How can treatment for eye disease be made easier?
Therapies currently in clinical trials could last longer and help to save more vision in people with age-related macular degeneration
Until about 20 years ago, people in the advanced stages of age-related macular degeneration (AMD) were almost certain to lose their central vision. Without the ability to see faces, read or drive, most people met the criteria for blindness.
That changed for some people in 2006. The US Food and Drug Administration (FDA) approved a treatment for an advanced form of the disease known as wet AMD, in which new blood vessels develop in the central part of the retina and leak fluid. “When I started practising, for a patient with wet AMD it was depressing. There wasn’t a whole lot we could do,” says Dante Pieramici, co-director of the California Retina Research Foundation in Santa Barbara. The arrival of the drug ranibizumab, which inhibits the growth of leaky blood vessels, was a major shift.
In trials, ranibizumab and subsequent similar drugs were shown to slow or prevent the loss of vision in most people with wet AMD, and even help to restore vision in some cases. Some trial participants are still taking the drug today, and still benefiting. “I have patients from the original clinical trials who are still reading and driving,” says Pieramici.
But results in the real world are not as good as they are in clinical trials. And for the most part, scientists think that’s because it’s too difficult for people to sustain the treatment regimen. Drugs such as ranibizumab must be given every month or every few months, and are delivered in clinics through injections into the eye. “In practice, there are a lot of barriers”, says Arshad Khanani, director of clinical research at Sierra Eye Associates in Reno, Nevada. “Patients miss appointments and get under-treated.”
Clinicians and researchers are now devising therapies that will be more effective in real-world conditions. Some are trying to make smarter use of existing therapies to reduce the burden on individuals; others are testing implants that can release these drugs over time. And gene therapies under development could potentially manage a person’s wet AMD for a lifetime with a single treatment. Eventually, these therapies might not only make treatment easier for people, but also do more to prevent loss of vision.
AMD is responsible for 6–9% of cases of blindness in people worldwide, and it is expected to affect about 288 million people by 2040. The disease mainly affects the macula, the centre of the retina, at which vision is sharpest. The greatest risk factor is age — AMD is rare in people under 50. But smoking and obesity are also contributing factors, and there is thought to be a genetic component too.
Saving sight
In the early stages of AMD, yellow or white deposits called drusen build up on the retina. These are visible during an eye examination, and are typically spotted by ophthalmologists before people experience symptoms. People then progress to dry AMD, also known as geographic atrophy, in which cells in the macula begin to break down. A person’s treatment journey often ends here — options for geographic atrophy are poor, and a person with the condition will gradually become blind. But 10–15% of people will progress to another disease stage, wet AMD, caused by the growth of blood vessels in the retina and the underlying tissues.
This growth might be triggered by tissue damage. “It seems to be a response from the body that there is not enough oxygen and nutrition there,” says Monika Fleckenstein, an AMD specialist at the University of Utah Health in Salt Lake City. In some people, these blood vessels might be beneficial, nourishing a stressed retina and helping some to preserve vision. But the vessels are often poorly formed, and instead exude liquid that further damages the macula.
When ophthalmologists see leaked fluid in the eye of someone with AMD, they can prescribe drugs such as ranibizumab that bind to vascular endothelial growth factor (VEGF) and inhibit blood-vessel growth. The drugs are administered by injection directly into the gel-filled vitreous chamber of the eye that separates the lens and the retina.
These intravitreal injections can work very well. In clinical trials for wet AMD, effectiveness is measured by monitoring change in the number of letters that a person can read on an eye chart. Phase III trials of ranibizumab1,2 showed that more than 90% of people given the VEGF inhibitor once a month for a year lost fewer than 15 letters in that time (one line on a standard eye chart has 5 letters). In the control groups, in which people were given either the standard therapy or sham injections, by contrast, only about 60% of people held this level of vision. Among people treated with ranibizumab, 25–40% even regained 15 letters of visual acuity.
Those initial trials involved people who had had wet AMD for years, some of whom had already experienced significant vision loss. Once these therapies became available, physicians began treating people at the first sign of vascular leaks; now, ophthalmologists try to begin these treatments before a person has lost any vision. Outcomes during the first year of treatment are still profound. In one study3, people with wet AMD who were treated with VEGF inhibitors gained, on average, about one letter of visual acuity in the first year. Another showed an average increase of about seven letters after two years4.
