in a laser-induced, choroidal neovascularization model of neovascular AMD in non-human primates.

“In that model, the vector behaves very similarly to native aflibercept,” Dr. Kiss said. “Not only that, but in 14 eyes out to 7 months–and in 2 eyes out to 1 year–we can still detect the aflibercept that is being made by this vector, and there may be enough aflibercept to have clinical efficacy.”

Gene therapy is here to stay, Dr. Kiss said.

“Hopefully, it is here sooner rather than later for macular degeneration,” Dr. Kiss explained. “Early studies show that it’s safe whether you go intravitreally or subretinal. It may just be that we’re using the wrong vector and it may be that we’re delivering the wrong molecule. With the delivery of ranibizumab and aflibercept, we may be looming into the era of anti-VEGF gene therapy for AMD.”


1. Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. The Lancet 2017;390:50-61.

Szilard Kiss, MD


This article was adapted from a presentation that Dr. Kiss delivered at Retina Subspecialty Day held prior to 2017 American Academy of Ophthalmology meeting. Dr. Kiss is a consultant for Adverum, Genentech, Optos, Regeneron Pharmaceuticals, RegenxBio, Santen, and Spark Therapeutics.

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