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Progress Inhibited?

But there is a big question: what if the amyloid theory is wrong? If it is, secretase inhibitors would be useless. “The field has been ‘sold,’ or has willingly bought into, the hypothesis that amyloid deposits, or possibly the precursors to the amyloid deposits, actually cause the disease,” says Potter. “It’s probably true.” But other factors-tangle formation, for example, or disruption of neurons’ stores of the calcium ions critical to nerve firing-could prove to be the real cause of Alzheimer’s. In that case, “getting rid of [amyloid] might make a cleaner brain, but it might not make a more functioning brain,” says Potter. “We won’t know until [drugs] are tried.”

Even if the amyloid hypothesis proves correct, side effects could ultimately doom secretase inhibitors. Gamma-secretase, for example, is closely related to a protein that is responsible for processing another protein called Notch. Since Notch is crucial for human development and cell division, a drug that blocked gamma-secretase might wind up causing chemotherapy-like side effects-something unacceptable in a drug that’s taken for life. “The Notch thing has everybody scared,” says one drug-company scientist.

Bristol-Myers Squibb and others are undeterred. Felsenstein says his company’s drug, in mice, inhibits gamma-secretase approximately 20 times more than it interferes with Notch activity: “That gave us a window of opportunity.” Felsenstein hopes that blocking perhaps 40 percent of the enzyme’s activity will be enough to keep plaques from forming but not enough to cause serious side effects. “[Notch] may be a theoretical issue, or it may be a show stopper,” says Amgen’s Citron. “Nobody knows.”

Beta-secretase inhibitors have their own question marks. Nobody knows what the enzyme’s normal function in the body is, so blocking it could conceivably cause anything from hair loss to psychosis. And random screening of naturally occurring and synthetic compounds over the last eight years turned up no inhibitors of the beta enzyme. “That’s very strange,” says Felsenstein. “I don’t know if that tells us that beta-secretase may not be a good target. Only time will tell.”

And if beta-secretase inhibitors work, companies will face another battle over the enzyme. That’s because, with four groups isolating the gene almost simultaneously, no one knows who will have first rights to the molecule. GlaxoSmithKline may have the edge, because it applied first for a patent-but before it knew the enzyme’s function. “It’s going to take an army of lawyers to figure out who owns it,” says Felsenstein. Meanwhile, the pressure to get to market ahead of competitors is intense. As one drug-company researcher confided, “My CEO says it’s costing us $150,000 a day not to have an Alzheimer’s drug on the market.”

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