FOCAL POINT
Age-related macular degeneration, the leading cause of blindness in American seniors, is the greatest challenge facing vision researchers today.
by Eva EmersonAll of her life, Penny Norman had envisioned the day she would see the ancient pyramids of Egypt. The only problem was that soon after booking her trip, something went terribly wrong with her vision. Norman clearly recalls the day when half of her world became distorted: "I always had a weak right eye, but that day my eye just went nuts. All of a sudden, everything on my right side looked wiggly."
Norman was diagnosed with age-related macular degeneration (ARMD), the leading cause of blindness in American seniors. Within a few months, a dark, blurred spot blocked the center of her vision and straight lines appeared wavy, as if she was looking through a piece of curved glass. "Put your thumb up close in front of your eye and look around. That's what it was like," she says.
Norman, like most patients with the disease, was not a good candidate for the standard treatment-laser surgery designed to halt further deterioration, but with no hope of restoring what has already been lost. But Lawrence Chong, M.D., USC associate professor of ophthalmology, offered her another chance. Chong leads the investigation of a new microsurgery that has the potential to stop the progress of the disease and improve vision (see page 17). After Norman had the two-hour surgery last fall, her vision improved to the point that she was able to make her long-awaited journey. "Egypt was more than I ever expected. I was so happy that my eyes were able to take it all in," she says.
"Macular degeneration represents the greatest challenge facing vision researchers today," says Stephen J. Ryan, M.D., the Grace and Emery Beardsley Chair in Ophthalmology and dean of the USC School of Medicine, who studies the disease. He quickly ticks off a few of the reasons why:
One, despite some evidence suggesting that overexposure to sunlight increases the risk of age-related macular degeneration, no one knows exactly what causes the disease.
Two, it is incredibly common, and as people live longer, sure to become more so.
Three, it is impossible to predict who will get the disease, and of those who have it, who will get worse and who will lose their vision.
At USC's Doheny Eye Institute, vision scientists are attempting to discover what causes the disease and how better to predict its course. At the same time, basic scientists and ophthalmologists are working together to lead the search for new treatments, while eye surgeons are pioneering techniques to help patients who already suffer from the malady.
We "see" when light enters the eye and is absorbed by the retina, a thin layer of light-sensitive tissue. Cells in the retina transform light into nerve impulses that race to the brain, allowing us to see an image. But to focus on a written word or a friend's face, we must turn our gaze to look directly upon them. That is because the macula, a tiny region in the center of the retina, is responsible for our sharp central vision, which allows us to see the finest details. The macula, only one millimeter across, boasts a dense array of light-detecting cells. Even more crucial for visual acuity, only a few of these cells hook up to each brain cell that passes on the nerve impulses to the brain. In contrast, hundreds of thousands of light-detecting cells feed into each brain cell in the outer areas of the retina. That is why it is so much harder to focus on objects through the corner of the eye, where we can see with only peripheral vision.
"As we age, the cells in the eye that allow us to focus on fine detail-the letters on the page of a book, the face of the person across from you-begin to slowly deteriorate," says David Hinton, M.D., USC associate professor of pathology, who leads a group of scientists investigating the disease.
Adds Ryan, "The vision cells are really an extension of the brain. And, as with brain cells, you are born with a fixed number of vision cells. When they drop out, they are not replaced."
Some theorize that radiation and sunlight slowly damage vision cells. Others point to the incredible metabolic activity of the cells in the macula and wonder if that carries its own price. Metabolic reactions involve oxygen, which can spin off oxidants, or free radicals, which damage DNA and cellular proteins. A smattering of evidence suggests that a diet rich in antioxidants-from vitamins or green, leafy vegetables-could help stave off this damage. Other research has focused on whether minerals such as selenium and zinc could help prevent ARMD. However, most scientists believe that results from these kinds of studies are still too unclear to make any recommendations.
About 20 percent of people over age 45 experience mild changes in the macula known as the dry form of macular degeneration. Although this wearing down of the cells may interfere with vision, it rarely causes blindness. However, as many as 1 to 2 percent of the population will go on to develop a more serious form of the disease, called wet ARMD.
"The wet form of the disease leads to dramatic vision loss," Ryan says. In the wet form, abnormal blood vessels form below the macula. Vision may change suddenly when these blood vessels leak, burst or swell, putting pressure on the retina and damaging the macula. Left unchecked, wet ARMD causes legal blindness (defined as not being able to recognize the largest "E" on a doctor's vision chart) in 90 percent of sufferers.
Laser surgery stops bleeding below the retina by sealing off blood vessels, but it cannot heal any part of the macula that has been destroyed. "It won't restore lost vision, but it can help prevent further deterioration," Ryan says. However, laser therapy can only be used on a small percentage of patients, in whom the blood vessels have grown away from the macula's center. Otherwise, the surgery itself may harm the macula and create more vision problems.
In the face of these few options for patients, Ryan and Hinton are working together to find new ways to help people with the disease. Hinton has attempted to trace the origins of the disease to pinpoint targets for new therapies. His research points to the housekeeping cells of the macula called the retinal pigmented epithelium (RPE) cells. "We think it may be these cells that are responsible for promoting the growth of the blood vessels that destroys vision," Hinton says.
