Brighter Prospects

BY GORDY SLACK

Sensing a little light goes a long way. Consider the first light-sensitive organisms back in the pre-Cambrian era, ~550 million years ago. Their ability to sense light just well enough to move toward or away from it broke evolution open. Seeing—even barely—meant acting before being touched, which revolutionized the rules of survival and catalyzed an arms race of navigation, predation, defense, and new reproductive strategies. Perceiving light impacts a host of behaviors as well as quality of life – just ask a dog, who, having lived in darkness for a year, can suddenly again sense the motion of a squirrel, or see well enough to ascend a few stairs and join its owner. Or ask a once-blind mouse suddenly able again to sense the shadow cast by a raptor swooping down from the sky.

Victoria Fong and Beatrice Le, two doctoral candidates in vision science at Berkeley, employed an assay to “ask” that blind mouse, but one that had been treated with a new and improved edition of optogenetic retinal gene therapy. Mice will energetically avoid light…if they can see it. The treated mouse was placed in a two-chambered cage, and a light was switched on in one of the chambers.

It was with satisfaction that Fong and Le, and their advisor, neuroscientist and professor of optometry & vision science John Flannery, observed their once-blind mice—after a single injection of a gene-modifying therapeutic agent—scramble to the darker chamber when exposed to even low levels of light. Their experiment, published in the July 1, 2025 Scientific Reports, marks a crucial advance in a form of treatment, optogenetic retinal therapy, that has for more than a decade been tantalizingly close to revolutionizing how human retinal diseases are treated.

From Curious Admiration to Urgent Mission

Thirty some years ago, as an undergraduate Flannery was drawn to study the retina simply as a masterpiece of evolutionary innovation. But at some point in his post-doctoral training, Flannery’s interest shifted from one of pure curiosity about the mechanisms of the intact retina to a set of questions with more urgent implications. “Instead of just how the retina works properly, I started questioning how different diseases undermine it. Why does the retina so often stop working? And what could be done to make it work again?” he wondered.

“Experimenting with a mouse is more meaningful when you know it represents a real person at risk of going blind,” he says.

Retinal diseases, such as age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, affect millions of people globally, leading to partial and often complete vision loss by impairing the retina’s ability to process light and send visual information to the brain.

In the mid 2000s, Flannery began hearing about a revolutionary new research tool, called optogenetics, designed to help study the workings of the brain at the cellular level. By packing genetic instructions for making light-sensitive proteins into a viral vector that ushered them into neurons in whatever part of the brain was under study, researchers could program those neurons to fire when exposed to light.

Flannery immediately saw the awesome implications of optogenetics for not only studying, but also for treating, the one part of the central nervous system that normally operates in the full light of day: the retina.

“It is the natural place to use optogenetics,” he says. “The retina already has an optical system, a cornea and a lens right in front of it.” And if neurons that didn’t respond in the slightest to light could be reprogrammed to fire in response to light, could retinal cells that had lost—or never had—that ability be re-purposed to see again?

Mutation Agnostic Gene Therapy

Flannery recognized that optogenetics presented an opportunity to create a kind of gene therapy that does not correct specific genetic mistakes but is “mutation agnostic.” It bypasses any genetic defect in the photoreceptors and could conceivably treat most of the 300-plus heritable retinal diseases. “Under most conditions, it can restore light perception, whatever mutation or mutations are causing the disease,” says Flannery.

Key was the observation that retinal diseases that destroy the two main kinds of light-sensitive neurons in the outer retina, cones and rods, typically leave the inner layer of ganglion cells intact and functional. Retinal ganglion cells normally collect light-stimulated input from cones and rods and send it to the brain. Effectively, Flannery repurposed ganglion cells into being photoreceptive cells that communicate directly with the vision-processing occipital lobe.

The Goggle Problem

Six years ago, Flannery’s lab tested the approach in blind mice, using his viral delivery system to express cone opsins (light-sensing proteins borrowed from cone cells) in the ganglion cells. The results, published in Nature Communications, were impressive. Treated mice demonstrated significantly improved vision. And the treatment’s benefits appeared to be permanent.

Optimism ran high after those mouse experiments with cone opsins, says Flannery. But while the first human trial did restore vision to patients, the optogenetic molecule used was insufficiently light sensitive to help patients see unless they donned light-intensifying goggles, which are uncomfortable and can cause phototoxicity—cellular damage triggered by excessive light exposure. The cone opsins also reacted too slowly, making vision blurry or laggy. These shortcomings held back popular adoption of the treatment.

Engineering Better Opsins

Enter Flannery’s collaborator Steven Brohawn, a cell biologist in Berkeley’s department of neuroscience, and a pioneering expert in the crystal structure of channelrhodopsins (a family of opsins borrowed from microbes that employ a different mechanism than cone opsins). Brohawn cracked the code of channelrhodopsins construction. “Now that Steve understands the structure and gene sequence of these opsins, he can engineer them to make them more sensitive, or faster or respond to different wavelengths of light,” says Flannery.

Using molecular biology and protein engineering techniques, Brohawn designed several new channelrhodopsins that were much more sensitive to light than those cone opsins tested in the human studies six years before. As described in that 2025 Scientific Reports paper, “The treated mice were sensitive to a range of light intensities, with ChRmine-T119A showing particular promise for its efficacy at indoor light levels.” ChRmine-T119A, one of Brohawn’s new channelrhodopsins, was at least an order of magnitude more sensitive than the old ones. If these results translated to humans, the new opsins would obviate a need for the cumbersome goggles.

