By David N. Leff

Everybody knows that clogging the coronary arteries that feed blood to the heart results in atherosclerosis, which can cause death.

Not everybody knows that clogging the eyeball's outflow channels results in glaucoma, which will inevitably cause near-total loss of vision. Those slender passages drain off aqueous humor from the eye's anterior chamber, and flush it away into the bloodstream via nearby veins. If some obstruction causes that fluid to build up pressure throughout the eyeball, it will inexorably destroy increasing numbers of the million or so optic nerve fibers that transmit the eye's visual images from the retina to the brain.

"Probably the most insidious form of the disease is open-angle glaucoma," observed ophthalmic pharmacologist Arthur Neufeld. "Something clogs up the outflow. Because of that, pressure builds in the eyeball. But people can walk around with it for years; there are no symptoms. You don't really know you have that primary glaucoma unless the ophthalmologist checks your pressure."

Neufeld continued, "As opposed to that common, open-angle form, there is the relatively unusual narrow-angle, or angle-closure, glaucoma, where some accidental event causes the pressure to go very very high very quickly. The patient is in a lot of pain, knows something's wrong, and goes immediately to the eye doctor."

Add to those two forms the fairly rare congenital glaucoma, in which newborns grow with enlarged eyes because their channels are occluded. Prompt surgery can correct this inherited condition.

"Primary glaucoma is the second most frequent cause of irreversible vision loss in the U.S. The first cause," Neufeld suggests, "depends on the age group. It's probably macular degeneration in the elderly. The primary form, we believe, occurs in some two to four percent of individuals over 60 to 65 years of age. And this percentage increases as one gets older.

"Some recent studies," he went on, "show that this prevalence is much higher in African-Americans. It's 10 to 12 percent in that population of older individuals. Occurrence of the other glaucomas is much less."

Eye-drops of various types are designed to lower intraocular pressure, but all such drugs suffer from a range of more-or-less severe side effects, plus uncertain efficacy.

Neufeld, endowed research professor of Ophthalmology and Visual Sciences at Washington University in St. Louis, has in recent years proposed a different explanation for the loss of nerve cells in glaucoma. "Having seen reports on nerve damage caused by excessive nitric oxide," he recalled, "we decided to look for evidence of high NO levels in human eyes with glaucoma.

"We had previously demonstrated the presence of a specific enzyme, nitric oxide synthase-2 [NOS-2], in human glaucomatous tissue," he told BioWorld Today. "We examined optic-nerve tissue from deceased donor eyes. Comparing them to normals, we were able to demonstrate that that NO-releasing enzyme is there. That was really the first demonstration anybody's ever done to show the presence of something that could actually be destructive to the optic nerve of glaucoma patients. So the question that then occurred was whether NOS-2 is cause or effect? Is it doing the damage, or is its presence just secondary there, because the tissue is already being damaged by intraocular pressure?"

To tackle that conundrum, he and his co-workers set up a rat model of glaucoma, in which they raised intraocular pressure in the rat's eyes, by cauterizing the blood vessels draining fluid from the eye.

"This resulted," Neufeld recounted, "in optic nerve degeneration, loss of retinal ganglion cells, and cupping of the rats' optic discs - due to the elevated pressure. It took a long time to develop, just as human glaucomas do. Six months or so in the rat. And we were able to demonstrate that in that animal model, NOS-2 appears when the optic nerve is degenerating because of pressure."

Enlisting a Diabetes Drug For Glaucoma Control

"The next step then," Neufeld continued, "was to use a drug against that enzyme, a specific pharmacological compound that would inhibit NOS-2, and see if that made a difference. Would it save those retinal ganglion cells from degeneration, prevent the optic nerve changes? And sure enough it did."

Neufeld and his co-workers report their findings in today's Proceedings of the National Academy of Sciences (PNAS), dated Aug. 17, 1999. Their paper is titled, "Inhibition of nitric oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma."

He summed up the results of that in vivo experiment: "The glaucoma that we established over a six-month period in the untreated control animals showed about a 40 percent loss of retinal ganglion cells, and cupping of the optic nerve - a very typical-looking human-like glaucoma. In the rats that we did treat, by adding oral aminoguanidine - an experimental diabetes drug - to their drinking water, over the six-month period, that inhibitor of NOS-2 almost completely blocked the loss of retinal ganglion cells and the optic disk changes."

Getting Big Pharma, Small Biotech, Into The Act

Given this preclinical success in halting - though not reversing - glaucoma's pitiless progress, Neufeld and his co-authors are now "certainly interested in getting the pharmaceutical industry interested in this project. And they are; we've had good responses. In order to get a drug for glaucoma on the market," he pointed out, "or at least into clinical testing, it really needs the industry to take over the project, either go with this molecule or a similar one, do all the things needed for FDA approval, then get it into the clinic. These discussions have begun."

Meanwhile, he and his team are testing other NOS-2 inhibitors, to see if there's some molecule that would work better or at a lower dose than aminoguanidine.

Those physiological quanta of nitric oxide, he explained, are released as needed by the NOS-1 and NOS-3 enzymes. NOS-2 wears the pathological black hat, producing NO far in excess of physiological requirements.

"Clearly, pharmaceutical neuroprotection is the next generation of glaucoma drugs," Neufeld observed, "and in therapy for other types of neurodegenerative diseases where NOS-2 is important. It's a reasonable target for a small company," he concluded, "and certainly the biotech world could make a contribution to that."