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Thursday, 02/09/2012 5:19:39 PM

Thursday, February 09, 2012 5:19:39 PM

Post# of 252509
Has this been posted here? If so, apologies.

WSJ:

>>Cancer Drug Shows Promise for Alzheimer's
By GAUTAM NAIK

A cancer drug has improved mental function and social ability and restored the sense of smell in mice bred with a form of Alzheimer's disease, suggesting a new way to tackle the illness in people.

Alzheimer's disease is associated with the accumulation of protein fragments called amyloid-beta in the brain. The new research shows that a skin-cancer drug called bexarotene cleared the protein in the brains of stricken mice within days. The study was published in the journal Science.

Because bexarotene is known to be safe for the treatment of skin cancer, "it might be worth trying in Alzheimer's patients as well," said Rada Koldamova, a neuroscientist who works on Alzheimer's at the University of Pittsburgh and who wasn't part of the study. However, she added, the drug's effectiveness against the brain malady would first have to be established in human trials. Test results in mice often don't pan out in humans.

Everyone's brain produces amyloid-beta protein, but while a healthy brain can efficiently remove the protein fragments, the brain of a person with Alzheimer's disease can't. The resulting buildup is believed to result in the impaired learning and memory functions seen in Alzheimer's patients.

The disease is a growing problem, especially in aging societies, but an effective treatment has eluded researchers. The drugs used today work for a short time and only relieve symptoms, instead of halting the disease. Over the years, drugs in about a half-dozen late-stage human trials have failed to make the cut.

In 2010, Eli Lilly & Co. abandoned a treatment that blocked an enzyme linked to amyloid formation; the trial was stopped because the medication appeared to worsen some patients' condition. Another technique, currently being tested in patients, is to reduce protein formation by triggering an immune response.

The new research, funded by a number of foundations, takes a completely different approach, said Gary Landreth, a neuroscientist at Case Western Reserve University in Cleveland and a co-author of the Science study. His team's method, he says, is to "help Mother Nature do what she normally does" in clearing away amyloid fragments from the brain.

Scientists know that a protein called ApoE acts as a sort of garbage-disposal unit, helping to degrade amyloid-beta proteins. Dr. Landreth figured that if he could get the brain to make more ApoE, the protein clearance would be enhanced.

He set his sights on bexarotene, an orally administered drug known to activate a protein that helps switch on the ApoE gene. In 2009, Dr. Landreth asked a newly minted postgraduate student in his lab to give the drug to some "Alzheimer mice." Three days later, the amyloid plaques in their brains had largely disappeared.

"It was unprecedented," Dr. Landreth recalled. "I initially thought she had screwed up."

In the Science study, Dr. Landreth and his colleagues describe similar tests done with over 100 mice. When the drug was fed to mice with Alzheimer-like symptoms, it quickly improved their cognitive, social and olfactory functions. Losing the sense of smell, a disorienting and often debilitating experience, can be one of the first signs of Alzheimer's.

Healthy mice will typically gather pieces of paper towels strewn around their cage and use them to make a nest. Alzheimer mice don't exhibit that behavior. In the lab experiments, when the treatment was given to diseased mice, they made nests, a sign of cognitive improvement. The benefits in the mice lasted for up to three months, at which stage the scientists stopped their observations.

In the U.S., bexarotene is sold under the name Targretin, which is owned and marketed by Japan's Eisai Co. Patents on the drug will start to expire this year, one reason drug companies may be reluctant to jump on bexarotene as a possible Alzheimer's treatment.

Dr. Landreth and a co-author, Paige Cramer, are founding scientists of ReXceptor Inc., which has licensing options from Case Western on the use of bexarotene to treat Alzheimer's disease.

Bexarotene is a long way from being an approved Alzheimer's drug, or even being deemed ready for off-label use—when a doctor legally prescribes a drug for an unapproved use. As a first step, Dr. Landreth is planning a safety trial in a dozen patients.

He needs to figure out the right dose and duration of the treatment for prospective Alzheimer's patients, and judge the effects over several months. If all goes well, he hopes to engineer a version of the medicine that is more potent and works at a lower dose than bexarotene.

Carl Wagner, an organic chemist at Arizona State University who is collaborating with Dr. Landreth on the project, said he had synthesized half a dozen such versions and was testing them.

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