In the August 2006 issue of PloS Medicine, researchers from Washington University in St. Louis Medical School reported findings that could give clinicians additional avenues for the treatment of age-related macular degeneration (AMD).

AMD is the leading cause of blindness in industrialized nations. There are two types of AMD: "Dry" AMD results from degeneration of the macula - the central and most cell-dense part of the retina - while "wet" AMD results from the inappropriate formation of blood vessels in the macula.

Wet AMD accounts for about only 10 percent of all AMD cases, but they are the most severe 10 percent; more than 90 percent of AMD-caused blindness stems from wet AMD cases.

Currently, two treatments exist for AMD. Photodynamic therapy is sometimes used, but "the most efficacious treatments so far are aimed at VEGF," or vascular endothelial growth factor, which is a major proangiogenic molecule, said first author Rajendra Apte, assistant professor of ophthalmology and visual sciences at Washington University Medical School in St. Louis. Those treatments include Lucentis (ranibizumab), from Genentech Inc., and Macugen (pegaptanib), from OSI Pharmaceuticals Inc. and Pfizer Inc. Genentech's antiangiogenesis cancer drug Avastin (bevacizumab), another VEGF inhibitor, also is used to treat wet AMD. (See BioWorld Today, July 5, 2006.)

Some previous studies found inflammation to exacerbate AMD, while others suggested that inflammation helped fight AMD; but on balance, the evidence favored the idea that macrophages make wet AMD worse.

The researchers studied the effects of chronic inflammation wet AMD and zeroed in on the role of macrophages by inducing AMD in an interleukin-10 knockout. IL-10 is an anti-inflammatory cytokine that usually inhibits macrophages, as well as T cells.

What they found was that in response to retina damage, IL-10 knockouts had significantly less blood vessel growth and increased numbers of macrophages in the macular area. The macrophages were able to respond to the retinal damage more efficiently because the IL-10 brakes were off. "There's no suggestion that there are an increased number of macrophages throughout the body," Apte said.

Injecting IL-10 directly into knockout eyes restored the blood vessel growth to that of controls, while injecting macrophages reduced its formation. As for the mechanism, the macrophages did not affect blood vessels directly, but via interaction with damaged retinal tissue.

"The finding opens up several therapeutic pathways," Apte said. For one thing, there's interleukin-10 itself; for another, the Fas-ligand pathway that it targets. Finally, another possibility is autologous cell based therapy with a patient's own macrophages.

The results, while pointing toward potential new treatments, do not speak directly to what causes people to develop AMD in the first place. But patients who are susceptible to AMD often have mutations in the gene for the immune system inhibitor complement factor H.

Given his teams' results, Apte speculated that "maybe patients who have AMD, or are susceptible to AMD, have similar differences in the IL-10 gene." He stressed that he and his colleagues currently have no data to back up that idea, but "if we are able to find such differences, we could really clue into what the cause of AMD is."