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Tumor necrosis factor-alpha (TNF-alpha) causes a cascade of events in the eye that ultimately leads to glaucomatous damage of the optic nerve head and visual deterioration.
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.
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.