RPE cells form a thin layer below light-detecting cells, supplying nutrients and oxygen while carting away wastes. The choroid layer, with cells rich in blood vessels, lies underneath the RPE cells and helps the RPE layer with its chores. In patients with macular degeneration, it is the RPE cells that change the most with disease. In the wet form of the disease, USC researchers have shown that RPE cells change shape and begin emitting VEGF, a compound that initiates the growth of new blood vessels. Supported by the new blood vessels, the RPE layer grows so thick that it blocks the passage of nutrients and oxygen to the dependent vision cells. Combined with the build up of leaking blood from the new vessels, the lack of nutrition damages the macula.
"What is really novel about our research is that we have identified the RPE cells as the critical, central player in the disease process. These cells appear to be regulating the whole environment of the macula. No one knew these cells were releasing all of these growth factors, and creating this whole series of changes in the eye," Hinton says.
Ryan hopes to discover what makes the RPE cells orchestrate the development of the new, damaging blood vessels. "In the normal eye, we think there is a well-controlled balance between stimulators of blood vessel growth and inhibitors. It's unclear to us why this biochemical barrier, which usually tells these blood vessels to stay out of the macula, breaks down during disease." Together, Ryan and Hinton are searching for other growth factors that act similarly to VEGF and may play a role in recruiting new blood vessels in the eye. In terms of new therapies, the team is attempting to find ways to shut off RPE production of growth factors like VEGF.
The team has begun to collaborate with campus researchers who study how to halt angiogenesis, the development of new blood vessels, in tumors. Working with Parkash Gill, M.D., professor of medicine and pathology, they hope to test novel angiogenesis inhibitors, discovered by Gill, in an experimental model of ARMD. "We want to see if these molecules will stop the sprouting of blood vessels in the macula, a key process in the path to ARMD blindness," Hinton says.
Another area under study is how the three layers of the macula-the light-detecting cells, the RPE cells and the choroid layer-signal each other. By understanding the normal signaling, the team hopes to block any mixed up messages that may accelerate the destruction of vision. "We may be able to inhibit angiogenesis in the macula by stopping the cell-to-cell messages," Hinton says.
In addition, an emerging idea is to try a new kind of transplantation. In animal studies, the team has had success transplanting healthy cells from the iris to the area under the retina where the damaged RPE cells reside. The iris, the colored part of the eye, has pigmented cells similar to the RPE in the macula, but which are not affected by the disease.
In another set of experiments, the team hopes to genetically engineer RPE cells to release compounds that will stop the growth of new blood vessels. Ryan grows the genetically engineered RPE cells on a layer of blood vessel cells in small plastic dishes in the lab. "In vitro, we can inhibit angiogenesis with these cells. One day, we may be able to transplant this type of cell below the retina in people with ARMD. Then, we might be able to prevent loss of further vision, and perhaps even restore sight," Ryan says.
Henry Fong, Ph.D., USC associate professor of ophthalmology, is also using the tools of genetics to gather clues about what goes wrong in macular degeneration. Fong's team discovered a gene important in vision, called RGR opsin. "When we began to look at the human form of the gene, we found something interesting: Humans produce two different forms of protein from this gene-a normal version and an abnormal version."
Fong speculates that perhaps age-related macular degeneration may result from subtle, chronic effects of these abnormal RPE proteins acting in the macula over a lifetime. Now, he is trying to determine what effects the abnormal protein may have on eye health and whether people with ARMD have higher levels of the abnormal form.
"Considering that the macula is one of the most metabolically active regions in the entire body, it's not amazing to me that we get macular degeneration with age," Ryan says. "What is amazing to me is that the system works so well for so long, allowing us to view the world in the kind of sharp focus that most animals could never hope to see."
For more information about vision research and treatment at the Doheny Eye Institute, or to learn about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).
ARMED AGAINST ARMD
At the Doheny Eye Institute, Lawrence Chong, M.D., is among a handful of eye specialists around the world performing retinal translocation-a delicate, experimental microsurgery that may help improve vision and prevent further deterioration in the central vision of those with wet age-related macular degeneration (ARMD).
"We hope that the procedure will stabilize vision in these patients, many of whom would have become blind within a few years," says Chong, a USC associate clinical professor of ophthalmology.
During the surgery, Chong removes the vitreous jelly, which fills the eye, through microscopic openings in the wall of the eye. Next, he pierces the retina with fine tubes the width of a human hair, which he uses to detach the retina from the back of the eye. Then he shortens the wall of the eye by creating a tuck or pleat within it from the outside. In this fashion he is able to shift the macular region away from the diseased tissue below it. He needs only move the macula a fraction of an inch. Then he can use standard laser surgery to cauterize the blood vessels responsible for the loss of vision without harming the macula.
The procedure is still in its infancy, Chong says, but notes that so far, two of his patients have shown dramatic improvement following the surgery. Another two patients have had visual stabilization and Chong feels confident that the surgery stopped the disease progression.
Jennifer Lim, M.D., USC associate professor of ophthalmology, is spearheading an advanced clinical trial of another promising treatment for patients with ARMD. Called photodynamic therapy, Lim injects a light-activated dye into the eye. The dye targets tissues where new blood vessels have formed. When she exposes the patient's retina to light, the light sets off a chemical reaction that enables the dye to shrink the blood vessels behind the macula.
The idea of pioneering a treatment for those who otherwise had no options to help stave off the disease inspires physicians like Chong and Lim. "There have been a lot of people with no hope out there. This and other new techniques give us all reason to hope," Chong says.
- Back
- Next
- Index
