Because so little is known about how visual injury can occur to an eye that has suffered no overt damage, VA’s Office of Research and Development funds biomedical and clinical studies aimed at unraveling the connections between injury and vision loss. In early 2015, Dr. Steven J. Fliesler, research health scientist at the VA’s Western New York Healthcare System, and Meyer H. Riwchun Endowed Chair Professor, vice-chairman and director of research of ophthalmology at the State University of New York/University at Buffalo Jacobs School of Medicine and Biomedical Sciences, launched the Buffalo VA’s first study into the effects of blast overpressure, or the shock waves generated by an explosion, on the eye.
A common cause of retinal injury – particularly among older Americans, a group disproportionately represented among veterans – is the vascular damage associated with diabetes.
In a preliminary examination of the eyes of rats that had undergone experimental blast injuries, Fliesler noted molecular changes in retinal cells that indicated a degenerative process likely caused by oxidative stress – essentially, a failure to detoxify the effects of free radicals within cells. “That’s when I started thinking we should be looking at this in more detail,” said Fliesler. Fliesler’s study, using a novel rat model to simulate the effects of blast overpressure in humans, will unfold in two phases: “The first thing is to look at the time course for the degenerative sequelae following a blast overpressure exposure,” he said. “We want to study when degenerative and functional deficits are first observed: How long do they occur? Do they dampen with time or do they get progressively worse? And the second thing is to test the efficacy of an intervention.”
Fliesler’s team will evaluate outcomes after feeding the rats a specially formulated antioxidant compound – importantly, beginning the treatments at different intervals following the blast. “Ultimately what we want to know,” he said, “is if you get a blast-exposed soldier into the field hospital within, let’s say six hours, 24 hours, 48 hours, and you start giving him or her a high dose of this multifunctional antioxidant, will that in fact lessen the severity of their degenerative sequelae? And how long before it is no longer efficacious?” In a separate series of studies, Fliesler’s team will treat rats with the antioxidant compound at intervals prior to blast exposure, to test whether or not such prophylactic treatment can actually offer some degree of protection against the damaging effects of blast overpressure on the retina. “We envision the possibility that soldiers would take a potent antioxidant pill – in the same way that many people take a daily multivitamin supplement – prior to being deployed in war zones, as part of their daily routine.”
When veterans do suffer overt injuries to the eye, they most often involve the cornea, the transparent covering of the iris, pupil, and anterior chamber. Dr. Balamurali Ambati, an ophthalmologist and research scientist at the Salt Lake City VA and director of corneal research at the University of Utah School of Medicine, has been studying a problem unique to patients with blast injuries of the eye: The cornea, typically free of blood vessels, is often invaded by blood vessels during the healing process. “That leads to a vicious cycle of inflammation and scarring in the cornea,” said Ambati, “and increases the risk of rejection of any corneal transplant. This is a major problem for our returning warfighters.”
Ambati’s laboratory is working on intracellular therapies that target the proteins, known as chemokines, that signal for the formation of these abnormal blood vessels. “By doing so, we prevent blood vessel invasion of the cornea, reduce the invasion or infiltration of the cornea and thereby improve the probability of success with corneal transplants,” said Ambati. “We’ve shown benefits both for low-risk and high-risk corneal transplant models in mice. And we hope to soon pursue that in larger animals.”
The reason light therapy works isn’t yet fully understood, Kern said: “It has many beneficial effects. It seems to inhibit the oxidative stress. It inhibits the inflammation that is developing within the retina. And the interesting thing is this is having a beneficial effect also in other parts of the body. It’s simply such a low-cost therapeutic approach that it could have some pretty significant implications.”
