Experimental therapy may lead to macular degeneration, an international team of researchers caution
Having discovered a genetic trigger for age-related macular degeneration, the leading cause of vision loss in people over 50, researchers report that an experimental state-of-the-art therapy for treating eye disease could adversely affect the vision of some patients with the "wrong" genetic makeup. In the August 28 online issue of the New England Journal of Medicine, a multi-institutional team, including an interdisciplinary contingent from Johns Hopkins, reports that a mutation in toll-like receptor 3 (TLR3), a protein known to help cells fight some types of infection, is associated with protection from geographic atrophy. Geographic atrophy, also known as the "dry" form of macular degeneration, is the progressive shriveling of retinal cells in the central part of the tissue called the macula where cell loss equates to irreversible vision loss.
The new study implies that there could, in fact, be adverse consequences in some individuals who undergo a new treatment using a method called RNA interference to silence genes in the wet form of age-related macular degeneration (AMD), where growth of abnormal blood vessels causes vision loss.
RNA interference (RNAi) can be used in some cases to turn off disease-causing genes. Human trials using RNAi therapy already are under way for a host of diseases, including AMD. In theory, turning off a disease gene is a good idea, but it may not be good for everyone because everyone differs in their genetic makeup, cautions Nicholas Katsanis Ph.D., an associate professor of ophthalmology, molecular biology and genetics and member of the Institute of Genetic Medicine at the Johns Hopkins School of Medicine.
"The problem is that if you happen to be an individual who has the 'wrong' genetic code in TLR3, you might inadvertently trigger a detrimental effect in your retina," he explains. "You might cure the individual of one thing and increase their risk in something else." In this case, it's possible to cure the wet form of AMD but at the same time increase risk for the other form.
"This discovery has significant implications for diagnosing the dry form of (AMD), which is the most prevalent form, affecting more than 8 million Americans," says Kang Zhang, M.D., Ph.D., a professor of ophthalmology and human genetics and member of the Shiley Eye Center at the University of California San Diego. "It also allows us to develop new drugs to treat the dry form of AMD, for which there currently is no treatment."
In the current report, the team describes experiments on mouse and human genes showing that the activity of your TLR3 can determine whether or not you're afforded a degree of protection from geographic atrophy. TLR3 is activated in response to viral infection; it causes infected cells to die. Based on one's genetic code, some people have more active TLR3 while others, less active.
"What TLR3 does in the case of infection is sacrifice an infected cell to protect the neighborhood," Zhang explains.
Biologically well-intentioned though the sacrifice may be, it can lead to blindness.
Based on previous reports hinting to TLR3 involvement in macular degeneration, Katsanis, Zhang and colleagues first set out to determine whether that link was real.
By analyzing the DNA of patients in a case-control study, the researchers not only verified previously published reports indicating an association between TLR3 and macular degeneration, but also went on to show a specific association between one "fairly common" variant of TLR3 and geographic atrophy. They found that people with specific chemical difference in the TLR3 protein were less likely to have geographic atrophy.
To test the assumption that the chemical difference rendered TLR3 less active, the researchers next used cells from human eyes containing either a "normal" or variant version of TLR3. To activate TLR3, they infected these cells with fake RNA mimicking genetic material common to many viruses, and measured how many cells died. Fifty percent fewer cells with the variant version of TLR3 died compared to cells containing the normal version, leading the researchers to conclude that the variant version of TLR3 must be less active and therefore kills fewer cells.
Finally, to be sure that differences in TLR3 activity cause similar differences in cell death in whole eyes (and not just isolated eye cells), they teamed up with the team of Jayakrishna Ambati, M.D., a professor of physiology, ophthalmology and visual sciences at University of Kentucky and injected RNA into mice, one set of which was genetically engineered to have no TLR3. Two weeks later, researchers examined their eyes and found that those mice with TLR3 exhibited 61 percent more dead eye cells than mice without TLR3, further indicating that TLR3 activity triggers cells to die, which in turn can lead to geographic atrophy.
"You and me, we have a good 20 to 30 percent chance of getting macular degeneration," Katsanis says. "So when the time comes for us to start thinking about intervention, we might want to get genotyped first, and then decide what kind of therapeutic paradigm might be most appropriate for us."
The researchers envision a day when vaccines might protect us from the viruses that trigger the pathways that are inappropriately activated or repressed in models of macular degeneration: "If we can figure out which viruses might be acting as triggers, we might be able to find a way to combat them. This would be a far more effective therapy, in my view, than trying to design a gene therapy approach," says Zhang.
The TLR3 discovery bolsters a growing body of research that illustrates how genetic information stratifies individuals for responses to particular therapies; it is the first involving the retina.
"Clearly, the statement that we're not all the same is not exactly novel, and yet, I'm still struck by how homogenized people become when it comes to clinical trials," Katsanis says. "It baffles me, frankly."
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Articles on the same topic
- Genetic link to dry macular degeneration foundWed, 27 Aug 2008, 17:35:50 EDT
- First gene associated with dry macular degeneration foundWed, 27 Aug 2008, 17:35:42 EDT
- First Gene Associated With Dry Macular Degeneration Foundfrom Science DailyWed, 27 Aug 2008, 21:21:20 EDT
- First gene associated with dry macular degeneration foundfrom PhysorgWed, 27 Aug 2008, 18:21:09 EDT
- Genetic Link to Dry Macular Degeneration Foundfrom Newswise - ScinewsWed, 27 Aug 2008, 17:35:14 EDT
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