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Gene
Linked to Glaucoma May be New Therapy Target Most cases of glaucoma may be caused by a gene that becomes highly active in response to biological stress, UCSF researchers reported yesterday. The origins of glaucoma, which affects three to four million people in the United States and blinds 12,000 of them each year, have long been a mystery, but new evidence that a gene and its encoded protein are involved raises hope that an understanding of the mechanisms of the disease is within reach, and also suggests new treatment possibilities. Within the eye, sources of biological stress such as trauma or injury generate injurious forms of oxygen called "free radicals," which can damage cells and contribute to glaucoma, according to Jon R. Polansky, MD, associate professor of ophthalmology. Furthermore, cortisol, a steroid made normally by the body, may also contribute to glaucoma, Polansky says. The UCSF researchers now report that eye cells comprising a special structure called the trabecular meshwork respond to steroids or free radicals through activation of a gene called TIGR. In their studies, activation of the gene in response to these chemicals resulted in the production of the TIGR protein. The findings were presented at the annual meeting of the Association for Vision in Research and Ophthalmology, in Fort Lauderdale, Fla. According to Polansky, the discovery that the TIGR protein is mass-produced in response to stress implicates TIGR in the most common form of the disease, called primary open angle glaucoma (POAG). POAG affects about one out of every one hundred Americans. "This is a finding of major importance," Polansky says. "In the United States alone it markedly expands the number of cases of glaucoma that are expected to involve this gene from the hundreds of thousands to the millions." The results also will appear in this month's issue of the journal Ophthalmologica. Collaborators on the study include researchers from the Mayo Clinic and the University of Erlangen-Nurnberg, in Germany. Polansky has spent the last 18 years developing and perfecting ways to grow in the laboratory the eye cells that are affected by glaucoma. The UCSF research effort received a major boost recently from a molecular biology group headed by Thai D. Nguyen, PhD, also with the department of pphthalmology at UCSF. Nguyen's group isolated
and cloned the gene that encodes the TIGR protein, and
now has identified and mapped out the part of the gene
that governs how much TIGR protein is produced. The researchers also reported yesterday that TIGR gene activity is elevated in the laboratory-maintained cells and tissue by oxidative stress. This refers to disabling damage incurred by the body's various molecules due to interactions with oxygen that is coupled to other atoms in a highly reactive chemical form known as a free radical. Free-radical damage is common in stroke, for example, and is believed by many scientists to be a fundamental aspect of aging. The UCSF researchers used a free radical called hydrogen peroxide to induce TIGR production in the trabecular meshwork cells. In an unanticipated finding, the scientists found that diclofenac, a non-steroidal anti-inflammatory drug used after eye surgery, reduced both steroid and free radical-induced TIGR gene activity. "The result suggests that a new formulation of diclofenac might be useful in glaucoma therapy," Polansky says. This serendipitous discovery suggests that drugs targeted against activation of the TIGR gene might serve as a new approach to treating the disease, according to Polansky. The UCSF researchers are already investigating this strategy. "Conventional
glaucoma treatments in a sense turn off the faucet that
supplies fluid and nutrients to the aqueous humor. Our
research supports the idea that clearing and preventing
clogging of the drain is also a promising strategy,"
Polansky said. By Jeffrey Norris 1st appeared 5/14/97
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