Experimental Therapy May Lead to Macular Degeneration

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.