First Gene Associated With Dry Age-Related Macular Degeneration Found

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Title: First Gene Associated With Dry Age-Related Macular Degeneration Found
URL: http://www.pslgroup.com/dg/22A1E2.htm
Doctor's Guide
August 28, 2008

SAN DIEGO -- Researchers have discovered the first gene related to "dry" age-related macular degeneration (AMD) and show that there could be adverse consequences, including blindness, if individuals who possess a particular variation of this gene are treated with an experimental therapy currently being tested for another form of AMD.

The study, published in the August 28 online issue of the New England Journal of Medicine, underscores the important role that individual genetic profiles will play in the development of new therapies for disease.

Kang Zhang, MD, Shiley Eye Center, University of California at San Diego, School of Medicine, San Diego, California, and colleagues discovered the link between dry AMD and toll-like receptor (TLR) 3 -- a key molecule that alerts the immune system to the presence of viral infections.

"Because of speculation among scientists that viral infections provoke the inflammation that increases the risk of macular degeneration, we tested for associations between AMD and TLR3, which is known to support innate immunity and host defense," said Dr. Zhang.

The researchers found that a genetic variant associated with low activity of the TLR3 receptor appears to confer protection against dry AMD, probably by suppressing the death of certain retinal cells.

Importantly, this research indicates that individuals with a genetic variant of TLR3 who undergo RNA interference (RNAi) could be at risk. Several ongoing clinical trials are using RNAi to treat the "wet" form of AMD. Dr. Zhang warns that those testing RNAi therapies for wet AMD need to be cautious and aware of a possible unintended side effect.

"If you are genetically susceptible to macular degeneration and are exposed to a virus that activates TLR3, it could lead to the death of cells in the macula," said Dr. Zhang. "Ironically, in some individuals, using RNAi to cure wet AMD might actually increase the risk for blindness from dry AMD."

Use of RNAi can have the inadvertent effect of suppressing the TLR3 protective role because it induces TLR3 activation. This activation signals other cells to increase their antiviral defenses; in essence, sending a message to kill what are recognised as infected cells.

The researchers tested for these functional effects in both human and mouse retinal pigment epithelial cells and showed that approximately 60% more retinal cell death resulted when TLR3 activation was triggered.

"What TLR3 does in the case of perceived infection is to sacrifice infected cells -- in this case, retinal pigment epithilial cells -- to protect the neighborhood," said co-lead author Nicholas Katsanis, PhD, Johns Hopkins School of Medicine, Baltimore, Maryland. "Biologically well-intentioned though the sacrifice may be, it can lead to blindness."

The discovery may have major preventive and therapeutic implications, according to Hemin Chin, PhD, National Eye Institute, Bethesda, Maryland. "Given its high prevalence in the US and the world, finding effective prevention and treatment strategies for AMD is of critical importance. This finding represents a major advancement in our understanding of dry AMD, for which effective treatment is not yet available."

SOURCE: University of California San Diego

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