Advertisement

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Business

Movers And Shakers

Paul Greengard

Nobel Laureate holds forth on the state of Alzheimer’s drug discovery

by Carmen Drahl
October 18, 2010 | A version of this story appeared in Volume 88, Issue 42

[+]Enlarge
Credit: Courtesy of Paul Greengard
Credit: Courtesy of Paul Greengard

Paul Greengard is no stranger to the ups and downs of developing new medicines. Most researchers recognize him as a Nobel Prize-winning academic neuroscientist who’s had stints at Yale University and Rockefeller University, his current home. But Greengard spent a good chunk of the 1960s directing the department of biochemistry at Ardsley, N.Y.-based Geigy Research Laboratories, which today is part of Novartis. And last month, he published a paper with a mix of industry and academic scientists that delivered a breath of fresh air to a beleaguered area of drug discovery: Alzheimer’s disease research.

Many pharmaceutical companies have poured money and manpower into investigating whether blocking production of amyloid-β, the peptide behind the plaques that mar Alzheimer’s patients’ brains, can slow or stop the progression of the disease (C&EN, April 5, page 12). But testing that hypothesis has been taking its toll on the industry’s collective psyche. For one thing, amyloid-β can accumulate into different aggregates with varying degrees of toxicity, and there’s considerable debate about which form leads to Alzheimer’s.

What’s more, several promising Alzheimer’s treatments aimed at amyloid-β have not panned out in the clinic. The latest to stumble was Eli Lilly & Co.’s drug candidate semagacestat. The molecule, designed to block a protease enzyme called γ-secretase, which is involved in amyloid-β production, was pulled from development in the midst of late-stage clinical trials.

The withdrawal didn’t come just because the drug wasn’t working. Patients who took it actually fared worse—with more memory loss and less ability to perform daily activities—than patients who took a placebo. Patients on the drug also had an increased risk of skin cancer. For some in the research community, the news shook confidence in the so-called amyloid hypothesis.

But Greengard thinks the amyloid hypothesis is very much alive. “There is, I think, incontrovertible evidence that amyloid-β plays a role in some types of Alzheimer’s disease,” he says. The best evidence is in familial, or inherited, varieties.

Greengard points out that not every scientist thinks amyloid causes the disease. Several other nervous system proteins, such as tau, are also thought to be players (C&EN, May 3, page 36). “There are various reasons why there have been proponents and opponents of the amyloid hypothesis,” Greengard says. “Part of it is the egos of scientists, saying things like ‘I bet on tau, so amyloid has to be wrong.’ When people’s egos get involved, they lose their objectivity. I think both the pro-amyloid and anti-amyloid schools suffer from that.”

Greengard calls the semagacestat trial outcome disappointing, but he sees a couple of reasons why it and other clinical-trial setbacks for Alzheimer’s drugs might have happened. One problem is that drug candidates might not have been sufficiently selective for their targets, he says. Although γ-secretase, the enzyme target of semagacestat, plays a major role in amyloid-β production, that is not its only job.

The enzyme also has a hand in processing other proteins in the body, including the critical transcription factor Notch, which is involved in many events, including cell-to-cell communication. Medicinal chemists have taken pains to ensure that γ-secretase inhibitors for Alzheimer’s disease don’t have a big impact on Notch, but it’s possible that, without exquisite selectivity, patients taking γ-secretase inhibitors could suffer a significant negative effect, Greengard says.

His team recently discovered a potential way to sidestep the selectivity issue. Instead of targeting γ-secretase itself, Greengard’s team advocates an alternative target they discovered, called γ-secretase-activating protein. This protein switches on γ-secretase and guides its activity toward amyloid-β, ensuring it steers clear of Notch (Nature 2010, 467, 95). The intellectual property covering blockers of the activating protein is owned by New York City-based Intra-Cellular Therapies, a biotech company Greengard cofounded in 2002. Some of the coauthors on Greengard’s study are affiliated with the company.

Selectivity isn’t the only problem dogging Alzheimer’s studies, Greengard says. Researchers can end up hamstrung simply because of the way clinical trials for a drug are conducted. “These clinical trials are started rather late in the course of the disease,” he says. “By that stage a lot of the damage has been done.” In some cases of mid-stage dementia, a phase of Alzheimer’s common among patients in clinical trials, much of the cortex, a part of the brain that plays a role in memory and attention, is already severely damaged.

“But if you start a trial too early, it’ll be a very long-term study to see who develops Alzheimer’s and who doesn’t,” Greengard says. “What companies have to do for purely economic reasons is to test fewer patients over a shorter period of time,” even if this approach doesn’t provide the best picture of whether an Alzheimer’s drug candidate will slow the progress of the disease.

However, technology could solve that conundrum, Greengard says. He’s buoyed by the prospect of improved diagnostic techniques for detecting early-stage Alzheimer’s. Such technologies would tell researchers at an earlier point whether an experimental Alzheimer’s drug is working. And diagnostics could pave the way to a new generation of Alzheimer’s drugs—be they inhibitors of γ-secretase-activating protein or any of a number of other targets. For those therapies, “I think the commercial potential is just enormous,” he says.

Advertisement

Article:

This article has been sent to the following recipient:

0 /1 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.