Gene Variant Protects Against Geographic Atrophy in Macular Degeneration

Jacquelyn K. Beals, PhD

September 02, 2008

September 2, 2008 — A gene variant that protects against geographic atrophy has been identified by investigators from several institutions in China and the United States. The variant appears to protect against geographic atrophy by suppressing the death of pigment epithelial cells in the retina.

Geographic atrophy, an advanced stage of dry age-related macular degeneration (AMD), causes 10% of the cases of blindness resulting from AMD. Senior author Kang Zhang, MD, PhD, professor of ophthalmology and human genetics, Shiley Eye Center, University of California –San Diego, La Jolla, described the disease to Medscape Pathology & Lab Medicine in a telephone interview.

"The wet or dry [macular degeneration]...usually do not happen together. So wet can come from dry, but dry does not come from wet.... Occasionally you have both, but it's very, very rare," said Dr. Zhang. "Geographic atrophy, by definition, is the most severe form of dry macular degeneration."

There is increasing evidence that AMD susceptibility is driven by inflammation provoked by bacteria and viruses. Variants of the toll-like receptor 4 gene (TLR4), a receptor for bacterial endotoxins, have previously been associated with AMD. The new study, published online August 27 in the New England Journal of Medicine, investigated the association between AMD and variants of toll-like receptor 3 (TLR3), a gene that codes for a viral sensor that functions in immunity and defense. The protective variant substitutes phenylalanine (Phe) for leucine (Leu) at position 412 of the gene product.

One branch of the study investigated the association between TLR3 variants and the viability of human retinal pigment epithelial cells in culture. Following treatment with a synthetic double-stranded RNA (dsRNA) molecule that activates TLR3, apoptosis occurred in more cells homozygous for the Leu form of the protein than in cells heterozygous for Leu-Phe (P = .02).

The investigators also assessed TLR3 variants in patients with choroidal neovascularization (wet AMD; n = 441), geographic atrophy (n = 232), and early-to-intermediate AMD (n = 152), as well as control patients (n = 359). A significant association was found between the Phe variant and protection against geographic atrophy (P = .005; odds ratio [OR] in Leu/Phe patients, .712; 95% confidence interval [CI], .503 – 1.00; OR in Phe/Phe patients, .437; 95% CI, .227 – .839). The TLR3 variants showed no significant association with wet or early-to-intermediate AMD.

Replications in patients with geographic atrophy (n = 271) and choroidal neovascularization (n = 179), as well as control patients (n = 421), found a significant association between the same variant and geographic atrophy (P = 5.43 × 10−4) but not choroidal neovascularization. An additional case-control replication demonstrated the same association (P = .002).

The authors suggest that activation of the TLR3 viral dsRNA receptor may underlie the progression of geographic atrophy from the initial region to adjacent areas of the retinal pigment epithelium. One possibility is that the viral dsRNA receptor is activated by RNA from dying or damaged adjacent cells. Another possibility is that cell-to-cell transmission of viral particles or transcripts may activate the receptor.

Dr. Zhang noted: "We haven't identified a specific double-stranded virus, but in general...if you have been having common colds, which all of us have, you are exposed to dsRNA viruses. Rhinovirus, parainfluenza virus, influenza virus are all dsRNA viruses. There's no question that we are all exposed to the dsRNA virus. However, if this is the one that actually causes cell death in the genetically susceptible patients, we don't know."

This possibility raises concerns about a new treatment for wet AMD that uses RNA interference (small interfering RNA; siRNA) to inactivate disease-causing genes. Treating a susceptible patient with RNA interference might trigger the TLR3 receptor and lead to geographic atrophy.

"It doesn't matter if it's viral, siRNA, or some similar molecule, if it can activate TLR3 that leads to apoptosis, that should be able in theory to cause geographic atrophy," said Dr. Zhang. However, he added, "you know, there's only very few people that are going to get siRNA, but a lot of people are going to get dsRNA viruses."

Medscape Pathology & Lab Medicine also contacted David M. Brown, MD, FACS, for comments. Dr. Brown is in practice at Greater Houston Retina Research, Vitreoretinal Consultants, The Methodist Hospital, Houston, Texas. "TLR3 receptors are by design very nonspecific," he said. "Theoretically...any nonendogenous RNA could potentially turn it on."

In terms of genotyping screens for AMD to determine the appropriate treatment, Dr. Brown expressed some concerns: "It would be easy and relatively cheap if it became commonplace. However, it really wouldn't be that helpful except for counseling [about] risk of geographic atrophy and potentially to screen prior to giving a patient an siRNA drug," he said.

"Although our research center was involved in several siRNA phase 1 and 1-2 trials, we would be reluctant to enroll any patients in any future siRNA trials given this current report.... The implications that the siRNA could potentially increase geographic atrophy in susceptible patients [are] very scary," observed Dr. Brown. "Unless this process is proven not to occur in human eyes, patients enrolled in continuing siRNA trials need to know the possible implications of this therapy and be followed closely for geographic atrophy."

Dr. Zhang reports having an equity interest in Navigen and has received grant support and lecture fees from Genentech and consulting fees from Acucela and Oxigene. Dr. Brown reports having participated in several siRNA therapeutic trials, and he has served as a consultant for Genentech, Regeneron, Novartis, Allergan, Pfizer, and Alcon.

N Engl J Med. 2008;359. Published online August 27, 2008.

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