Biomedicine

An End to Alzheimer's?

Isolation of key genes at the heart of Alzheimer’s disease has set off a frenzied race to find a drug to stop this cruel affliction in its tracks.

When molecular biologist Bob Vassar joined biotech giant Amgen in 1996, his mother was suffering from advanced-stage Alzheimer’s disease. For years he’d taken care of her himself, since his father had died young. “Once she became incontinent I couldn’t keep her at home any more,” he recalls with more than a trace of guilt. In a nursing home, Vassar’s mother slid rapidly downhill. In 1999, at age 78, she died-17 years after her diagnosis of Alzheimer’s, which gradually but inexorably drains its victims of memory, judgment and reason.

Vassar was helpless to stop, or even slow, his mother’s descent into dementia. But unlike most Alzheimer’s caregivers, he was in a position to help others avoid her fate. At Amgen, in Thousand Oaks, CA, he designed and implemented an ingenious method for isolating the gene for an enzyme called beta-secretase-a key culprit in the disease. “It was a high-risk project, and there was no guarantee we could get it,” says Vassar. In fact, his group individually tested 860,000 gene copies before finding beta-secretase and publishing the discovery in late 1999.

With success came hope. The U.S. Food and Drug Administration has approved three drugs for Alzheimer’s disease, but these only temporarily improve brain function, without slowing or stopping progression of the disease. Other treatments are in advanced development (see “Bulging Pipeline” sidebar), but none has yet shown good long-term results. The discovery of beta-secretase, on the other hand, opens the possibility of halting the disease. “It’s a huge leap forward,” says Lennart Mucke, director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco. Possession of beta-secretase (discovered, almost simultaneously, by three other drug companies) has now set off a frenzied race to find and test a drug to block the enzyme and stop Alzheimer’s in its tracks.

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Blunting the Scissors

Although the cutting enzymes themselves proved maddeningly elusive, this model of Alzheimer’s offered an obvious strategy for attacking the disease: block the enzymes and prevent the plaques. Since 1992, many drug companies have been looking for “secretase inhibitors,” molecules that would block either gamma- or beta-secretase. One compound, a gamma-secretase inhibitor discovered at Bristol-Myers Squibb using mass screening techniques, entered early human trials in April 2000. “We’re on the verge now of either preventing amyloid deposits from building up, inhibiting the production of amyloid, or actually being able to reverse plaque deposition,” says Felsenstein, who leads Bristol-Myers Squibb’s amyloid program. Other pharmaceutical firms-including DuPont, Merck, Elan and Eli Lilly-are testing gamma-secretase inhibitors as well, but haven’t yet disclosed human trials.

But the drug-discovery process has been agonizingly slow. Just randomly sprinkling compounds on cells and measuring amyloid levels requires both time and luck to get a good hit. In fact, many drug companies ignored the secretases, since without the enzymes in hand, there’s no way to know how specifically a compound is targeting them-making toxic side effects largely unpredictable.

Finding beta-secretase changes everything. Now medicinal chemists can design molecules to fit precisely into the enzyme’s “active site.” In theory, such drugs should be exquisitely specific, avoiding the worst side effects. Citron says Amgen is very excited about that possibility. The company has figured out the three-dimensional structure of the beta enzyme and is fashioning molecules to block its activity.

Industry insiders say that Amgen has lots of competition, though companies are more open about their gamma programs. GlaxoSmithKline of London, another company to have isolated the beta-secretase gene, is one player officially working to inhibit it. And Dublin, Ireland-based Elan and its partner in Peapack, NJ, Pharmacia, have also launched a major push. “Both of us view beta-secretase as a terrific target,” says Dale Schenk, vice president of discovery research for Elan. “I don’t think it’s going to be terribly long before the field has clinical candidates.”

Schenk’s optimism is based, in part, on an obvious precedent: AIDS. That’s because beta-secretase is a protease, or protein-cutting enzyme, in the same class as the HIV protease, which proved to be a great drug target. Once the HIV-protease structure was discovered in 1989, it took less than three years to get “protease inhibitors” into the clinic. These drugs have changed AIDS from a death sentence into a usually manageable condition. “Pharmaceutical companies like sure things,” says University of South Florida Alzheimer’s researcher Huntington Potter. Blocking enzymes “is something they can do easily and be sure that they have something fairly successful at the end.”

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.”

Stocking the Armamentarium

Though each company is desperate to be first, many will likely emerge with successful (and lucrative) drugs. “The field is wide open,” says Needham’s Monane. “There’s room for multiple winners in the race.” And, indeed, most researchers in the field agree that no single drug is likely to work for every Alzheimer’s patient.

Instead, it will probably take a “cocktail” approach, analogous to today’s AIDS therapy. So, although secretase inhibitors and a vaccine effort at Elan (see companion article “Injection of Hope”) hold the most promise now, other classes of drugs could also be useful. “We will probably find out that many different things are contributing to this disease,” says the University of California, San Francisco’s Mucke. “And it is worthwhile to develop treatments to hit each one of those, and then see what combination will be most effective.”

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