“We looked at the activity of a single retinal cell that had been gene-modified with one of the new channelrhodopsins and saw bursts of signals at low light levels, which made us really excited,” says grad student Le. The new opsin, ChRmine-T119A, was an order of magnitude more sensitive than the old ones, says Flannery. If these results translated to mice and eventually humans, the new opsins would obviate a need for the dreaded goggles.

The mice in the study didn’t regain detailed, normal sight. But recovering sufficient light sensitivity to move through environments in ordinary lighting conditions was a huge step toward therapies that could one day help people with advanced retinal degeneration see again.

Dog Trials

Instead of going straight to time-consuming and regulation-laden human trials, Flannery and his team are taking a different tack. They’ve entered a collaboration with UC Davis veterinary ophthalmologist Sara Thomasy who has also been working on the problem of retinal disease for more than a decade—her scientific and clinical preoccupation is with retinal blindness in dogs, where it is a heart-breaking problem.

Thomasy had long been interested in Sudden Acquired Retinal Degeneration Syndrome, or SARDS, one of the most common causes of blindness in dogs, and one that hits especially hard and fast.

“I talked to the owner of a dog with SARDS last night,” says Thomasy. “Over the past week his dog has gone from normal, to some vision impairment, to completely blind. The dog’s personality almost completely changed overnight, too. It’s devastating.”

Thomasy, both a board-certified veterinary ophthalmologist and researcher at Davis, had been trying to sort out the pathogenesis of SARDS in dogs for a decade. “But what causes it is still a mystery. We thought maybe it was an autoimmune disorder, that antibodies were attacking the photosensitive cells. But when we do histology on the retinas, there’s just not a lot of inflammation. So, it’s been tough to figure out. And if you don’t understand why a disease occurs, it’s hard to treat it.”

SARDS was one reason Thomasy had been tracking research on using optogenetics to treat retina-related blindness. “We wouldn’t need to figure out what causes SARDS,” she says. “As long as those retinal ganglion cells we’re targeting are still there, we can bypass the problem and restore some vision.” But while she was hopeful that optogenetics might help her blind canine patients regain sight, Thomasy was discouraged by the need for goggles. “That just wouldn’t work for my patients,” “There’s no way dogs are going to wear goggles,” she says.

Then, in 2024 at a meeting in Seattle, Thomasy met Leah Byrne, a former post doc of Flannery’s. Byrne told Thomasy about the promising results Brohawn was having engineering more sensitive and faster channelrhodopsins, and she introduced her to Flannery’s team. “We forged a really great collaboration,” says Thomasy. “And we began to work together on a trial of ChRmine-T119A in my dog patients with SARDS.”

As the Flannery lab did in their mouse studies, Thomasy injects one eye of each blind canine patient with the vector carrying ChRmine-T119A, and then waits two months before putting her patients twice through an obstacle course, once with each eye covered. By comparing the two performances, she can measure the effect of the improvement of the treated eye. After two days of tests and observation, the dogs are sent home again with their owners, who continue to update Thomasy on their progress.

“We won’t be publishing results for another year or year-and-a-half,” Thomasy says. But she acknowledges that after treating four dogs in her clinic so far, she remains “hopeful” that the therapy will make a significant improvement in her patients’ quality of life and that of their owners, and one day of humans suffering from vision loss.

The collaboration with Thomasy is great for his team, too, Flannery says. “It’s very hard to run sophisticated, visually guided behavior tests in rodents. Mice rely a lot on their whiskers, hearing, and smell to navigate. Dogs are much more visual, so behavioral evaluations of them are more relevant to human patients and straightforward to interpret,” Flannery says.

“The drug kinetics are much closer. What we’re learning from the dogs will make scaling up to human eyes much easier,” Flannery says. And the surgery used to administer the treatment is much more similar in dogs and humans, too, so, the team is getting a clearer idea of how well human patients will tolerate the procedure itself. “So far, surgery has gone very well for all the dogs the Davis team has treated,” Flannery says.

Toward Human Trials

In addition to the canine studies, Brohawn’s lab continues to engineer increasingly sensitive channelrhodopsins, and he’s exploring proteins that are triggered by different wavelengths of light as well as responding in different ways to that light. “Someday we may be able to insert multiple opsins recapitulating both on and off circuits to get more motion-vision resolution, letting these damaged retinas work even more like normal ones,” says Thomasy.

“And because it’s a gene therapy, it’s ‘one and done,’ she says. “Patients would just need a single treatment.”

“It’s probably never going to restore normal vision,” she continues. “These ganglion cells weren’t designed to sense light. But getting light perception back, large object detection back, being able to detect moving objects, those things are all extremely valuable.”

If a formerly blind patient can see the bowl of food in front of them, or the outline of a doorway, or if they can step safely up onto a curb, or see the face of their kid, that’s life changing... for a person or a dog!

If Thomasy’s patient-subjects demonstrate that the treatment is working in dogs, several challenges still must be met before a human trial could be launched. Flannery’s team would have to make a human medical-grade version of their viral vector and then, to find the minimum therapeutic dose, they’d have to do a dose escalation study of it in several more dogs with SARDS. After that, they’d do a study of the vector in primates to show that the treatment doesn’t harm any other organ systems in the body. All of this, assuming things proceed smoothly, says Flannery, will cost upwards of $10 million and take a year and a half at the very least. But, given that it took about 550 million years before those pre-Cambrian creatures were first blessed with the ability to see light, a couple of years doesn’t seem all that long. And for patients who may again be able to see the light of day, it would be well worth the wait.

Related Information

See Magazine
Flannery Lab
About Dr. Flannery
About Beatrice Le
About Dr. Sara Thomasy