Two potential new targets recently have been identified for the treatment of glaucoma. A paper in the Proceedings of the National Academy of Sciences showed that two proteins involved in Alzheimer's disease also appear to play a role in glaucoma, while a paper in Science identified a risk gene for one particular subtype of glaucoma known as exfoliation glaucoma.

Glaucoma, which accounts for some 10 percent of blindness cases in the U.S., currently is conceptualized as a disease caused by high pressure inside the eye, which results in damage to the optic nerve. Treat the eye pressure, so the thinking goes, and the optic nerve damage can be halted.

Increased eye pressure definitely can cause glaucoma, but there is more to the story: Normalizing eye pressure will not necessarily halt the disease, suggesting that other factors must be at work as well. As a result, the search is on for novel approaches to treating glaucoma.

In their Aug. 14, 2007 PNAS paper, researchers from University College and the Western Eye Institute in London, the University of Parma in Italy, and the Institute Cochin in Paris focused on amyloid-beta, an old enemy for those looking for ways to treat Alzheimer's disease. Amyloid beta plaques are one of the hallmarks of that disease.

Recent studies showed amyloid beta can lead optic nerve cells to commit cellular suicide. The researchers first showed that inducing glaucoma in mice led to both increased levels of amyloid-beta and increased optic nerve cell apoptosis, and that injecting amyloid-beta directly also led to apoptosis.

The researchers then used three separate treatments, alone and in combination, to try to prevent amyloid-beta induced cell death. They administered a beta-secretase inhibitor, which prevents a precursor of amyloid beta from being processed, Congo Red, which blocks amyloid-beta aggregation, and an anti amyloid-beta antibody.

Dublin, Ireland-based Elan Corp plc and collaborator Wyeth, of Madison, N.J., plan to start phase III clinical trials to treat Alzheimer's patients with bapineuzumab (AAB-001,) an antibody which also targets amyloid-beta, later this year. (See BioWorld Today, May 22, 2007.)

While each of the three agents alone reduced the amount of cell death in the optic nerve, the combination of all three was the most effective. It led to a roughly 85 percent reduction in optic nerve cell apoptosis, as compared to 75 percent for bapineuzumab alone, which was the most effective of the three treatments as a single agent.

Beyond the research's potential for glaucoma treatments, it also suggested that the optic nerve, which is part of the brain in terms of its cellular composition and heritage, could be harnessed for CNS drug discovery: "Since we have shown that drugs for Alzheimer's disease can tackle glaucoma, then potentially we could use damaged retina to screen Alzheimer's drugs that target beta-amyloid buildup," noted senior author Francesca Cordeiro, head of the glaucoma and neurodegenerative disease research group at University College London.

In a separate paper, published in the Aug. 10, 2007 issue of Science, researchers from deCODE Genetics Inc. and the National University Hospital in Reykjavik, Iceland, and Uppsala University in Uppsala, Sweden, identify two SNPs that raise the risk of developing exfoliation glaucoma by 26-fold and eightfold, respectively.

Like so many diseases, glaucoma is actually a collection of disorders. The unifying theme is that all types of glaucoma damage the optic nerve. Exfoliation glaucoma is caused by fibrous deposits on the front of the eye, and is one subtype that often is impervious to treatments that lower eye pressure.

The researchers screened slightly more than 300,000 samples, and found that three SNPs showed an association with glaucoma risk. All three SNPs were clustered on a relatively short stretch of chromosome 15.

Further studies showed that stretch of the genome contains the gene for lysyl oxidase, an enzyme that can crosslink proteins. The enzyme's activity could lead to the elastin fiber polymers whose deposits lead to exfoliation glaucoma, though such a link has not been directly demonstrated. DeCODE CEO Kari Stefansson said the company plans "to conduct additional studies to examine how we can take advantage of this finding to begin drug discovery."

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