Gene Therapy Advances in Age-Related Macular Degeneration

That’s the goal of gene therapies that are being studied for treating both the wet and dry forms of age-related macular degeneration (AMD). Over the past 20 years, AMD has gone from being an untreatable disease to one that can usually be slowed and managed. For most people, current treatments for wet AMD prevent vision loss from progressing. While drugs for treating dry AMD, which are newer, are less effective than those used to treat the wet form, they do slow the development of a type of advanced dry AMD called geographic atrophy.

However, because these medications usually must be injected into the eye every four to eight weeks, some people miss treatments or stop them entirely. This can cause the medications to be less effective, and potentially allow AMD to worsen, which can lead to a decline in vision. Gene therapy could allow many more people to reap maximum benefit from treatment.

How Can Gene Therapy Be Applied in AMD?

In wet AMD, fragile, leaky new blood vessels grow from the back of the eye (choroid) into a space just beneath the retina. A protein called vascular endothelial growth factor (VEGF) drives the growth of these abnormal blood vessels. Drugs such as Lucentis® (ranibizumab) and Eylea® (aflibercept) block the action of VEGF.

In the dry form of AMD, the complement system—which is part of the immune system—mistakenly attacks cells beneath the center of the retina (macula), causing them to thin and age. In an advanced form of dry AMD called geographic atrophy, cells in the macula become damaged and die. The dead or atrophied patches usually start away from the central part of the macula (fovea), which is essential for seeing crisp detail and color. However, as the condition progresses, these patches can spread and eventually reach the fovea.

Current treatments for dry AMD, Syfovre® (pegcetacoplan) and Izervay® (avacincaptad pegol), slow progression of the disease by blocking the activity of proteins that spur this process, C3 and C5. Blocking these proteins helps slow what’s called the complement cascade, a sort of snowball reaction that can occur after the complement immune system becomes activated.

Gene therapy can allow the eye to make a constant supply of protein to block either VEGF or the complement system. How? A virus that doesn’t cause disease in humans (adeno-associated virus or AAV) acts like a Trojan horse: It is loaded with the instructions (DNA) for turning the eye’s cells into a factory for making the therapeutic protein. The virus is introduced into the eye, where it infects cells, and the cells begin producing an ongoing supply of the therapeutic protein that can slow the progression of AMD.

Since AAV does not cause disease in humans, the FDA considers it a relatively safe virus to use in gene therapies for eye diseases. A single injection of AAV could, in theory, allow the eye to continue producing the therapeutic protein for a person’s entire lifetime.

Ongoing Wet AMD Clinical Trials

As with any drug, gene therapy clinical trials need to be conducted in three phases. Phase I trials generally test the safety of a novel drug. Phase II and III trials evaluate how effective the drug is.

There are now three gene therapies for wet AMD in late-stage clinical trials. All three treatments have been found to be safe.

Current Gene Therapy Candidates for Wet AMD

ABBV-RGX-314

The most advanced of the three gene therapy candidates for wet AMD is ABBV-RGX-314, which is being developed by AbbVie and REGENEXBIO. ABBV-RGX-14 contains a gene for making a protein that destroys VEGF. In early trials, it stabilized or improved sharpness of vision (visual acuity) in people with wet AMD over two years. Most participants needed no additional injections during that time.¹

Data from two Phase III clinical trials, ATMOSPHERE and ASCENT, are expected to be released in 2026.² In these studies, the gene therapy is administered by subretinal (underneath the retina) injection, a technique that requires surgery. (By contrast, current AMD treatments are done intravitreally, or via injection into the fluid inside the eye, which is a routine, in-office procedure.)

However, a less invasive method of delivering the therapy is being tested in people with diabetic retinopathy in separate trials. The technique uses a specially designed microinjector device that delivers the therapy into an area at the back of the eye known as the suprachoroidal space.² This procedure may pose less risk of damage to the retina than subretinal injection. Similar to intravitreal injection, it can be performed in the office.

Ixo-Vec (formerly ADVM-022)

In March 2025, Adverum Biotechnologies Inc., announced the launch of ARTEMIS, the first of two planned Phase III clinical trials of Ixo-vec (ixoberogene soroparvovec), a gene therapy for wet AMD.³ Researchers expect to enroll approximately 284 individuals with the disease in the ARTEMIS trial, which will be open to both people who have previously been treated with other therapies, and those who have not.

