Imagine falling asleep with your vision intact and waking up without it—with no way to get it back. That’s the reality for the roughly 6,000 people in the United States who are diagnosed with non-arteritic anterior ischemic optic neuropathy, or NAION, every year, the vast majority of them adults over 50.
Now, a new gene therapy has made the first steps on the path to becoming the first-ever treatment for NAION, along with many other aging diseases of the eye. In a presentation on April 23 at the 2023 Association for Research and Vision Ophthalmology Annual Meeting, scientists at regenerative medicine biotech Life Biosciences and Harvard Medical School revealed data showing that the company’s gene therapy platform could restore vision loss in primate models of NAION.
“Everybody’s aware that for age-related diseases, healthy aging is the goal,” Bruce Ksander, Ph.D., who co-led the study alongside renowned longevity scientist David Sinclair, Ph.D., told Fierce Biotech Research. “For age-related diseases like vision loss, we need new approaches and I think this one is very promising.”
The primate experiments build upon earlier research that tested Life Biosciences’ gene therapy platform in mouse models of glaucoma. In that case, they were able to restore sight by altering epigenetic changes—modifications to the way genes are expressed that don’t affect the genetic code—in retinal cells. The most critical changes were in DNA methylation patterns, where methyl groups are attached to DNA molecules. While scientists don’t yet have a complete picture of the mechanisms controlling DNA methylation, it’s a well-established hallmark of aging.
Life Biosciences’ gene therapy platform works by inducing expression of the transcription factors Oct3/4, Sox2 and Klfr4, or OSK—three of the four Yamanaka factors. When all four Yamanaka factors are expressed together, have been shown to fully reprogram differentiated human, mouse and primate cells back into pluripotent stem cells, erasing their cell identity and resetting DNA methylation to an embryonic state. But while there may be some benefit to inducing all four factors at once, as seen in mouse models of the premature aging disease progeria, other research has shown that doing so continuously can cause cancer.
On the other hand, partially reprogramming the cells with OSK, even for prolonged periods, doesn’t appear to have deleterious consequences, as Ksander’s team showed in their study on glaucoma in mice. Armed with their findings, they set out to see if the platform could also work for NAION in primates too.
They started by using a laser to induce the same kind of damage and vision loss that’s seen in NAION, then injected the therapy into the eyes of six monkeys, while another four received a control solution. They followed the therapy with systemic doses of the drug doxycycline throughout the study, allowing the scientists to turn OSK expression on and off.
At one, two, three and five weeks after inducing the NAION-like injury, the researchers assessed the primates’ vision using a method called a pattern electroretinogram, or pERG, and compared it to pre-laser baseline readings. The technique works a bit like an electrocardiogram for the heart, but for the retina, looking at the way electrical signals that represent visual activity change in response to a changing pattern displayed on a screen.
The researchers found that visual function was restored nearly back to baseline in the treated primates’ eyes, while it remained unchanged in untreated animals. Immunohistochemistry studies on the animals’ eyes also showed that the experimental group had more healthy axon bundles compared to controls. They predict that this is because OSK transcription was both protecting the bundles from further degeneration and restoring their function.
Why study NAION and not glaucoma, like they did in the mice? Though the researchers plan to assess whether their platform works on glaucoma in primates as well, they wanted to use a disease with a very precise timeline. Glaucoma patients often can’t pinpoint exactly when their symptoms began, Ksander explained; many have early symptoms without even realizing it. Meanwhile, NAION has a well-defined timeline—clinicians know exactly when the injury occurred, which is one that’s rare for age-related diseases of the retina.
“It’s a blinding disease and there’s no treatment,” he said. “So we can very precisely try to deliver the treatment as quickly as possible after the injury occurs.”
It’s too soon to tell how long the improvements will last in the primates with NAION, though insights from the mouse models of glaucoma suggest they could stick around for a while. The mice’s restored vision lasted for 11 months before age-related changes began to set in again, new data to be presented on April 25 will show. Ksander thinks it will be possible to perform the treatment repeatedly, so the benefits are sustained.
“We’re working on an approach that will allow us to cycle the treatment,” he explained.
Life Biosciences is also conducting safety and dosing studies in primates in anticipation of filing an application with the FDA to begin a study of the platform in humans with NAION, which Life Biosciences expects to do in the next 18 to 24 months.
“I think we’re making really good progress,” Ksander said.
Biotechs have expressed plenty of interest in gene therapies for eye disease, though the only one with regulatory approval so far is Spark Therapeutics’ Luxturna, marketed for mutation-specific retinitis pigmentosa and Leber’s congenital amaurosis. GenSight reported in May 2021 that it had restored vision in a single retinitis pigmentosa patient with a different type of mutation using the company’s gene therapy. Other companies have been striking deals to make headway: Regeneron and ViGeneron entered an agreement in April 2022 to develop one for an undisclosed inherited retinal disease.
Meanwhile, failures have been piling up, too. Earlier this month, opthamology gene therapy biotech Vedere Bio II shut down after disappointing preclinical studies on its treatment for inherited or age-related macular degeneration. And Biogen tabled its choroideremia drug timrepigene emparvovec in June 2021 after it failed to meet recovery endpoints in a late-stage clinical trial—a month after the company announced it was dropping a different eye disease gene therapy, this one for retinitis pigmentosa.
Ksander is undeterred. While other biotechs are altering specific genes, his group’s focus is on epigenetic programming, he pointed out. And the results from Life Biosciences’ wide-ranging preclinical work across several different types of models gives the scientists confidence.
“The breadth of these successful studies indicates that partial epigenetic reprogramming to rejuvenate aging and injured cells is a robust and reproducible effect with enormous clinical potential,” he added.