“When you got this diagnosis prior to 2006, you were going to go legally blind,” says Peter Campochiaro, an ophthalmologist at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Ranibizumab changed that. “It has a dramatic effect — provided it’s injected frequently.”
Making it last
Adhering to ranibizumab’s regimen of monthly eye injections is challenging. Many people need a relative or carer to take them to their appointment. If they can’t attend appointments then their vision will decline.
Some people enjoy the social interaction of appointments, says Fleckenstein. But others find getting an injection into their eyeball to be psychologically taxing. The injection itself is not painful, but the eye must be washed with irritating antiseptic beforehand to prevent infection. This leaves people with a lingering sensation that they’ve got something in their eye that can last for days, but it keeps the rate of infection down to around one in 2,000–3,000 injections, says Fleckenstein.
Long-term studies have shown that gains made in the first two years of anti-VEGF treatment don’t last forever; people’s visual acuity wanes over time. “Real-world outcomes are different than in clinical trials,” says Khanani. An observational study3 that Khanani was a part of, and which followed around 80,000 people with AMD for 4 years, found that visual acuity held steady for the first 3 years of treatment, but declined in the fourth. This loss of visual acuity can have profound effects, Khanani says, including increasing a person’s risk of a fall and hospitalization.
A physician applies eye drops to a patient before she receives an eye injection.Credit: Dr P. Marazzi/Science Photo Library
Physicians can try to reduce the burden on their patients by extending the time between injections. An ophthalmologist might try giving ranibizumab every four weeks. If an examination shows that there’s no bleeding in the retina then they might extend the dosing interval to six weeks, and so on until they determine the longest safe interval between injections. For some anti-VEGF drugs that are longer-lasting than ranibizumab, such as a high-dose formulation of the drug aflibercept, people can go three to four months between injections.
Tailoring treatment regimens to individuals still requires them to attend regular vision tests and retinal scans. Last May, however, the FDA approved a home optical coherence tomography (OCT) imaging device called Scanly. The Internet-connected device sends images of a person’s retinas to a centre that detects changes and communicates information back to individuals and their physicians. This approach could help to reduce the frequency of appointments for some people with wet AMD, says Fleckenstein.
And people who have required frequent anti-VEGF injections now have an alternative: an implantable reservoir loaded with ranibizumab. Known as Susvimo and approved by the FDA in 2021, the implant delivers the drug to the eye gradually and needs refilling only every six months. Installing the device requires hospital surgery, but refills can be done at local clinics with a syringe.
Still, uptake of Susvimo has been slow. Although people don’t enjoy having frequent intravitreal injections, “it’s the devil you know,” Pieramici says. It didn’t help that its manufacturer, Genentech, temporarily recalled the device in 2022 because a part that seals in the drug could become dislodged inside a person’s eye, making it impossible to refill. The company has fixed the issue, and the product is back on the market. Pieramici says that his patients who have the implant are happy with it.
Other companies are working on drug-delivery devices that biodegrade over time. Ocular Therapeutix in Bedford, Massachusetts, is testing an implant made of a squishy, biocompatible polymer mesh called a hydrogel that dissolves as it releases the drug axitinib. Rather than act on VEGF directly, axitinib inhibits VEGF’s target, stopping the signalling cascade that leads to leaky blood vessels. This implant is in phase III clinical trials, and is designed to be injected into the vitreous chamber every six months — a similar procedure to administering ranibizumab, but less frequent.
Single shot
Another approach — gene therapy — aims to turn the eye itself into a drug factory. Instead of giving a person hundreds of injections of short-acting drugs over their lifetime, says Campochiaro, gene therapy “would potentially be a single treatment”.
Several gene-therapy trials for wet AMD are in progress. These use adeno-associated viruses (AAVs) to deliver a gene, usually encoding an anti-VEGF drug. “The beauty of AAV is, it’s a harmless virus that can deliver a large DNA cargo,” says David Schaffer, a bioengineer at the University of California, Berkeley.
The gene therapy that’s furthest along the pipeline, currently in phase III trials, carries a gene for a protein similar to ranibizumab. Surgeons use a needle to create a fluid-filled bubble between the light-sensing cells of the retina and the underlying epithelial cells that nourish them, then inject the therapy, called RGX-314, into this sub-retinal space.
