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An antihistamine’s hidden talent: Fighting prion disease

When they screened a library of existing drugs for their ability to treat neurodegenerative prion diseases, one team of researchers was in for a surprise. Astemizole, an antihistamine that’s been used to treat seasonal allergies since the 1970s, lengthened the survival time of mice infected with prion disease, the researchers report in a new PNAS Early Edition paper.

Scientists have previously shown that prion diseases, which include Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, and mad cow disease, are caused by the abnormal folding of a protein—the prion protein (PrP)—in the brain. When misfolded, infectious prion protein enters the brain, it launches a domino effect whereby normal PrP converts to the misfolded structure. Misfolded PrP damages brain tissue, causing neurodegeneration and eventually death.

“There have been many attempts to find drugs against prion diseases for almost 30 years,” says Corinne Lasmézas of the Scripps Research Institute, a lead author of the new work. “When Dr. Weissmann and I decided to tackle this problem, we realized that if we wanted something that would finally work, we’d have to take a different approach.”

Most efforts in the past have aimed to find drugs that stop the misfolding of PrP from its normal structure to its pathogenic form, but Lasmézas and her colleagues instead developed an assay to detect compounds that lowered the amount of normal PrP protein at the cell surface, a localization necessary for the ultimate conversion of the protein to the misfolded form. Previous studies have established that mice, goats, and cows entirely lacking normal PrP are not susceptible to prion diseases and don’t appear to have side effects from missing the protein. By screening for reduced cell-surface levels of normal PrP, the researchers could not only conduct a high-throughput search, but avoid having to handle the infectious protein.

To validate their screen, the team tested 1,280 drugs already approved for use in humans and catalogued by the US Pharmacopeia. With the advent of high-throughput screening, searching for new uses for old drugs has become more commonplace (read a recent PNAS news feature on the topic of drug repurposing).

“We didn’t really expect anything to stand out, although we thought it would be wonderful if, by chance, one of them worked,” says Lasmézas.

Surprisingly, nine drugs decreased cell-surface levels of PrP by at least half. One drug—astemizole—stood out not only because it reduced levels of PrP at the cell surface by more than 50%, but also because, when further tested in mice with a prion disease, astemizole increased their lifespan. While the increase was modest—around 6 days—it was enough to show proof of principle in vivo, says Lasmézas.

The researchers propose that the drug—which is no longer used in the United States because newer generation allergy drugs have come along, but is still marketed in other countries—could move quickly to being tested in patients with Creutzfeldt-Jakob disease, who currently have no treatment options.

But an important aspect of this is also that it can help advance basic research on the cellular biology of the prion protein, says Lasmézas. “The regulation of cell-surface PrP expression is not well-understood,” she says. “So any new molecules that affect this will be great tools to work out the life cycle of PrP in the cell.”

As well as studying astemizole further, the team plans to apply their new approach to other, larger libraries in a continued search for other drugs with prion-fighting capabilities. Compounds pinpointed by the assay could work by blocking the production of PrP, stopping its movement to the cell surface, or accelerating its degradation—biochemical studies will be needed to clarify the mechanisms in each case.

Moreover, they plan to adapt their assay to other diseases where it would be important to modulate the amount of a particular protein. “I certainly hope we come up with more drugs,” Lasmézas says. “We’ve already shown that this new assay works so expanding it to other diseases is definitely a next step.”

Categories: Cell Biology | Medical Sciences
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