Glaucoma, a leading cause of blindness, affects more than 4 million Americans, at least half of whom don’t even know they have the disease. Though the best-known symptom of glaucoma is elevated pressure inside the eye, blindness-inducing damage to retinal ganglion cells and the optic nerve can occur in patients with normal intraocular eye pressure. Earlier detection and treatment could have a powerful impact on preventing blindness due to glaucoma.

Professor Simon John, working with collaborators, identified a malfunctioning gene in a mouse strain that develops both cataracts and glaucoma. The gene fails to produce an essential protein, disrupting the development of the mouse eye lens. The mice developed high intraocular pressure and optic nerve damage—the hallmarks of glaucoma—as well as cataracts.

The new findings imply that mice and patients with these mutations may not have adequate protection from oxidative stress in the drainage structures of the eye. With increasing age, their tissues may be more susceptible to oxidative damage resulting in high intraocular pressure and glaucoma.

Although further experiments are needed to be certain, this work is the first to suggest that oxidative stress response is relevant to glaucoma. John notes, "There is a growing body of literature indicating that if you disturb oxygen levels in the eye—including after cataract surgery—the risk of developing glaucoma increases."

John says that mutations in the gene could cause a double jeopardy for childhood glaucoma. "First, they cause cataract, and cataract extraction may raise oxidative stress in the ocular drainage tissues. Second, they impair the  response to oxidative stress."

Detecting and targeting early disease processes

John and his team have also demonstrated a groundbreaking approach to analyzing genomic data from mice that typically develop glaucoma. Using this new analysis, which "clusters" relevant data from special computer chips called microarrays,  the researchers identified many molecular changes that occur very early, before detectable damage occurs.

Two of these changes—in molecular pathways known respectively as the complement cascade and endothelin system—have been associated with later stages of glaucoma in human patients. The researchers separately blocked each of those pathways and found that the mice were protected from glaucoma-related damage. The results are among the most potent neuroprotective treatments documented.

This research barely scratches the surface of all the molecular events that the team's cluster-based analysis revealed are altered in glaucoma-prone mice. They will make their findings available to the worldwide scientific community through a new database that they developed for this purpose.

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