Seeking A Cure
By Eric Craypo
Written by Zac Unger, Illustration by Marcin Wolski.
If you lived in ancient Egypt and found your vision getting cloudy as you aged, there was nothing to worry about: the physicians of the day had plenty of treatments ready at hand, including onions, myrrh, raccoon entrails, and antelope dung. None of these worked of course, but they were at least preferable to the cataract treatment you would have received during the Renaissance era, a technique known as “couching” that involved displacing the lens with a needle applied directly to the eye. For glaucoma in particular—the world’s second leading cause of blindness—doctors have spent thousands of years fruitlessly searching for a cure. Even today, eye doctors can only slow the disease’s progression and there is still no way to restore vision that has already been lost.
But all that may be changing with the groundbreaking work on lipoxins—tiny molecules that protect neurons and retinal ganglion cells—being done by the labs of UC Berkeley Herbert Wertheim School of Optometry and Vision Science professors John Flanagan and Karsten Gronert, along with collaborators at the University of Toronto. At the most basic level, glaucoma occurs because an imbalance in drainage and production of aqueous humor leads to an increase in intraocular pressure that reduces the blood supply to the back of the eye and eventually kills retinal ganglion cells, the neurons that carry visual information from the eye to the brain. Those cells are the final relay in turning visual stimuli into information that can be processed by the brain. Once they’re dead, they don’t regenerate. Up until now, treatment has consisted of working to lower that pressure and slow future degeneration. But the holy grail of glaucoma research has always been the search for neuroprotective factors that will stop the buildup of pressure that destroys ganglion cells.
“It turns out,” says Gronert, “that these neuronal cells are surrounded by supporting cells that keep them happy.” Astrocytes, a star-shaped type of glial cell, cluster around the nerves at the back of the eye, feeding and maintaining the ganglion cells, and they sense when there is danger present. For years researchers had assumed that when the glaucoma disease process started, something in the activation of the astrocytes was the trigger that killed off retinal ganglion cells.
But about ten years ago, Flanagan and his colleagues had a revelation. “We started looking at it the other way around,” Flanagan recalls. “We realized that it was actually what the astrocytes stopped doing that was important.” Rather than doing something toxic during the activation process, it turned out that glaucoma caused astrocytes to cease their normal maintenance work of keeping healthy eyes healthy. After the team discovered that activated astrocytes stop releasing their protective signals, it became clear that a true treatment could lie in figuring out exactly how that signal was being sent and received.
FACING GLAUCOMA ON THE FRONT LINES
“The onset of glaucoma is insidious,” says Clinical Professor Carl Jacobsen, “the progression is slow and it’s invariably worse in one eye or another.” While Flanagan, Gronert and their colleagues are hard at work on the theoretical and research aspects of glaucoma, Jacobsen works every day on the front lines of the disease as Chief of Berkeley’s Ocular Disease Clinic at the Meredith Morgan University Eye Center, not only treating patients but helping them understand that they’re even suffering from it in the first place. Unlike the itchy red eyes of an infection, glaucoma comes on over the course of years and may have no symptoms. “And if patients do come to us complaining about symptoms of glaucoma, that probably means it’s already at the end stage,” he says. This is a real challenge for the clinician, who, Jacobsen says, “must be astute enough to detect early changes in glaucoma that do not give patients functional loss of vision.” Flanagan, who maintained a clinical practice along with his research lab until becoming dean of the school in 2014, concurs with Jacobsen about the urgent need to find a cure. “For some patients it’s just devastating,” he says. “Their whole life revolves around how they’re managing their glaucoma.” And for the small percentage of patients for whom the basic stabilizing treatments prove ineffective, “that’s when you have to have the drainage surgery where we are taking desperate actions to keep the pressure low in the eye and try to stop the patient from losing vision too quickly.”
The Centers for Disease Control estimates that over four million Americans suffer from some level of glaucoma, many of whom are completely unaware, making the need for treatment a key national priority. While Flanagan knew that small molecular weight lipids potentially played a key role in glaucoma progression, finding the precise type of lipid and figuring out how it worked was beyond his area of expertise. But, in one of those happy accidents that can only occur at a worldclass research institution like Berkeley, Flanagan’s lab happened to be right next to Gronert’s, who had extensive experience in the intersection of lipid mediators and disease as well as advanced analytic tools. “We persuaded him to run this through his equipment,” Flanagan recalls of the early work with Gronert. “And this is something he’d studied for years in terms of immunology and he was interested enough to join us in figuring out what on earth this was.”
