When Prions are Personal

BETHESDA, Md., Oct. 21, 2019 /PRNewswire/ -- A research team with an especially personal stake in prion diseases reports in the journal Molecular & Cellular Proteomics a new measurement that may be useful in testing the future treatments that they aim to pioneer.

Almost everyone produces the prion protein, known as PrP for short, which is found in the brain and cerebrospinal fluid. Like most proteins, PrP folds into a characteristic structure when it is produced. But sometimes that structure can be changed. When one copy of PrP adopts a misfolded shape, it encourages the other prion proteins it comes into contact with to do the same. The misfolded proteins spread like an infection, causing fatal damage to the brain. There is no cure.

For husband-and-wife team Sonia Vallabh and Eric Vallabh Minikel, prions became personal when Vallabh's mother died of a mysterious, rapidly-advancing neurodegenerative disease. The family learned from an autopsy that the culprit had been a genetic prion disorder, a variant in PrP that makes the protein more likely to adopt a pathogenic conformation. A test revealed that Vallabh has the mutated form of the gene, too.

"She has a very high probability of developing the same disease," Minikel said. "And once it strikes, it's rapidly fatal."

After that genetic test five years ago, Vallabh and Minikel changed their lives. They founded Prion Alliance, a nonprofit dedicated to finding a cure. This spring they defended their Ph.D. theses, which focused on therapeutics for prion disease, in back-to-back seminars. Now, they're looking ahead toward testing treatments.

A major hope for treating prion diseases is to reduce the amount of prion protein in people like Vallabh who are genetically predisposed. Researchers hope this will reduce the chances that one misfolded protein will spread and cause disease. But there is a challenge: How will researchers know if a potential treatment is working?

"The first and most basic thing you do in a clinical trial is try to find a dose that is potent and tolerated," Minikel explained. Researchers usually test potency by measuring how a candidate drug affects its target. In this case, that would mean looking for a drop in PrP after treatment.

However, scientists know that the amount of PrP they can detect drops dramatically after a person begins to show symptoms.

"It's very nonintuitive... trying to lower a thing that already goes down at the onset of disease," Minikel said. If disease progression and an effective drug candidate truly had the same effect on PrP level, he added, researchers could not test the drug's potency in patients who had the disease.

What the researchers couldn't say for sure was whether that drop in PrP in test results reflected reality. Maybe PrP circulating in the cerebrospinal fluid dropped because it was clumping into toxic aggregates in the brain. But the test researchers usually use depends on an interaction between PrP and an antibody that recognizes its shape. As PrP misfolds researchers wondered, could it become invisible to the antibody while still present in the cerebrospinal fluid?

As part of his thesis work, Minikel helped develop a new test to resolve this question. With colleagues at the Broad Institute, he developed a way to detect PrP that doesn't depend on the protein's shape. Instead, using a mass spectrometry technique called multiple reaction monitoring, the approach breaks the protein into bits and measures them. Even if the protein has changed shape, this new assay can still detect it.

Using the test on samples from patients, the scientists confirmed that PrP in the cerebrospinal fluid drops in the course of prion disease. That gives them a roadmap: they need to test potential drugs in people at high risk of prion disease who have not yet shown symptoms.

Working with Ionis Pharmaceuticals, Vallabh and Minikel have started testing drug candidates in mice. They are using antisense oligonucleotides, which should suppress the production of prion protein, in hopes that it will slow the processes of misfolded PrP originating, spreading, or doing damage. Some early trials in mice give Minikel hope, he said: mice infected with prions, if treated before they show symptoms, survive longer without disease.

Minikel is optimistic that the antisense approach will work in humans, too. But even if this particular drug candidate doesn't prove effective, he looks at the groundwork they've laid with pride. "I'm hopeful that we've made tremendous progress in making this a what people in the industry would call 'developable disease.' And I think that's a really promising step forward, independent of any one drug."

DOI: mcp.RA119.001702
This study was funded by the National Institutes of Health (HHS F31 AI122592), National Science Foundation (GRFP 2015214731), Robert Koch Institute (1369-341) and Broad Institute (Next Gen Fund).

Other authors on this study include Eric Kuhn, Alexandra Cocco, Sonia Vallabh, Christina Hartigan, Andrew Reidenbach, Jiri Safar, Gregory Raymond, Michael McCarthy, Rhonda O'Keefe, Franc Llorens, Inga Zerr, Sabina Capellari, Piero Parchi, Stuart Schreiber and Steven Carr.

About Molecular & Cellular Proteomics

Molecular & Cellular Proteomics (MCP) showcases research into proteomes, large-scale sets of proteins from different organisms or biological contexts. The journal publishes work that describes proteins' structure, function and interactions with cellular partners. For more information visit www.mcponline.org.

About Prion Alliance

Prion Alliance is a 501(c)(3) non-profit devoted exclusively to advancing scientific research towards a treatment or cure for human prion disease, including Creutzfeldt-Jakob disease, fatal familial insomnia, and Gertsmann-Sträussler-Scheinker disease. Learn more and support research at prionalliance.org.

About the American Society for Biochemistry and Molecular Biology

The ASBMB is a nonprofit scientific and educational organization with more than 11,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in government laboratories, at nonprofit research institutions and in industry. The Society publishes three journals: the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics. For more information about ASBMB, visit www.asbmb.org.

CONTACT: Angela Hopp, [email protected]

SOURCE American Society for Biochemistry and Molecular Biology