TED GRIGGS

Drs. Puran and Nalini Bora are helming groundbreaking research into macular degeneration at UAMS.

In legends, the scientific breakthrough always strikes like lightning. Inspiration comes out of the blue. The apple falls from the tree, and presto: Newton’s universal law of gravity.

In reality, scientific advances involve little instant gratification. The researcher chooses a field and works in it. The breakthroughs come slowly, an inch at a time, each advance laying the groundwork for the next.

That’s how it worked for Nalini Bora, Ph.D., director of research at the Pat and Willard Walker Eye Research Center, Harvey &
Bernice Jones Eye Institute, University of Arkansas for Medical Sciences.

Bora began investigating the eye’s complement system, the eye’s innate immune system, in 1990 for her doctoral thesis.

“The eye is different from the rest of the organs in our body,” Bora said. “I thought I must investigate the role of the complement in the protection of the eye first, and then in various ocular diseases because of the unique role of the complement and unique nature of the immune system in the eye.”

Over the years, she and the other members of the research team slowly made progress and some basic contributions to the field, while garnering a number of research firsts.

Bora was the first to demonstrate the importance of the complement’s role in protecting the eye from infections. The lab also discovered an important link between innate immunity and ocular immunity using an animal model of idiopathic anterior uveitis. The research team was also first to show that the activation of the complement system is crucial for the development of choroidal neovascularization, the growth of abnormal blood vessels in wet-type, age-related macular degeneration and keratitis.

“In the eye, complement functions as a double-edged sword,” the researchers say in “Complement, Innate Immunity and Ocular Disease,” published last year in Immune Response and the Eye.

The complement system helps defend the eye from pathogens, the paper said. But the complement also has the potential to inflict damage to the eye; uncontrolled activation of the system may cause inflammation, cell death or abnormal cell growth.
When Bora first began her research, the idea that macular degeneration was an inflammatory disease and that the eye’s immune system played a role in its development was, well, inflammatory.

“After we published our first paper in 2005, it really changed the field and the way people … think about this disease in particular,” she said. “People never thought this was an inflammatory disease. Actually people kind of laughed at our idea, that the complement could have a role in this disease. But now it’s a very well-established fact.”

One area on which the research team is now concentrating its efforts first sprang from another: the discovery that in mice, a single complement regulatory protein controls choroidal neovascularization, or the growth of abnormal blood vessels under the retina and macula.

The new blood vessels tend to be fragile and often leak fluid and blood, causing the macula to bulge. The pressure distorts or even destroys vision.

Controlling the growth of those vessels is a key to treating people with age-related macular degeneration, the leading cause of blindness for people over 55, Bora said.

The Eye Research Center scientists’ paper, published in 2006 in The Journal of Immunology, suggested that the regulatory protein could be used to treat choroidal neovascularization.

This would mean new, and potentially safer, treatments for patients with age-related macular degeneration, as well as those suffering from keratitis and uveitis, Bora said.

“The next goal of our lab is to see if we can translate the lab results to humans,” Bora said.

That research is probably four to six years away, but if the lab can show that its observations in animals hold true for humans, the researchers can take the obvious next step: trying to block macular degeneration in humans, Bora said.

The research team has shown that recombinant proteins inhibit both macular degeneration and uveitis in animals, Bora said. Lab members hope to do preliminary studies in humans, and then with the Food and Drug Administration’s approval, inject the proteins into the eyes of AMD and uveitis patients.

It may also be possible to use the treatment for patients with uveitis, glaucoma, and ocular tumors, such as uveal tumors that grow in the retina, Bora said.

The results so far are promising, and the lab expects to publish papers on glaucoma and ocular tumors within a year.
“Right now our concentration is mainly in wet form, and that’s because it causes irreversible blindness,” said Puran Bora, Ph.D., a professor in the UAMS Department of Ophthalmology and Nalini’s husband.

However, other researchers have shown that inhibiting the complement can treat the dry type of AMD, he said.

“It’s like if we inject for wet-type it might also cure dry-type,” he said.

Researchers at the center are also looking at the role of the complement in herpes simplex-induced keratitis, or inflammation of the cornea, Nalini Bora said. The virus is very common.

About 50,000 cases of keratitis are reported each year, according to the U.S. National Institutes of Health’s National Eye Institute. Most of those are recurrent cases.

Nalini Bora said that it may eventually be possible to place the recombinant, complement-related proteins into a spray.
The spray could be used to treat ocular disease in general and would provide a better alternative to the current treatments for wet-type macular degeneration and uveitis, she said.

Puran Bora said for now, the researchers hope to come up with a drug that AMD patients won’t have to inject so frequently.
Right now, the FDA has approved two drugs, Lucentis and Macugen, for treating AMD, he said, but both can cause hemorrhages.

“The main drawback is you have to inject these drugs in the eye again and again, every month or so,” he said. “Our objective is to develop a drug which you have to inject once in a year, maybe six months. That would be a good alternative to these drugs.”
Another approach for wet-type AMD also has serious side effects.

Although photodynamic therapy reduces the rate of vision loss in most patients, it does not significantly improve vision, according to the Boras.

In this treatment, a light-sensitive dye is administered intravenously, and then an ophthalmologist treats the choroidal neovascular membranes with a laser. The laser activates the dye, coagulating and reducing the growth of blood vessels.

However, repeated treatments can be expensive and can cause severe damage to the posterior segment of the eye. According to FDA studies, five to six treatments were needed in the first two years to stabilize a patient’s vision.

Nalini Bora said any alternative would be better than the current, nonspecific treatment for uveitis: steroids.

Steroids can result in a lot of complications, she said. Clinicians are not very happy about the treatment, and they are hoping that better therapies can be developed for uveitis patients.

By the time the researchers develop their treatment, it will be even more badly needed.

In the United States, approximately 1.9 million people, almost all over 55, have an advanced form of AMD, according to the National Institutes of Health. The number will more than triple by 2030 as the country rapidly ages; by then, the number of people over 65 will be six times what it was in 1990.

Whether they develop a spray or a shot, the researchers will require funding, Bora said.

“If anybody is ready to donate some money, we’d be very glad to accept that,” she said.

Age-related macular degeneration

• Macular degeneration is the leading cause of blindness for people over 55. In the United States, an estimated 10 million people have some signs of the disease. Approximately 1.9 million U.S. residents have an advanced form of macular degeneration. By 2030, an estimated 6.3 million Americans could have an advanced form of the disease.


• AMD is caused by the deterioration of the central portion of the retina. The retina’s central portion, known as the macula, allows a person to see fine details.


• There are two types of AMD. Wet AMD accounts for 15 percent of the cases and occurs when fragile blood vessels grow behind the retina, rupture and leak blood and fluid, damaging the macula. Loss of central vision takes place quickly. In dry AMD, the light-sensitive cells in the macula slowly break down, gradually blurring central vision. One common early sign is drusen, or yellow deposits under the retina.

Uveitis

• Uveitis is an inflammation inside the eye affecting the uvea, the layer of the eye between the sclera and the retina.


• The most common form is anterior uveitis, which involves inflammation in the front part of the eye. The inflammation is usually limited to the iris.
• Causes can include autoimmune diseases, infection and exposure to toxins. In many cases, the cause cannot be determined.


• Approximately 38,000 U.S. residents develop uveitis each year. The disease causes 10-15 percent of blindness in the United States.