An influential review published earlier this year lent theoretical gravitas to the mechanism (Science, 327, 296–300, 2010). Juerg Tschopp, of the University of Lausanne, Switzerland, and his colleagues propose a central role for the NLRP3 (NOD-like receptor family, pryin domain containing 3) inflammasome—a multiprotein sensor for metabolic danger. This 'sensing' complex, they contend, initiates the inflammatory response by promoting the processing of pro-IL-1β into its active extracellular form, in the pathophysiology of type 2 diabetes. “A lot that was known about the IL-1 pathway has been now shown to involve the inflammasome,” says Marc Donath, of University Hospital, Zurich. The first therapies that target inflammasome-associated conditions have already appeared. The anti-IL-1β mAb, Ilaris (canakinumab; human IgG), developed by Basel -based Novartis, and the IL-1 trap Arcalyst (rilonacept), developed by Regeneron Pharmaceuticals, of Tarrytown, New York, have both gained approval for familial Cold Auto-inflammatory Syndrome and for Muckle-Wells syndrome, two of the three genetic disorders of the innate immune system that are collectively known as cryopyrin-associated periodic syndromes. These rare diseases result from mutations in NLRP3, which encodes the inflammasome component cryopyrin, and all are characterized by a harmful overproduction of IL-1β.
A rapidly growing body of basic and clinical research implicates the inflammasome—and, by extension, IL-1β—in a host of other conditions, including gout, multiple myeloma, central nervous system disease, type 1 diabetes and cardiovascular disease. One recent study, for example, provides evidence that tiny crystals of cholesterol are responsible for the initiation and progression of atherosclerosis. It suggests a role for therapies that block the inflammasome pathway in tackling the problem (Nature 464, 1357–1362, 2010). “That's the real opportunity here. This is a multi-indication situation we're talking about,” says Xoma CEO Steven Engle.
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