Three people have received an innovative treatment designed to rejuvenate vision cells. In a presentation at the annual meeting of the American Academy of Ophthalmology, researchers from Life Biosciences reported that the treatment appears safe, and two of the recipients show early signs of improved vision.

The study is among the first approved by the U.S. Food and Drug Administration using a novel strategy of reprogramming cells to restore their normal function—essentially rejuvenating them. The scientists used a modified version of a reprogramming strategy that earned a Nobel Prize in 2012 for turning mature, adult cells back to an embryonic-like state from which they could become any of the cells in the body—including healthy new versions of diseased or older cells. In that work, Japanese scientist Shinya Yamanaka used four genes to trigger the cellular time warp.

In the current Phase 1 trial, which is ongoing, scientists used three of the four factors to perform a modified reprogramming of diseased retinal ganglion cells in the eye in people with a form of glaucoma—not returning the cells all the way back to their embryonic-like state, but to a point before they stopped functioning properly. Retinal ganglion cells have long arms that connect them from the retina in the eye to the optic nerve, which transmits visual signals to the brain. In some people, over time, fluid in the eye fails to drain properly, putting pressure on the retinal ganglion cells, which lose their delicate connections to the optic nerve, causing loss of vision. While the cells don’t necessarily die, they become dramatically less able to do their job of transmitting critical visual signals.

To try to restore their function, in the trial, scientists injected specially designed proteins, or transcription factors, coding for three of the genes into the vitreous: the gel-like fluid cavity at the back of the eye near the retina. It’s an advantageous location to test such a therapy, since it’s protected from the body’s immune defenses which could attack the newly made proteins. The proteins then did their work to reprogram the damaged and aging cells so they became functional again.

The experimental therapy is based on work from the lab of David Sinclair, professor of genetics at Harvard Medical School and co-founder of Life Biosciences. It’s a test of his theory that aging cells lose their ability to work properly because they accumulate too many confusing instructions for which genes they need to turn on or off—so-called epigenetic noise that disrupts the original marching orders cells follow. Sinclair believes that restoring the proper epigenetic information, and removing the epigenetic “noise” by reprogramming the cells to a younger, more functional state could address diseases associated with aging, such as glaucoma.

“We are scientifically reversing epigenetic age to restore youthful function,” Sinclair says.

“We think of it as restoration,” says Sharon Rosenzweig-Lipson, chief scientific officer at Life Biosciences, who presented the new data at the conference. “We’re restoring the code back to what it was when [the cells] were healthy and functional.”

Full reprogramming with the four Yamanaka factors comes with a risk of cells growing out of control and forming teratomas, a type of tumor that can sprout partially or fully developed tissues like teeth, muscle, and bone. Sinclair’s goal was to exploit this reprogramming process to help cells regain their proper instruction manual, and together with his graduate student Yuancheng Lu, launched studies involving just three of the genes, dropping one that is most associated with cancers. There was no guarantee that using three of the factors would trigger reprogramming, since all of the previous studies employed all four. And for three years, Lu learned why—while working with mice with age-related vision loss like glaucoma, he struggled to reprogram retinal ganglion cells with only three of the factors. Experiment after experiment failed. Frustrated, Lu sought out Sinclair, hoping to move onto another project. “He said reversing aging is probably the hardest biological question in the world, and if it were easy, it would have been done already,” Lu says. But there was at least one element working in Lu’s favor. “Removing the fourth factor allowed the three other factors to be small enough to fit into the viral tool we used to deliver them into [animals],” he says. “If the three genes were a little bigger, then we couldn’t fit them into the viral vector.”

In 2018, Lu finally succeeded and texted Sinclair images of the first mouse with glaucoma that had regenerated the delicate connections between the retinal ganglion cells and the optic nerve that had been lost. When Lu asked Sinclair what he saw, Sinclair replied: “the future.”

Lu and Sinclair published their findings in 2020, and that therapy is very close to the one that Life Biosciences ended up using in its trial in people. Two days before the trial was launched in June, Rosenzweig-Lipson gave Lu the good news that the experiment he had worked on for three years was ready to test in the first people with glaucoma. “I was in the lab, and I couldn’t believe it,” Lu says. “I know these patients are suffering. My own family has the macular degeneration risk allele, and I carry the risk allele. So it means a lot to me. My great aunt died when she crossed the street because she couldn’t see well, so I feel like it’s destiny helping these people.”

While the study’s main goal is to show that the therapy is safe, two of the three participants showed early signs of improved vision as well, Rosenzweig-Lipson says. All three took a test before receiving the therapy to establish their visual field by noting when they could see strategically placed lights that flashed above, below, or to the left or right when they looked straight ahead. Eight weeks after receiving the reprogramming factors, two of the participants had improvements in their visual fields. “In places where they weren’t seeing as well, or weren’t identifying lights, we are now seeing better evidence that they can,” says Rosenzweig-Lipson.

She says the results are encouraging enough to begin testing a higher dose—three times that of the initial one—to determine if the treatment remains safe, and, ultimately, what dose would bring the biggest improvement in vision to patients.

The results could also lay the foundation for including people with another eye disease, NAION, which occurs mostly in people over 50 and is similar to a stroke in the eye. NAION causes sudden vision loss when retinal ganglion cells stop functioning for still unknown reasons. If the reprogramming factors can restore the function of some of these cells, the researchers are hopeful that people could regain some of their vision and avoid the blindness that results if left untreated.

So far, the researchers have not seen any adverse effects from the therapy: only side effects related to the injection, they say, and not the reprogramming itself. To be safe, however, the three factors can only be activated in the presence of the antibiotic doxycycline, which acts as an on-off switch for the treatment. After receiving the injection of the three factors, the participants took doxycycline for eight weeks, which ensured that the factors were active and produced the proteins needed to reprogram the retinal ganglion cells. Once they stopped taking the antibiotic, the proteins were no longer made. If further studies show that additional reprogramming is needed to improve vision, they could begin taking the antibiotic again to reprogram more aging or damaged cells.

These initial results will fuel additional studies on using the same method to rejuvenate other cells. Sinclair’s lab has reported promising findings with brain, knee, back, and liver cells in animals.

If the approach continues to be safe and show benefit, eye diseases could be just the beginning of rejuvenating different cells. “We have a wide array of [animal data] support now to suggest that it’s not just a one-organ phenomenon, but that it’s something that transcends organs and potentially has opportunities across a wide range of age-related diseases,” says Rosenzweig-Lipson.