New research from Children's Hospital Boston and the Massachusetts Eye and Ear Infirmary (MEEI) may help explain how glaucoma causes blindness, revealing the chain of cellular and molecular events that ultimately damage the optic nerve, preventing visual information from traveling from the eye to the brain. The study, done in mice, indicates possible targets for intervention, including an inflammatory molecule called tumor necrosis factor-alpha (TNF-alpha), which is already targeted by some existing drugs.
"These findings give a whole new approach to thinking about glaucoma therapy," says Joan Miller, MD, chief of Ophthalmology at the MEEI and a coauthor of the study, which will appear online December 6 in the Journal of Neuroscience.
Glaucoma affects an estimated 3 million Americans, and it's speculated that an equal number of people are affected but undiagnosed. The disease is six to eight times more common in African-Americans (in whom it is the leading cause of blindness) than in Caucasians, and six times more common in people over age 60 than in younger people. The primary risk factor for glaucoma is increased pressure in the eye, measured by the familiar "puff" test and other screening examinations. If glaucoma is diagnosed early, eyedrops or surgery to lower intraocular pressure can often prevent further optic-nerve damage and halt vision loss. However, it has not been understood how the increased pressure leads to optic-nerve damage.
Working in a mouse model, lead author Toru Nakazawa, MD, PhD of Children's and MEEI, senior author Larry Benowitz, PhD of Children's Neurobiology Program and Department of Neurosurgery, and Miller and colleagues at the MEEI, made several key observations. They showed that:
1) elevated intraocular pressure causes levels of TNF-alpha to increase in the retina;
2) the rise in TNF-alpha activates microglia, cells that comprise part of the eye's immune system;
3) the activated microglia kill many of the optic nerve's oligodendrocytes (support cells that produce and maintain myelin, the insulating coating on nerve fibers);
4) retinal ganglion cells (RGCs), the nerve cells in the eye that send visual information to the brain via the optic nerve, subsequently die off, consistent with previous research establishing that oligodendrocyte loss leads to the death of RGCs. "The end stage of glaucoma is a loss of retinal ganglion cells," says Benowitz. "We now have good evidence that TNF-alpha plays an essential role in this loss."
When TNF-alpha was injected directly into the eyes of mice with normal intraocular pressure, the same chain of events occurred: microglia were activated, oligodendrocytes died off, and RGCs were lost. But none of these events occurred in genetically engineered mice that were unable to produce TNF-alpha (or its cellular receptor, TNFR2), even when intraocular pressure was raised.
Moreover, the researchers showed -- for the first time -- that blocking TNF-alpha's action with an antibody prevented loss of oligodendrocytes and RGCs when intraocular pressure was raised. In addition, genetically engineered mice that were unable to activate microglia (lacking the CD11b genes) enjoyed similar protection when intraocular pressure or TNF-alpha levels were raised.
"In the clinic, lowering intraocular pressure is a reliable treatment for glaucoma, but sometimes it is hard to lower the pressure even after eyedrop treatment or surgery," says Nakazawa, now at Tohoku University in Japan. "Here we show that blocking TNF-alpha function may have a benefit as a neuroprotective treatment."
Drugs that inhibit TNF-alpha -- including monoclonal antibodies and soluble receptors that soak TNF-alpha up and remove it from action -- already exist and have been used to treat other inflammatory diseases such as rheumatoid arthritis, the researchers note.
"These drugs have potent systemic effects, so we'd want to develop a very safe long term and local treatment," says Miller. "Theoretically, it might be possible to put slow-release TNF alpha inhibitors just outside the eye, so you wouldn't have to have frequent injections."
Blockade of downstream microglial activation with anti-inflammatory agents might represent another therapeutic strategy, adds Benowitz.
The study was supported by an Alcon Research Award, a Bausch & Lomb Vitreoretinal Fellowship, the National Institutes of Health and the National Eye Institute.
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