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Eisai Lymphoma Drug Reverses Alzheimer's Disease Symptoms

By Anette Breindl
Science Editor

Researchers identified a drug which, in animals, rapidly decreases both plaque area and soluble amyloid beta levels in mouse models of Alzheimer's disease. And it's FDA-approved.

The drug in question is Targretin (bexarotene, Eisai Inc.) which was approved for the treatment of cutaneous T-cell lymphoma in 2000.

Gary Landreth told BioWorld Today that "our results on plaque clearance are unprecedented." In mice treated with Targretin, plaque levels declined by more than 50 percent within three days, and ultimately declined by more than 75 percent.

"We were stunned," he added, "and it took quite a while for us to believe our own data. The speed is shocking." Landreth is a professor of neuroscience at Case Western Reserve University School of Medicine and the senior author of the paper describing those data, which was published in the Feb. 9, 2012, advance online issue of Science.

Landreth and his team decided to test Targretin in Alzheimer's mice because it affects the retinoic X receptor. That receptor, in conjunction with two other proteins, controls brain levels of apolipoprotein E, or ApoE, which, in turn, is the protein that clears amyloid beta. That protein is overproduced in Alzheimer's disease, and the amyloid plaques it forms are the anatomical calling card of the disease – those plaques also were once thought to be the cause of the memory problems that are its behavioral calling card.

As several drugs targeting amyloid plaques have failed in late-stage clinical trials, it has become clear that plaques themselves are not overly harmful, and they may even be protective against what many now consider the real villain: soluble amyloid beta, especially so-called oligomers.

Targretin, Landreth said, "targets both soluble amyloid beta and plaque. [It] drives up ApoE expression in astrocytes, which clears soluble Abeta, and this likely improves cognition." But it also "provokes the change in activation state of microglia and reanimates their phagocytic machinery, and this is responsible for plaque clearance."

When Landreth and his team treated several different mouse models of Alzheimer's disease with Targretin, levels of soluble amyloid beta decreased within six hours. The team tested their mice on several learning tasks; in some of those tasks, they saw improvements with as little as one week of treatment, though in others, longer treatment was necessary. The drug also improved the animals' olfactory abilities, which are normally impaired by plaque deposition. Finally, animals that had lost the ability to build nests – a social behavior for mice – were once again able to do so after Targretin treatment.

Although he has no solid proof, Landreth's hunch is that the drug's effectiveness at improving behavioral symptoms is in large part due to its effects on soluble amyloid beta, not plaques. "I think that as we pull down Abeta levels, synaptic function improves, and that subserves the improvement in behavior," he said.

Landreth stressed that the results are as yet preclinical, and that the model his team used is unable in principle to give any clues to how Targretin will affect individuals with advanced Alzheimer's. The reason, he said, is that in mouse models of Alzheimer's disease, "the neurons don't die, and that is a serious problem for extrapolating to later stages of the disease."

Still, he said, his team's results showed that, in animals, "early in the disease the effects . . . are largely reversible."

And on the plus side, because Targretin is an approved drug, "we have just cut 10 years off of the developmental timeline." That doesn't mean he's not in a big hurry to get started. "I want to be in the clinic with this within the next two months," he said.

Given the known, albeit indirect, connection from the retinoic acid receptor to ApoE levels and, from there, to amyloid, in hindsight the notion of trying to treat Alzheimer's disease with Targretin might seem obvious enough to be tested a long time ago. But Landreth said, a priori, there were also a number of reasons to suspect that such an approach would fail.

Specifically, he said, "one might have predicted a boatload of side effects," since the retinoic X receptor "works in coordination with a number of other receptors." That those side effects did not occur "is just serendipitous."