Age-related macular degeneration is the leading cause of blindness in people over the age of 65, and it affects more than 10 million people in the United States. The disease erodes the macula, the center of the retina, slowly eclipsing central vision and potentially causing blindness. Currently, there is no treatment for dry macular degeneration, the most common form, in which more and more cells within the macula slowly die off.
Eye gene: Researchers have found a genetic link between a molecule involved in immune response and a common form of macular degeneration. When tlr3 is activated by genetic expression, it causes cell death similar to macular degeneration in areas of mouse retinas, indicated by the arrows.
Now a team of researchers from multiple institutions, including the Shiley Eye Institute, at the University of California, San Diego (UCSD), have identified a genetic link associated with dry macular degeneration, which they say may lead to treatments for the debilitating disease. However, they caution that an experimental therapy for another form of macular degeneration may cause adverse effects in patients who possess the genetic variant.
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Kang Zhang, a professor of ophthalmology and human genetics at UCSD, led the study, which is published in the online edition of the New England Journal of Medicine. In their experiments, Zhang and his colleagues zeroed in on the genetic expression of a key molecule involved in the body’s immune response. This molecule, called tlr3, jumps to action in the presence of RNA, which can take the form of invading viruses. As part of the immune response, the molecule kills infected cells, preventing the virus from spreading further. But in some cases, this defense can go haywire in the eye.
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The molecules’ “role in life is to kill cells to protect the universe around healthy cells,” says Nico Katsanis, Zhang’s collaborator on the study and an associate professor of ophthalmology, molecular biology, and genetics at the Johns Hopkins School of Medicine. “But if they are too sensitive towards viral insults, they might kill cells a little too eagerly, and that might be a predisposing factor that leads to macular degeneration.”
The group hypothesized that a gene that increases the activity of tlr3 may in fact lead to overeager cell death in response to RNA and viruses, and it may increase a person’s risk for dry macular degeneration.
To investigate this potential link, the team first performed a genetic association study, and obtained blood samples from three groups of patients, each with a different form of macular degeneration, including those with wet macular degeneration, a severe form characterized by an overgrowth of blood vessels behind the retina. The researchers also included more than 300 samples of unaffected controls.
After doing DNA analysis of the samples, the group identified a genetic variant that promotes low tlr3 activation. Patients possessing this variant were in a sense genetically “protected” against dry macular degeneration, whereas patients with a variant that promotes high tlr3 activity were 20 percent more likely to develop dry macular degeneration.
Since tlr3 is activated in response to RNA, Zhang says that this genetic association may raise concerns over RNA-based therapies for wet macular degeneration. Currently, clinical trials are under way for RNAi therapies to treat wet macular degeneration and turn off the genes responsible for blood-vessel overgrowth in the eye. However, Zhang says that these RNA-based therapies may have adverse effects for people with the genetic variant that increases tlr3 activity. In essence, the otherwise therapeutic RNA would trigger tlr3 to kill cells in the retina, which could ultimately lead to vision loss.
“We are able to see if we can develop a therapy to modulate or inhibit tlr3 to treat dry macular degeneration,” says Zhang. “Also, people undergoing RNAi therapy need to be aware of potential harmful effects of tlr3 activation.”
However, Rando Allikmets, director of the molecular-genetics laboratory at Columbia University, says that, compared with other genes associated with macular degeneration, the tlr3-linked association that Zhang found is not very strong, and should not have much effect on RNAi therapies. “Their data shows that [tlr3] is technically associated with dry macular degeneration,” says Allikmets. “But even if there is something, 20 percent risk [of dry macular degeneration] is very, very minor.”
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More likely, Katsanis says, the group’s findings may illustrate a masking effect for otherwise beneficial RNAi therapy. For example, patients who unknowingly overexpress tlr3, and who are treated with RNAi therapy, may still experience the positive effects of RNA, but also the negative effects of cell death. The overall effect may be no effect at all.
“The genotype may counterbalance beneficial effects of RNAi treatment, and the final analysis may be that this treatment is noneffective, and you may be throwing away a perfectly good treatment,” says Katsanis. “What this says is, potentially, people with the right variant might be better candidates for RNAi therapies, and vice versa, and we may target disease more effectively according to genotype.”