An early-stage trial enrolled people with wet AMD who were known to respond well to intravitreal injections of ranibizumab. People who received what Campochiaro describes as a ‘medium’ dose of RGX-314 still had constant levels of the anti-VEGF protein that its cargo encoded after two years. Campochiaro, Pieramici and Khanani each had patients enrolled in this trial and were co-authors on a study describing it5.
Even in the relatively ‘calm’ sub-retinal space, immune responses pose a risk for wet AMD gene therapy. In the RGX-314 trial, some people developed pigmentary changes below the injection site that might have been the result of an immune reaction, says Campochiaro, but this did not affect their vision. Physicians are concerned, however, that repeated injections — either in the same eye if another dose is required, or even to treat a person’s second eye — might lead to a stronger response from a now-primed immune system.
Preliminary data from the RGX-314 trial, presented by Khanani at the American Academy of Ophthalmology meeting in Chicago last October, show that people treated with the same vector in their second eye did not have a dangerous immune reaction. It’s still possible that a primed immune system might render the treatment less effective in the second eye, owing to less of the gene construct being installed in the cells, but Pieramici says there’s not enough data yet to know.
It is also not yet clear whether a single dose will be enough. “Is it a one and done,” says Campochiaro, “or is it a treatment that reduces the burden, but doesn’t eliminate it?”. Schaffer thinks that these therapies will last as long as the cells being targeted stay alive. “As long as the cell doesn’t turn over, the virus sticks around,” he says.
Combination punch
Administering therapies to the sub-retinal space, as is the case for RGX-314, carries some risk of complications — for one, the retina has to heal at the point at which the bubble was placed. If it were possible to administer a gene-therapy vector into the vitreous chamber, the procedure could be carried out at a clinic, reducing cost and eliminating the risks of surgery.
Schaffer has spent decades fine-tuning AAVs to target the retina so well that they can be injected into the vitreous chamber and find their own way to the retina. AAVs have many advantages as gene-therapy vectors, but they are first and foremost respiratory viruses. “Natural versions haven’t evolved to deliver DNA to the eye,” Schaffer says.
Scientists can’t quickly engineer viruses to be better at complex tasks such as infecting the retina. So Schaffer and his team took advantage of a method called directed evolution. They injected millions of AAVs into the eyes of mice, then recovered those that established themselves in the retina. They repeated the process over and over, selecting for viruses that excelled at targeting the retina. Then, they repeated the process in non-human primates, the eyes of which are much more similar to ours than are the tiny eyes of mice. The resulting engineered viruses can be injected just like antibody drugs, and will make their way to the retina6. To prevent inflammation as the AAVs travel around the eye, people in clinical trials have been given steroids.
Schaffer has licensed his retina-targeting AAVs to 4D Molecular Therapeutics in Emeryville, California. Its wet AMD vector, called 4D-150, codes for a protein that targets the most prevalent form of VEGF, and for an interfering RNA that tackles another form, called VEGF-C. In some people, multiple forms of VEGF (as well as proteins called angiopoeitins) contribute to the disease. Over a long course of treatment with a certain anti-VEGF agent, the eye might upregulate other pathways to compensate. Targeting these pathways as well as the most common form of VEGF might therefore provide greater benefits than a single anti-VEGF agent, such as ranibizumab.
Closer investigation of the biological pathways that drive wet AMD could also lead to more affordable drugs. Antibodies are expensive compared with small molecule drugs, says Levon Khachigian, a vascular biologist at the University of New South Wales in Sydney. His team discovered a molecule called BT2, which makes endothelial cells less ‘sticky’ in animal models of AMD and could slow the production of blood vessels7. Khachigian hopes that the compound, which has been licensed to biotechnology company Filamon in Camberwell, Australia, might help people who do not benefit from existing therapies.
With several therapies in trials that could be easier to take or more effective than current treatments, it’s an exciting time for wet-AMD specialists. “We’ve found these agents that work very well,” says Pieramici. “Now the focus is on making the therapy more durable.”
Nature 639, S4-S6 (2025)
doi: https://doi.org/10.1038/d41586-025-00655-6
This article is part of Nature Outlook: Vision, a supplement produced with financial support from Astellas Pharma. Nature maintains full independence in all editorial decisions related to the content. About this content.
This story originally appeared on: Nature - Author:Katherine Bourzac