Ixo-vec contains a gene with the code for making aflibercept, a drug that blocks VEGF activity. Afilbercept is the active ingredient in Eylea®, which is already used to treat wet AMD. In ARTEMIS and the upcoming AQUARIUS trial, half of participants will receive a single injection of ixo-vec, while the other half will be given standard 2 mg injections of aflibercept every eight weeks. Like Eylea®, ixo-vec is given by intravitreal injection.

In an early Phase II trial that tested two different doses of ixo-vec, less than half of participants needed additional treatment in the year after the initial treatment. Most of those who did received fewer than two follow-up injections.⁴

4D-150

In July 2025, 4D Molecular Therapeutics (4DMT) announced the start of 4FRONT-1, a Phase III clinical trial to evaluate their gene therapy, 4D-150, for the treatment of wet AMD.⁵ The trial will test a single injection of 4D-150 against an established AMD treatment regimen: a 2 mg injection of aflibercept every eight weeks. Enrolment in 4FRONT-1 will be limited to people with wet AMD who have received no previous treatment. However, plans are underway for a second trial, 4FRONT-2, which will be open to people who have been treated in the past, as well as those with no such history. One-year results of these trials are expected in 2027.

4D-150 is a dual-action gene therapy. It contains instructions for making both aflibercept, which blocks VEGF; and a second protein that targets VEGF-C. Like VEGF, VEGF-C promotes the growth of new blood vessels. Like ixo-vec, and existing AMD treatments, 4D-150 is given by intravitreal injection.

In a Phase II clinical trial, 70% of study participants needed one or no injections in the year after receiving the gene therapy, and 57% were injection-free.⁶

What About Dry AMD?

There is currently one investigational gene therapy being studied for treating dry AMD. The Janssen Pharmaceutical Companies of Johnson & Johnson is conducting clinical trials of JNJ-81201887 or JNJ-1887 for short. (Originally developed by Hemera Biosciences, the therapy was previously known as HMR59.) JNJ-1887, which has been found to be safe in a Phase I clinical trial for dry AMD, is given by intravitreal injection.⁷

JNJ-1887 uses an AAV to target the part of the immune system known as complement. In the end stage of complement activation, membrane attack complex (MAC), a sort of net of proteins, forms in the eye. Research has shown that levels of MAC are high in the eyes of people with dry AMD, and that a build-up of MAC on cell surfaces leads to cell damage and death.

JNJ-1885 contains the code for making CD59 (protectin), a protein that interferes with MAC formation. This may potentially slow the progress of dry AMD and keep the retinal cells that give us sharp central vision functioning for longer.

In April 2025, Johnson & Johnson announced the beginning of a Phase II clinical trial which will test JNJ-1885 in an estimated 300 participants with geographic atrophy due to advanced dry AMD.⁸ Called PARASOL, the study will compare two different doses of the gene therapy to a sham treatment.

Future Perspectives

Of the gene therapies for wet AMD, RGX-314 is injected subretinally, while Ixo-vec and 4D-150 are injected intravitreally into the eye. While intravitreal injections are a standard and routine office procedure, subretinal injections require surgery and pose significant risks of damage to the retina.

On the other hand, intravitreal injections are generally more likely to cause unwanted immune system reactions. They also do not deliver the DNA deep into the retina, which is where the leaky new blood vessels form in wet AMD. Both Advernum Technologies and 4D Molecular Therapeutics have developed novel retinal-penetrating AAVs to try and overcome these technical limitations.

To address the same technical issues, REGENEXBIO is using a specially designed microinjector device to deliver their gene therapy into the subchoroidal space. Data from eight clinical trials using the device to deliver a different medication for three other eye diseases suggests this technique is as safe as intravitreal injection.⁹

In addition to the clinical trials discussed above, several preclinical studies of gene therapy show significant promise for the treatment of AMD. While it is too early to know whether any of these approaches will be effective for treating AMD, the field is rapidly evolving and likely poised to make a big impact on the lives of people with AMD in the future.

Summary

Gene therapy techniques can essentially turn an individual’s body into a factory for producing a target protein that slows the progression of both wet and dry AMD. The instructions for making this protein are loaded into a virus that is injected into the eye, where it travels to specific cells. The cells then produce the drug continuously. In theory, this could eliminate the need to inject medication into the eye every four to eight weeks.

In Phase II clinical trials of three gene therapy treatments for wet AMD, many participants needed few or no follow-up injections in the year after receiving the initial dose. One investigational gene therapy treatment for dry AMD has advanced to Phase II clinical trials. More research is needed, but so far, these approaches show promise for freeing people with AMD from the need for regular eye injections.