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Study Finds that Inflammation, Within Limits, Protects in AMD

By Anette Breindl
Science Editor

In findings that run directly counter to prevailing wisdom, researchers have found that proinflammatory responses may be protective against the progression of age-related macular degeneration (AMD), which is the leading cause of blindness in the developed world.

The studies, which identify the proinflammatory cytokine interleukin-18 (IL-18) as an upstream regulator of vascular endothelial growth factor (VEGF) may lead to new ways to treat AMD and prevent its progression.

More generally, they give inflammation a partial rehab.

"Inflammation is always thought of as a bad thing," corresponding author Matthew Campbell told BioWorld Today. But "our studies show that [proinflammatory] IL-18 is essentially protective in the eye." Campbell is a researcher at the Irish Trinity College Dublin.

Not that Campbell is trying to say 'I told you so.' In fact, he said, when he and his team started their studies, which were published in the April 8, 2012, online issue of Nature Medicine, they were expecting the opposite results from the ones they got. Their findings, he said, were "completely unexpected."

In their study, Campbell, first author Sarah Doyle and their team looked at the relationship between drusen, inflammatory responses and the growth of new blood vessels. Drusen are deposits of proteins and lipids that build up in the eye. They appear to be, to some extent, an inevitable part of aging. But at higher-than-normal levels they are a sign of dry AMD, which can develop into wet AMD as blood vessels grow under the retina at the back of the eye.

Campbell and his team hypothesized that mice lacking an inflammasome – a protein complex that regulates inflammation – would be protected against developing AMD that develops when normal mice are subjected to eye injury via laser. But what they found was that knocking out either the inflammasome protein NRLP-3 or the proinflammatory cytokine IL-18, which is produced when the inflammasome is activated, exacerbated the disease instead.

Further experiments showed that drusen and proteins bound to them were able to both prime and activate the inflammasome. The activation led to the production of cytokines, and one of those cytokines, IL-18, inhibited the production of VEGF and so prevented the formation of new blood vessels that are the cause of vision loss in end-stage AMD.

Though it's early days, the findings suggested that delivering IL-18 to the eye via gene therapy might be a strategy to head off wet AMD, which develops from dry AMD, at the pass. Currently, there is no therapy at all for dry AMD, and wet AMD is treated with VEGF antibodies Avastin (bevacizumab) and Lucentis (ranibizumab; both Roche AG). By increasing IL-18 levels in the eye, Campbell said, "theoretically, you could prevent the switch from dry AMD to wet AMD," though he also cautioned that "we haven't done the experiments yet" to demonstrate that this is in fact what would happen in practice.

Still, the approach has several factors working for it. First, the eye is well suited to gene therapy approaches due to both its accessibility and its relative compactness, as successes in diseases like Leber's Congenital Amaurosis have demonstrated. (See BioWorld Today, April 29, 2008, and Aug. 13, 2009.)

And as the eye is a good target organ for gene therapy, so IL-18 is a good candidate gene. The IL-18 gene codes for an inactive precursor form of the cytokine that becomes active only when it is cleaved by the enzyme caspase-1.

Delivering a precursor gene amounts to an additional insurance policy against excessive activity that tips from beneficial to detrimental. Campbell said that IL-18 "should only be active in the presence of inflammation," because its activating enzyme "is only around when there are bad things happening in the eye in the first place."

Beyond the specific findings his team has published about IL-18 and AMD, Campbell contended that science – including the part of the biopharma industry that is looking for new drug targets – "needs to take another look at inflammation."

The current assumption tends to be that any proinflammatory gene that is up-regulated in disease is part of the problem. But like recent studies showing that IL-18 has protective effects in colitis, his team's work implies that they may be part of the solution instead, with problems arising not so much when inflammatory processes begin, but when they won't end.

"The innate immune system, all those Toll-like receptors, . . . they are there to protect us in the first instance." Campbell added.