• February 29, 2024, 3:34 pm

How gene therapies can fix our eyes SoftAIT

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Update : Friday, November 17, 2023

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OUR EYES, unlike other organs hidden deep within our bodies, sit in plain sight. They have been inspirations for artists, symbols for the superstitious, and objects of scientific fascination for centuries. In ancient Greece, medical pioneers cut them open in public dissections, revealing delicate layers of retina, cornea, and iris. In the early 10th century, Persian physician al-Razi discovered that the pupil dilates and contracts to control the amount of light that enters. Six centuries later, the Renaissance-era anatomist Vesalius sketched a cross-section of the orb—with some errors. But eyes themselves are imperfect: Just one fault could cause the whole organ to glitch or break down. 

It turns out that flaws are common in our vision. More than 7 million Americans have some form of vision loss, which can include partial or full blindness, according to a 2021 analysis of 25 years of data from the US Census, the Centers for Disease Control and Prevention, and others. Many of these conditions are present from birth. Mutations in particular regions of DNA can lead to incorrectly formed optical parts. This can distort a person’s sight, especially if the issues are in the retina, the layer of cells at the back of the eye that captures incoming light and transmits it to the brain. But what if we could give someone with limited vision a corrected version of their genetic material to fix the malfunctioning parts?

Currently, there is no way to fully reverse inherited forms of blindness, which are traditionally managed with adaptations rather than treatments. “I speak to a lot of parents who are really frustrated about the lack of standard of care,” says Shannon Boye, a professor in the pediatrics department at the University of Florida. “They’re desperate for cures.”

But understanding the genetic roots of the disability helps. In theory, if scientists can pinpoint the problematic or missing DNA that’s hampering a person’s vision, they can design a rectified copy. The new genetic code is loaded into harmless viruses that deliver therapeutic genes to selected cells, and the viruses are then injected into the affected eye. There, the replacement DNA instructs the eye to make the proteins it needs to see again. 

In practice, it’s not so easy. The Food and Drug Administration (FDA) has approved only one gene therapy to treat a form of blindness—the first gene therapy the agency ever greenlit. Called Luxturna, it was OK’d in the US in 2017 to treat patients with mutations that lead to Leber congenital amaurosis (LCA). In people with this uncommon flaw, light-detecting photoreceptor cells in the retina develop incorrectly, become malformed, or die, leading to rapid vision loss early in life. Luxturna provides the correct version of the gene, partially restoring vision.

“This was a godsend scenario,” says Claudio Punzo, an expert in vision genetics at the University of Massachusetts Chan Medical School. There are several types of LCA, but the retina degrades more slowly in the form of the disease that Luxturna treats, which creates a larger window for the gene therapy to work. What’s more, people with the condition are often completely blind, so even a small improvement in their sight is life changing.

After that first FDA approval, “Unfortunately, the field hit a lull,” Boye says. But she is confident that with new genetic tools, Luxturna’s success story can be replicated on a much larger scale. 

One big step has been designing better couriers for the corrected code. Many gene therapies use naturally harmless adeno-associated viruses, which researchers modify to home in on retinal photoreceptors or other key cell types. Boye imagines a modular system using a suite of viral vessels designed for different destinations, in which any gene can be loaded as cargo. 

“Will we get it to work for everyone? With every mutation? Most likely, yes, at some point,” says Punzo. “It just becomes a logistical problem.” There are hundreds of different mutations that can cause blindness, and finding the right gene to fix in the right cell is no small task. For genes that are too large to fit inside a virus, CRISPR editing technology might offer an alternative method to correct the mutation directly in the patient’s DNA. In 2022, biotech company Editas tried using CRISPR to treat a form of LCA by removing a mutation in the retinal gene CEP290, but it paused the trial when vision in only three out of the 14 participants improved.

For people with visual disabilities, the invasiveness of current treatments is another major hurdle. These methods typically require surgeries to deliver the gene close to the retina, a process that itself can cause mild retinal damage. For someone with a less severe disease, such as night blindness or color blindness, the risks may not be worth the modest benefit. Shots in parts of the eye farther from the retina would be less invasive, but they are not yet standard for gene therapy. Another appealing option would be eyedrops, which were recently used for the first time in an experimental treatment at the University of Miami on a 14-year-old boy with corneal scarring. After months of the topical treatment, his sight returned to near-normal levels.

Cost is another obstacle. When Luxturna first hit the market in 2018, its price tag was $425,000 per eye. In part, the expense comes from the meticulous process of making a virus that won’t harm a patient. But the other part of the equation is the biotech industry’s irresistible pitch: We can help you see again. For people who are progressively losing their vision, even slowing down the process could be priceless—or so gene therapy companies hope. 

Most major insurers cover one dose of Luxturna per eye for patients whose retinas are intact enough to heal. But the hopefuls may still be on the hook for out-of-pocket costs associated with the procedure, or the cost of travel to one of 14 certified treatment centers in the US. “[It’s] an insanely expensive treatment,” Punzo says. “If there are cheaper drugs that would work, I think it will change the market.”

Currently, dozens of gene therapy clinical trials for hereditary forms of blindness are in progress, and many more are in the planning stages. They span diverse conditions, including Stargardt disease (which causes fat to build up in the eye), achromatopsia (a form of color blindness), and retinitis pigmentosa (which makes the retina break down). But progress is slow: Many have been at it for more than a decade with years to go.

Boye knows this firsthand. She co-founded a company called Atsena Therapeutics that is currently conducting a clinical trial for a virus-delivered code to correct an LCA-causing mutation. Her confidence that gene therapies can reverse blindness stems from both data and patients’ stories. She recalls a young girl who got the corrective treatment: As her vision improved, the child was able for the first time to see snowflakes—delicate, magical, and unlike anything she had experienced in her life.

Read more PopSci+ stories.



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