For years the medical community thought elevated pressure inside the eye was the main cause of most glaucoma cases, the leading source of incurable blindness in the United States and the world. Based on that belief, most treatments were aimed at reducing intraocular pressure.

Recently, however, there has been a growing awareness that perhaps as many as a third of the people who develop glaucoma have normal or near-normal intraocular pressure.

So if increased intraocular pressure isn’t the only cause of most glaucoma, what is?

That’s what researchers at the Duke Eye Center are trying to figure out. In the laboratories of the Albert Eye Research Institute, they are delving into the inner function of the eye from every angle.

Glaucoma is an optic nerve disease (actually a group of more than 60 diseases) characterized by the loss of optic nerve tissue, which ultimately leads to vision loss and blindness.

Elevated eye pressure is a major risk factor for most forms of glaucoma because it can cause damage to the optic nerve. Yet as many as 25 to 30 percent of individuals who develop glaucoma do so with normal or near-normal intraocular pressure, and their glaucoma is indistinguishable from that of people who have elevated pressure. Of all the individuals who have an elevated eye pressure, only about 10 percent will develop glaucoma.

“Your eye pressure can be normal, and you can develop glaucoma, or your pressure could be elevated, and you may not develop glaucoma. So pressure is a terrible way to screen whether you have glaucoma,” says Rand Allingham, M.D., chief of Duke’s Glaucoma Service.

Worldwide an estimated 70 million people have glaucoma; seven million of these people are blind. That makes glaucoma a major public health issue.

One of the biggest challenges with glaucoma is that, in most cases, it is an asymptomatic disease. It rarely causes pain or symptomatic vision loss until late in the course of the disease. Vision loss from glaucoma is not reversible, so while researchers strive to find a cure for glaucoma, diagnosing it at a treatable stage remains a major goal.

Current treatments for glaucoma include medication, laser surgery, and conventional surgery that lower eye pressure to slow or stop the progression of the disease, and, in some cases, surgery to clear a plugged fluid drain. Even in cases where pressure is not elevated, treatment is directed at lowering eye pressure (from the high-normal range to the low-normal range). Now it is still the only proven way to control vision loss from glaucoma.

When elevated eye pressure does occur, it is caused by a blocked fluid drain in the eye. Aqueous humor is the colorless liquid that fills the eyeball. It is pumped through the eye continuously, even before birth. It circulates within the eye, nourishes it, and keeps the eye inflated. The aqueous fluid is constantly produced by the ciliary body, and it must be drained continuously through a fluid flow drain.

When the drain doesn’t work efficiently, eye pressure increases. The elevated eye pressure damages the optic nerve fibers that carry all visual information to the brain.

In many glaucoma cases where pressure is elevated, the fluid flow drain isn’t working well. Duke basic science researcher Pedro Gonzalez, Ph.D., associate professor in ophthalmology, is studying how the drain works at the molecular level.

“Glaucoma usually has a very slow progression and, in general, it affects people after the age of 40,” says Gonzalez, who worked at the National Eye Institute laboratories before coming to Duke. “We want to know, first, how normal drain tissue works, and then what goes wrong with that mechanism in glaucoma. If we can understand what is responsible for the failure of this tissue in the fluid drain, we can develop treatments to delay the disease’s progression.”

Gonzalez and his research team use pig eyes for most of their studies. They take tissue samples from the front of the eye (the part responsible for draining the aqueous humor), pump fluid into these samples, and measure the speed at which the liquid drains. They also modify cells in this tissue by genetically introducing, altering, or removing genes related to the drainage process.

Gonzalez’s lab is currently focusing on oxidative stress as one of the main factors that could cause glaucoma. Oxygen is used by cells to breathe and to obtain energy. But it can also form a series of molecules that can damage the cells in the drainage system.

“We think it may be possible for us to develop medications that could prevent the damage caused by oxidative stress so the drain tissue will be functional for a longer time,” Gonzalez said.

Researcher Stuart McKinnon, M.D., Ph.D., associate professor of ophthalmology, is starting there. The optic nerve, which is in the retina in the back of the eye, is made up of about 1.5 million nerve fibers that arise from ganglion cells that transmit signals between the eye and the brain. In glaucoma these ganglion cells begin to die, which causes vision loss. McKinnon is trying to understand the molecular process by which this cell death occurs.

“Now that we know elevated intraocular pressure is not the only cause of glaucoma, it’s important to find therapies to protect the optic nerve itself,” says McKinnon. “Glaucoma is a long-term, chronic disease, and the longer we can delay the process, the more useful vision people will have.”

McKinnon’s lab uses rodents to test different therapeutic approaches, such as using viruses to deliver genes that will produce proteins capable of protecting the ganglion cells.

McKinnon was the first researcher to discover that molecular events that take place in glaucoma are similar to those that occur in Alzheimer’s disease, a finding recently confirmed by British researchers.

Proteins that affect the brains of people with Alzheimer’s also appear to cause the death of the optic nerve cells in glaucoma. This means that therapies used to treat Alzheimer’s potentially could be used to treat glaucoma, McKinnon says.

In the research laboratory next door to McKinnon’s, Vasanth Rao, Ph.D., associate professor in ophthalmology with a secondary appointment in the Department of Pharmacology and Cancer Biology, is applying his expertise in cell biology and cytoskeletal signaling to both the aqueous fluid flow drain and the optic nerve. “The immediate goal of our lab in the area of glaucoma is to understand the cell biology of the aqueous humor drainage pathway,” says Rao.

Using human and pig eyes as samples, Rao’s lab has already found several molecular targets that increase aqueous outflow, and pharmaceutical companies are now running clinical trials on some of the promising drugs and drug-delivery systems to target these molecules.

Rao’s research interests complement those of David Epstein, M.D., professor of ophthalmology and chairman of the Department of Ophthalmology, and a renowned glaucoma researcher in his own right.

And then there’s genetics. It appears that certain genes increase susceptibility to damage of the optic nerve or fluid drains, says Allingham, who has been leading a large-scale study to find the genes that cause glaucoma.

Allingham, Gonzalez, McKinnon, Rao, and other glaucoma laboratory researchers and clinician-scientists at Duke are in close communication, sharing their findings and collaborating on several projects. Allingham’s genetic findings can tell Gonzalez which genes or proteins to look at in the drain tissue he’s studying, for instance, or guide McKinnon to study those genes in his mice. Or Gonzalez may find proteins that appear to play an important role in fluid flow in the eye, and Allingham can use that information to look at candidate genes for glaucoma.

What is the cause of glaucoma? As these Duke Eye Center detectives pursue every lead, each new insight raises more questions and more avenues to pursue.

A longer version of this article appeared in the fall/winter 2007 edition of Vision, a publication of Duke Eye Center.