A gene called TLR3 may play a pivotal role in the common form of age-related macular degeneration, the leading cause of blindness in the elderly.

The new finding, reported online August 27 in The New England Journal of Medicine, reveals that roughly three in 10 people harbor a variant form of TLR3 that subdues its normal activity, seeming to provide a partial safeguard against the dry, common form of the eye disease.

In the dry form of macular degeneration, deposits clutter the center of the retina, or macula, and can lead to cell death. That can damage vision to the point of blindness. A less-common form called wet macular degeneration causes vision loss as rogue blood vessels grow in the eye and leak, clouding the macula.

In recent years, scientists have discovered several genes implicated in macular degeneration. With the new finding, TLR3, which encodes the protein Toll-like receptor 3, becomes the first gene associated exclusively with the dry form.

Researchers tested more than 2,000 people with wet, dry or no macular degeneration. Those with the dry form were less likely than the others to carry the protective variant form of TLR3.

These data, combined with results from lab experiments using mice and human eye cells, suggest that people carrying the common form of TLR3 are two to five times as likely as those with the variant form to develop dry macular degeneration.

“This is a really big step forward in macular degeneration research,” says ophthalmologist Emily Chew of the National Eye Institute in Bethesda, Md., who didn’t work on the study. “We know very little about the pathogenesis of this disease, and this addresses the dry form.”

While the cause of macular degeneration remains unknown, the new findings bolster a hypothesis that viral infections play a role in causing the dry form and suggest that TLR3 overactivity is a contributor. TLR3’s normal job is to detect viruses, says study coauthor Nicholas Katsanis, a geneticist at Johns Hopkins University in Baltimore. TheTLR3 gene gets switched on in the presence of double-stranded RNA, which viruses make in abundance but which humans produce only in small amounts.

It is this double-stranded RNA that viruses inject into cells as they commandeer them, a process that enables the virus to replicate and spread.

Unfortunately, the protein encoded by TLR3 orchestrates a take-no-prisoners approach to killing off the virus. “TLR3 detects the infiltrating virus’s genome and instructs that cell to die, to protect the neighborhood,” Katsanis says. While that strategy might work well in fighting routine infections, the retina is another matter. Cell loss there can be disastrous, and can cause dry macular degeneration.

The new findings indicate that the variant form of TLR3 dampens this process, lessens cell death in the eye and thus offers partial protection from dry macular degeneration, says study coauthor Jayakrishna Ambati, a retinal surgeon at the University of Kentucky in Lexington.

Ambati’s lab is now testing compounds that suppress TLR3 and curb the cell death cascade. These have shown promise in early lab tests in mice and in human eye cells. Ambati hopes to begin recruiting patients with early-stage, dry-form macular degeneration by the end of this year for a trial to suppress TLR3 and fend off that form of the disease.

Meanwhile, in a curious twist, the new study also suggests that people who lack the beneficial variant form of TLR3 — the majority of those tested in this study — might be poor candidates for a new treatment called RNA interference, which is now being tested for macular degeneration and other diseases.

Because RNA interference uses double-stranded RNA, it might risk stirring up excess TLR3 activity and its harsh cell-disposal approach, Ambati says.

RNA-interfering drugs are being tested for the wet form of macular degeneration. In those people, RNA interference might have the unintended side effect of placing those patients at risk of developing the dry form from cell death in the retina, Katsanis says.

Testing the genetic makeup of candidates for RNA interference would reveal who has the variant form of TLR3, Ambati says. These people would produce less TLR3 protein and be at less risk of the dry form of macular degeneration, he suggests.

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Found in: Body & Brain