TBI is one of several things, along with glaucoma, optic nerve stroke, and other vascular problems, that can damage the retinal ganglion cells (RGC), the neurons that translate visual information from photoreceptors and send this information to the brain. “Retinal ganglion cells are particularly sensitive to injury,” said Dr. Nicholas Brecha, a research career scientist with the VA’s Los Angeles Healthcare System and a distinguished professor of neurobiology, ophthalmology, and medicine at the UCLA David Geffen School of Medicine, “and they’re particularly sensitive to a type of injury that occurs when there’s an increase in calcium levels within the ganglion cells. The increase in cellular calcium initiates a vortex of cellular changes that kills the ganglion cells. Once the ganglion cells are killed, this results in blindness, obviously, because you cannot get the visual signal from the eye to the brain.”
Throughout his career, Brecha has studied the problems associated with retinal cell damage and vision loss; more recently he’s begun to isolate the type of calcium channel – the membrane pores that regulate the flow of calcium ions into the RGC – involved in these kinds of injuries. “We’ve approached a fundamental question,” he said, “and we’re asking if we can control the calcium levels within ganglion cells by manipulating the calcium channel.”
In mice and rats with injured optic nerves, Brecha’s team has investigated several drugs that regulate calcium levels in the RGCs. “We have preliminary data for two drugs,” he said. “These are basic research findings in animal models, and of course we don’t know how far this is going to go. The findings look good, but we’ll learn more as we go forward.”
A common cause of retinal injury – particularly among older Americans, a group disproportionately represented among veterans – is the vascular damage associated with diabetes. Dr. Timothy Kern, research career scientist at the Louis Stokes Cleveland VA Medical Center and professor of medicine, pharmacology, and ophthalmology at Case Western Reserve University, has spent much of his career studying diabetic retinopathy. “The focus in my lab,” said Kern, “is trying to figure out what’s going on in the early stages of the retinopathy, so can we prevent that from ever developing. Oxidative stress seems to play a major role – and if we block the oxidative stress, we can block the early lesions, which clearly lead to the later, clinically significant aspects of the retinopathy.”
“Blindness is a horrible disease. And it’s not reversible when retinal cells die. The new therapies many people are talking about – genetic therapies, stem cell replacement, and prosthetic devices – are very promising but they’re a long way off, in my opinion. I think we’ll be much better off in the immediate future if we attack these problems on the front end and prevent deleterious progressive changes to retinal cells.”
Kern’s research is two-pronged: first, looking at how oxidative stress triggers the inflammatory response in photoreceptors, the neurons that convert light into neural signals; and second, observing – in animal models and more recently in a limited number of VA patients – the effects of light therapy in reducing this inflammation. “We’ve found in animal studies that a particular wavelength of red light, administered for three to four minutes a day, has very beneficial effects on things that we believe cause the retinopathy,” Kern said. “And in a small number of patients, we have actually shown that the exact same therapy reverses existing retinal edema that is caused by diabetes.” Kern’s laboratory is gearing up for a larger VA-sponsored trial, to see if these initial findings hold up.
The reason light therapy works isn’t yet fully understood, Kern said: “It has many beneficial effects. It seems to inhibit the oxidative stress. It inhibits the inflammation that is developing within the retina. And the interesting thing is this is having a beneficial effect also in other parts of the body. It’s simply such a low-cost therapeutic approach that it could have some pretty significant implications.”
Diabetic retinopathy accounts for 12 percent of all new cases of blindness every year in the United States, and it’s the leading cause of blindness for people between the ages of 20 and 64. If Kern and his colleagues can find a way to inhibit or delay its onset, it would be a discovery that would literally benefit millions of Americans.
There’s a simple reason, said Nicholas Brecha, for VA researchers to be focusing on the prevention side of vision loss: “Blindness is a horrible disease. And it’s not reversible when retinal cells die. The new therapies many people are talking about – genetic therapies, stem cell replacement, and prosthetic devices – are very promising but they’re a long way off, in my opinion. I think we’ll be much better off in the immediate future if we attack these problems on the front end and prevent deleterious progressive changes to retinal cells.”
This article first appeared The Year in Veterans Affairs & Military Medicine 2015-2016 Edition.