Eyes On The Prize: The Latest Developments in Retinal Gene Therapies

Originally published on Forbes on 6/26/2023



This story is part of a series on the current progression in Regenerative Medicine. This piece is part of a series dedicated to the eye and improvements in restoring vision. 

In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.


Age-related macular degeneration is a complex disease influenced by various genetic factors. A research consortium uncovered 34 genome-wide loci that contribute significantly to the condition. These loci are why gene therapy is an effective avenue for treating macular degeneration and other retinal diseases.

Recent advances in gene therapy methods and delivery systems have led to a surge in clinical trials for retinal gene therapies. Researchers are exploring various approaches, including subretinal and suprachoroidal injections and using adeno-associated viruses (AAVs) as vectors for gene delivery.

This article will discuss some of the most promising gene therapies for age-related macular degeneration, including ADVM-022, RGX-314, GT-005, and HMR59. These potential therapies have shown encouraging results in preclinical and clinical trials, with sustained expression of therapeutic proteins and reduced need for repeated injections. Moreover, they have exhibited a relatively low incidence of adverse events, making them viable candidates for widespread use.

Despite the challenges associated with gene therapy, including the need for long-term efficacy and safety data, these developments offer hope for patients with retinal diseases. 


New Approaches to Retinal Gene Therapy


Researchers have recently focused on developing delivery methods for gene therapy products that limit inflammation in the eye. Two new approaches that have shown promise for treating wet age-related macular degeneration are the subretinal and suprachoroidal approaches. 

The subretinal approach injects the gene product beneath the retina prompting retinal pigment epithelial and retinal cells to produce anti-VEGF protein. This surgical approach has shown almost no inflammation and minimal side effects and is similar to the technique used with Luxturna, an FDA-approved gene therapy for inherited retinal disease.

The suprachoroidal approach involves injecting the product behind the retina into the suprachoroidal space. Initial impressions from the first few cohorts indicate suprachoroidal delivery is relatively safe and well-tolerated. However, long-term safety and efficacy data are limited for this approach. 

These two methods and the recent studies on the effectiveness of viral vectors have made clinical trials for retinal gene therapies skyrocket in recent years.


Innovative Retinal Gene Therapies


ADVM-022 is a promising gene therapy developed by Adverum Biotechnologies to treat neovascular age-related macular degeneration. The treatment aims to deliver a protein via a single intravitreal injection, thereby reducing the need for repeated injections every 4-8 weeks.

Preclinical studies in nonhuman primates have demonstrated sustained expression for up to 30 months after a single intravitreal injection of ADVM-022. Further trials found that a single intravitreal injection of ADVM-022 significantly reduces the frequency of anti-VEGF injections. 

While inflammation has been the main adverse event in the trial, no ADVM-022-related non-ocular adverse events have been reported. The lower dose of ADVM-022 has been associated with fewer cases of inflammation, and all treatment-related ocular adverse events have been mild or moderate.

RGX-314 is another promising gene therapy for treating neovascular age-related macular degeneration. It is developed by REGENXBIO Inc. The treatment employs an adeno-associated virus vector-based gene delivery system that expresses a monoclonal antibody fragment resembling ranibizumab, a well-established anti-VEGF therapy. 

RGX-314 is delivered either subretinally or suprachoroidally and offers the potential for sustained anti-VEGF antibody production while reducing the burden of multiple intravitreal injections. RGX-314 is generally well-tolerated, with no reports of an abnormal immune response, drug-related ocular inflammation, or post-surgical inflammation made thus far.

GT-005 targets dry age-related macular degeneration patients. Dry macular degeneration accounts for most age-related macular degeneration cases, and currently, no effective therapies are available. Advanced dry macular degeneration, or geographic atrophy, is a debilitating eye condition that can lead to permanent vision loss due to the irreversible degeneration of retinal pigment epithelial cells and their overlying retinal photoreceptors.

GT-005 uses an AAV vector to deliver a protein that acts as a natural inhibitor of the complement system. The safety and efficacy of GT-005 are currently being evaluated in multiple clinical trials. Thus far, no GT-005-related severe adverse events (SAEs) have been observed. 

HMR59 is another new retinal gene therapy in the form of an AAV2 vector-based treatment. This therapy is administered intravitreally, seven days after a single intravitreal injection of anti-VEGF treatment. HMR59 intends to provide protection against the complement cascade and reduce the incidence of macular neovascularization. Clinical trials have shown promising results, and ongoing studies will be evaluated for long-term safety and efficacy. 

Despite the immense potential of gene therapy, there are still many issues that must be addressed for it to become widely used. However, recent improvements, such as dose optimization, efficient administration routes, effective management post-injection, and long-term benefits, have yielded promising results, offering hope for the future of gene therapy.

The discussed advances in gene editing and therapy have made retinal gene therapies a dynamic and ever-evolving field. There’s much to anticipate in improved conditions and the clinical potentials that lie ahead.

© William A. Haseltine, PhD. All Rights Reserved.