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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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7 Responses to An antihistamine’s hidden talent: Fighting prion disease

  1. It is so ironic that this article was posted on April 4, 2013. It is the day my mother died from Prion Disease following 63 days in a hospital and 11 in a rehabilitation facility. I would like to raise funds and find ways to bring awareness of this disease. When the doctor told us he suspected this diagnosis but only 1 in a million people get the disease I thought odds would work in our favor. That was not the case. If the study described above is a start to help patients and families be spared our pain, I hope the odds will begin to prove this medication in higher doses or variations can develop a treatment for this fatal disease. If someone knows of any organizations or family support groups that exists. Please let me know. If not I would love to be the one to start one. God bless those working to cure this disease and the families of those who lost a loved one to it!

  2. Please tell your friend to be brave and that I am praying for them. I would sit at mom’s bedside and recite stories of our happiest moments. I thanked her everyday for being an awesome wife, mom, grandma and best friend. I told her how much I loved her everyday and I believe that is these are the last things she heard before she passed away. So if your friends family feels helpless they can feel powerful by sharing love with their loved one until his suffering ends.

    • It’s difficult to see the blessings in the midst of brokenness. My heart goes out to you & your family. Your Mom was so lucky to have you and your love to carry her. I’ll pass your email to my friend. Thank you for sharing your thoughts & prayers. God bless you Sharla

    • Hi Sharla. My name is Michelle and I am from Michigan. I am so sorry about your Mom. I know that hurts. My brother was recently diagnosed with this monster, and I was wondering how your Mom’s was diagnosed. Did they do a biopsy or a spinal tap? We are so confused and scared. Any info would help. Thanks, Michelle

      • Sorry it took me so long to get back to you. I receved your message on my birthday and wanted to think about mom at happier times. I am so sorry about your brother. How old is he? My mother was 68 the median age that people get this horrible disease. My mom kept a diary so we were able to trace back that she started having strange things happen even 12 months before her death. Of course she had no idea what was going wrong. 6 months before her death she started feeling dizzy all the time. She was constantly visiting doctors and specialist and they found nothing. 3 months before they finally found something abnormal on an ekg. Through her appearance and slurred speech we thought she had a mild stroke but they could not find evidence of a stroke. 3 weeks after admission to the hospital she could do nothing. She could not hold up her head, talk, walk or eat. At that point our neurologist suspected prion disease and we did a spinal tap/lumbar poke and sent it to Mayo Clinic. When they told us 1 in a million people get it, I thought we would surely dodge that bullet. It came back with a result of high levels of the prion protein in her blood. She died 36 days later. Remember, the hearing is the last thing to go. My mom jerked violently until a few days before she died. The day she died she appeared to open her eyes. Probably wishful thinking but I believe she heard us until they end. So I told her everyday how much we loved her and what a wonderful daughter, sister, wife, mom and friend she was. I sang to her, read to her and held her until she took her last breath. So love your brother fiercely everyday. Love is more powerful than this disease. Soon he will take his rest from suffering and you will know that you did all you could…love! The amazing thing is love never dies!

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