TNF-alpha may be responsible for glaucomatous damage of optic nerve

Boston-The chain of events in the eye that ultimately leads to glaucomatous damage of the optic nerve head and visual deterioration has been determined in an animal study. Tumor necrosis factor-alpha (TNF-alpha) causes a cascade of events leading to loss of the retinal ganglion cells.

The results are highly clinically relevant because they represent an impending sea change in how glaucoma ultimately will be treated.

To investigate the pathophysiologic mechanisms of glaucoma, the investigators used a murine model to induce ocular hypertension using laser irradiation. This treatment resulted in increased levels of TNF-alpha that, in turn, caused microglial activation, loss of the oligodendrocytes in the optic nerve, and delayed loss of retinal ganglion cells.

The study included lead author Toru Nakazawa, MD, PhD, from the Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, the Department of Neurosurgery and Neurobiology Program, Children’s Hospital, and the departments of ophthalmology and surgery, Harvard Medical School; senior author Larry I. Benowitz, PhD, associate professor of neurosurgery in the Department of Neurosurgery at Children’s Hospital; and co-author Joan W. Miller, MD, the Henry Willard Williams Professor of Ophthalmology, chairwoman, Department of Ophthalmology, Harvard Medical School, and chief of ophthalmology, Massachusetts Eye & Ear Infirmary, all in Boston. They reported their results in the Journal of Neuroscience (2006;26:12633-12641).

In a control group of mice with normal IOP levels, the same sequence of events was observed after injection of TNF-alpha. Interestingly, when animals were treated with TNF-alpha inhibitors, or genetically engineered mice that could not produce TNF-alpha were studied, no damage occurred despite increased IOP.

The authors concluded, “Our studies in an experimental mouse model show that TNF-alpha plays a central role in the pathophysiologic events that result from elevated IOP. TNF-alpha is upregulated as a consequence of increasing IOP, and, like IOP, exogenous TNF-alpha leads to a loss of oligodendrocytes and delayed loss of retinal ganglion cells.”

The next considerations

Investigators offered three potential avenues by which to explore future treatments for glaucoma: a blocking antibody that interferes with TNF-alpha, which already has been used to treat other inflammatory processes; a soluble receptor and a TNF-alpha-converting enzyme inhibitor are other possibilities.

“Blockade of TNF-alpha function and downstream microglial activation may be an important approach for the treatment of glaucoma,” the investigators stated.

Dr. Miller commented on the potential therapies that might emerge from the study findings.

“Additional animal studies need to be done to test these possible treatments,” Dr. Miller said. “One approach would be to test some agents that are already available. If these drugs are administered systemically, we need to study how the drugs might be delivered to treat glaucoma. The preferable route would be to deliver the drugs locally. More studies need to be done to determine how the agents work over time. If the drugs already exist, a logical route would be to start with these drugs.”

In addition to testing the drugs, it still needs to be determined whether targeting TNF-alpha is an approach that will work with all types of glaucoma.

“Because we used a particular animal model, applying this treatment approach to all situations in human glaucoma is a big leap,” she said. “One thing we are interested in pursuing is to see if the same mechanism seems to be in operation in other animal models of glaucoma. We are currently investigating some collaborations along those lines.”

Dr. Miller speculated that approaching glaucoma through the TNF-alpha pathway is likely to require chronic treatment in patients.

“This would depend on how the agents are delivered and may be in the form of a slow-release drug or a refillable device that delivers the agent over time to the optic nerve,” Dr. Miller continued. “From what is known about glaucoma, the disease is chronic and, while we have determined what happens at the early stage of the disease, we are not eliminating the root cause of the disease. Treatment with TNF-alpha blockers would be required for a long period.”

She explained that the difficulty with studies that will be necessary to prove the efficacy of TNF-alpha blockers is determining the study end point.

“In neuroprotection in general, investigators have had some difficulties with that because they have tried to show preservation of visual function, which is not what has been done in glaucoma in the past, where the goal has been to lower the IOP. Showing prevention or preservation of vision in a slowly progressive disease is harder because it requires more patients and longer follow-up periods,” Dr. Miller commented.

“The results of this study were impressive and more than we had hoped for. Our findings were exciting because they suggest a novel way to treat glaucoma, which is one of the major blinding conditions worldwide,” she said.

In addition to Drs. Miller and Benowitz, Dr. Nakazawa was joined in this study by Chifuya Nakazawa, MD, Akihisa Matsubara, MD, Kousuke Noda, MD, Toshio Hisatomi, MD, Haichend She, MD, Norman Michaud, MS, and Ali Hafezi-Moghadam, MD, PhD, from the Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and the Department of Ophthalmology, Harvard Medical School.OT