Genetic link to dry macular degeneration found

LEXINGTON, Ky. (Aug. 27, 2008) – A University of Kentucky ophthalmologist, along with a team of scientists, has discovered a genetic mutation that offers protection against a type of age-related macular degeneration (AMD), a disease of the eye that is the leading cause of blindness in adults over age 50.

The study, published Wednesday in The New England Journal of Medicine, identifies a functional link between mutation of an immune-system receptor called toll-like receptor 3 (TLR3) and the "dry" type of AMD known as geographic atrophy. The untreatable, progressive disease affects an estimated 8 million Americans, causing permanent vision loss.

The discovery of the first gene associated specifically with dry AMD opens the door to developing treatments, said Dr. Jayakrishna Ambati, a retinal surgeon-scientist in UK's Department of Ophthalmology and Visual Sciences, who along with Dr. Kang Zhang, a retinal specialist and human genetics pioneer at the University of California San Diego, and Nicholas Katsanis, a molecular geneticist at The Johns Hopkins University School of Medicine, led the multi-institutional collaborative study.

Ambati's lab first discovered a relationship between a dysfunctional TLR3 mutation and decreased ocular cell toxicity in a study published in Nature earlier this year. The current study reports that TLR3 activation leads to death of specific cells in the retina and that people with the normal TLR3 gene are two to five times more likely to develop geographic atrophy than those who carry an inactive TLR3 gene mutation.

Ambati's group plans to start clinical trials next year in patients at risk for developing geographic atrophy using new TLR3 inhibitors developed in his lab.

"We finally have a potential therapy for preventing vision loss from dry AMD," Ambati said. "I am very excited by this discovery."

The study may have major preventive and therapeutic implications, according to Hemin Chin, director of the ocular genetics program at the National Eye Institute.

"Given its high prevalence in the United States and the world, finding effective prevention and treatment strategies for AMD is of critical importance," Chin said. "This finding represents a major advancement in our understanding of dry AMD, for which effective treatment is not yet available."

Of more immediate significance, an investigational drug modality known as short interfering RNA (siRNA) – currently in advanced phase trials for the "wet" type of AMD – also activates TLR3, as shown by Ambati's earlier Nature study and recently confirmed by another laboratory in the journal Nature Structural & Molecular Biology. The New England Journal of Medicine study raises the possibility that siRNA-based therapies could cause geographic atrophy.

"Collectively, these studies highlight the importance of critically assessing the potential risk posed to patients by siRNA-based therapies," Ambati said.

Source: University of Kentucky