THE PROMISE OF LIPOXIN B4
The first move, says Gronert, “was that we analyzed this unknown protective soup that came from the astrocytes,” which led to the discovery of the unique lipid molecule Lipoxin B4. You can think of lipid mediators as short-lived messages between cells; they can trigger inflammation when the body needs to fight infection or switch inflammation off once healing begins. Common drugs like aspirin and ibuprofen work by blocking specific lipid mediators that cause pain and inflammation. What Gronert found was that a unique class of lipid signals associated with regulating and terminating inflammation in the eye were released by the astrocytes as part of their normal work of maintaining cellular function. Astrocytes at rest are in a homeostatic state, maintaining a normal physiology for the retina. “But when you stress them, they stop making these lipid signals,” he says. “So these lipid signals are not just regulating inflammation; they’re released by homeostatic cells in the healthy retina and directly act on the neuronal cells to protect them and prevent them from dying.”
“Cells die by apoptosis in glaucoma,” Flanagan says, referring to the slow process of degeneration in the retinal ganglion. “But the lipoxins can stop that process once it’s started. They’re neuroprotective.” These lipid signals, therefore, are the key messengers calling on the body to terminate a neuro-inflammatory response in a healthy ocular physiology. After so many years of merely trying to slow the inevitable, this new discovery offers tantalizing promise of stopping glaucoma’s punishing progress—and possibly even reversing it.
But the road from “aha moment” to reliable treatment for humans is long and full of difficulty. As far back as 2017, Gronert, Flanagan, and Toronto researcher Jeremy Sivak began experimenting with using Lipoxin B4 on rats in which rapid glaucoma had been induced. The treatment stopped the degeneration process, earning the team a patent on the process of amplifying the lipoxin pathway as a neuroprotective signal. Yet the team knew the challenges that would follow in attempting to move a treatment from the lab out into the real world. “The worry in bringing this to the next level is whether you fully understand all the little nuances of what this lipid or the signal actually is,” Gronert says. “You need to make sure you are hitting the right cell with the right dose at the right time and really understand how it works in the real world, not just under your contrived and optimized conditions.” Figuring out the delivery mechanism is both daunting and exciting. In addition to the potential for drops or injections, the team is working at the cutting edge of genetic therapy by designing a virus to deliver an enzyme directly into the mouse retina, which will supercharge the action of the neuroprotective Lipoxin B4 signals.
A novel threat to the research has also emerged in the form of uncertainty around grant funding from the federal government. The glaucoma group has just reached the end of a five-year funding cycle from the National Institutes of Health, and what had been expected to be a simple renewal process is now less assured. Moreover, the work Gronert and Flanagan do is inherently collaborative and builds on the work of academic researchers around the world. In particular, their colleague Jeremy Sivak at the University of Toronto has been a key partner. But new NIH policy placed a roadblock in funding collaboration with foreign partners, even those in friendly countries like Canada. And until that policy is revised, says Gronert, the grants are ineligible for renewal. “We have really exciting new data that we’ve had to withdraw and we cannot resubmit. Now we’re just waiting.” While others outside the US will no doubt continue this work, the loss of expertise from the Berkeley team will slow the progress of this desperately-needed research.
THE POTENTIAL TO SLOW OR REVERSE OTHER NEURODEGENERATIVE DISEASES
Part of the excitement around this research—and the potential tragedy of cutting it off—is that this work on glaucoma may yield similar breakthroughs on other, unrelated neurodegenerative diseases. As chair of the Glaucoma Research Foundation, Flanagan has in recent years convened a multidisciplinary team that brings together bioinformatics experts with researchers working on glaucoma, Parkinson’s, Alzheimer’s disease, and even some brain cancers. The root cause of glaucoma is unique to the eye, Gronert explains, “but the cascade that initiates the eventual death of the retinal ganglion cells is something that’s shared among many central nervous system degenerative diseases.” With Alzheimer’s, the relevant immune cells in the brain fail to remove the disease-causing plaques; in theory, the same type of lipid signaling that the Berkeley team studies in glaucoma could be used to slow or reverse the progression of dementia.
As people live longer and longer, glaucoma will affect more of us, and, with no cure yet available, more people are at risk of significant vision loss as they age. While there is still a long road ahead before the research into these tiny signalers can be actualized into a therapy, the potential alleviation of suffering is enormous. “It may not end up being the single thing that cures the disease, but at the moment we have no reason to believe that it’s not,” says Flanagan. For his part, Dr. Gronert is excited by the future of this type of collaboration between researchers from different disciplines. “We all have completely different perspectives on the problem, and unique sets of expertise,” he says. “And that leads to novel experiments, novel approaches, even ideas for therapeutic amplification for other diseases.”
Related Information
About Dr. Flanagan
About Dr. Gronert
About Dr. Jacobsen