Mortberg MA et al. 2022, Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS (JCI Insight 7(6):e156532, PMID 35133987, doi 10.1172/jci.insight.156532)

Open-access paper from the Broad Institute and Massachusetts General Hospital, with Ionis co-authors, published in JCI Insight on 22 March 2022. It reports a plate-based immunoassay for prion protein (PrP) that works across six species in brain tissue and CSF, maps how PrP varies between brain regions, and shows in rodents that lowering brain Prnp RNA lowers brain PrP and CSF PrP in step. Its practical message is that CSF PrP can serve as a pharmacodynamic marker for PrP-lowering drugs, best read as change from each person's own baseline.

Key facts

  • Bibliographic record: 20 authors (first author Meredith A Mortberg, last author Eric Vallabh Minikel), JCI Insight volume 7 issue 6, article e156532, DOI 10.1172/jci.insight.156532, PMID 35133987, PMCID PMC8986079.
  • The immunoassay detects PrP in human, cynomolgus macaque, mouse, rat, bank vole and Syrian hamster samples, with a stated range of 0.05 to 5.0 ng/mL, and meets FDA bioanalytical criteria apart from higher interplate variability near the lower limit.
  • Initial assay development and rat CSF validation were done at BioAgilytix Boston (then Cambridge Biomedical); the assay was then moved to the Broad, which did the mouse brain validation and all later work.
  • PrP differs widely by brain region: in five human control brains, parietal cortex was nearly 10-fold above the olivary nuclei, and macaque (n=6) and mouse (n=8) showed similar disparities. Cortex was generally higher than subcortex and cerebellum, and brainstem lowest.
  • No association of PrP with age or sex was found (GTEx data, CSF from 47 people, rat tissue), and the common variants M129V and rs17327121 did not track with CSF PrP.
  • In an aggregate comparison of CSF from a Massachusetts General Hospital biomarker study (47 participants including 21 non-carrier controls), CSF PrP was about 55% of control level in the P102L group and about 31% in the D178N group; the E200K group (about 78%) did not reach significance. Group sizes were small.
  • In rats, brain PrP knockdown was matched by CSF knockdown, with CSF slightly understating the brain reduction (about 1.4% brain per 1% CSF); mass spectrometry on several PrP peptides supported the ELISA results.
  • In naive mice each 1% fall in Prnp RNA went with about 0.62% lower PrP at 2 weeks and 0.83% at 4 weeks; prion-infected mice showed comparable RNA and protein reductions.
  • The authors argue for relative reduction from individual baseline, not a single absolute CSF threshold, and note the regulatory idea of provisional approval based on CSF PrP lowering.
  • Funders named in the paper: Prion Alliance, CJD Foundation, Ionis, the Broad Institute, NIH (R21 TR003040), Ono Pharma Foundation and an anonymous organisation.

Timeline

  1. 2021Manuscript received by JCI Insight.
  2. 2022Manuscript accepted.
  3. 2022Published online in JCI Insight.

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Last checked 1 November 2026

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