Vallabh SM et al. 2019, Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development (PNAS 116(16):7793-7798, PMID 30936307, doi 10.1073/pnas.1901947116)

This 2019 PNAS paper, led from the Broad Institute with European and US clinical collaborators, tested whether prion protein (PrP) measured in cerebrospinal fluid by a commercial ELISA is reliable enough to show that a drug has lowered PrP in the brain. It found that sample handling matters a great deal (PrP sticks to plastic unless a detergent is present), that blood contamination does not distort the reading, and that repeat samples from the same person under controlled handling vary by about 13 percent. The authors concluded that the measure is workable as a pharmacodynamic marker for PrP-lowering drugs. It is a feasibility and assay-performance study, not a trial. The record was verified on PubMed, Europe PMC and Crossref; the open-access main text was read through a fetch summary, without the supplement or figures.

Key facts

  • The paper is Proc Natl Acad Sci U S A 2019 Apr 16;116(16):7793-7798, epub 1 April 2019, DOI 10.1073/pnas.1901947116, PMID 30936307, PMCID PMC6475435; PubMed lists 16 authors from Sonia M Vallabh to Stuart L Schreiber, with Eric Vallabh Minikel as penultimate author.
  • Funding listed in Europe PMC is mainly US NIH institute grants (NIA, NCATS, NIGMS, NIAID, NIMHD), with a UK Medical Research Council grant and a US National Science Foundation fellowship also listed.
  • The study used the commercial BetaPrion human PrP ELISA kit from Analytik Jena on about 225 CSF samples across 41 plates, drawn from symptomatic prion disease, presymptomatic carriers and several non-prion control groups, plus 28 postmortem brain samples.
  • PrP in CSF is lost to plastic surfaces: three transfers without detergent removed at least 73 percent of detectable PrP, against 7.1 percent with 0.03 percent CHAPS; the detergent did not protect against loss to glass.
  • Spiking CSF with up to 1 percent whole blood did not raise measured PrP, and CSF hemoglobin did not track PrP, which the authors read as showing the protein is overwhelmingly derived from the central nervous system.
  • Assay precision was about 8 to 11 percent within a plate and 22 percent between plates, so the authors advise placing samples from one person on the same plate.
  • In a placebo-arm cohort of 9 people with controlled handling, mean within-person variation over 8 to 11 weeks was 13 percent; in three cohorts with less uniform handling it was 33 to 41 percent.
  • Diagnostic group explained only a minority of the variance in CSF PrP (adjusted R squared 0.23), and symptomatic prion disease showed lower PrP than other groups, which the authors flag as a complication for symptomatic trial populations.
  • The authors propose CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and, in presymptomatic genetic carriers, as a possible surrogate endpoint; they note the kit suits relative better than absolute quantification and that ELISA may miss some PrP forms.
  • Samples were de-identified and the work was approved by the Broad Institute research subjects office.

Timeline

  1. 2019Paper published online ahead of print in PNAS.
  2. 2019Paper appears in PNAS volume 116, issue 16, pages 7793-7798.

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Last checked 1 November 2026

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