The Generative Brain

CSF PrP quantification (ELISA and mass spectrometry)

CSF PrP quantification measures total prion protein in spinal fluid. It is the proposed drug-effect (pharmacodynamic) marker for PrP-lowering drugs and the central biomarker in the pre-symptomatic trial argument: it is stable over months in healthy carriers, falls in symptomatic disease, and is the first human readout in ION717 and PRiSM. Inter-laboratory validation is still the regulator's ask.

Key facts

  • A commercially available ELISA (BetaPrion human PrP) quantified CSF PrP reproducibly and precisely in 225 samples across 41 plates, including symptomatic patients, pre-symptomatic carriers, non-prion dementia and normal pressure hydrocephalus.
  • Handling matters: CSF PrP is lost to plastic adsorption unless detergent is added; blood contamination does not alter it and it is uncorrelated with hemoglobin, indicating a CNS origin; within-person test-retest variation was 13 percent (samples 8 to 11 weeks apart).
  • A targeted mass spectrometry method (multiple reaction monitoring of nine PrP peptides) analyzed 55 clinical samples; six of six peptides tested were uniformly decreased in prion disease, matching the ELISA findings.
  • CSF PrP decreases in active prion disease, which can confound the drug-effect readout in symptomatic patients and may limit its use as a drug-effect marker to pre-symptomatic people.
  • Mutation and region effects: a cross-species ELISA meeting FDA bioanalytical validation criteria found that heterozygous carriers of some mutations have lower baseline CSF PrP (the excerpt gives 55 percent for P102L and 31 percent for D178N), so relative change from each person's own baseline is the right metric.
  • In 27 pre-symptomatic carriers and 16 mutation-negative controls followed for 2 to 20 months at MGH, CSF PrP was stable; NfL and tau were normal and RT-QuIC was positive in one carrier, so those markers may not serve as primary endpoints in pre-symptomatic trials.
  • ION717's PrProfile measures percent change from baseline in CSF PrP up to Week 25, and PRiSM lists CSF PrP lowering as a secondary objective, making this assay the first human drug-effect readout.
  • FDA's 2019 Type C feedback did not accept CSF PrP lowering as a surrogate. It advised on assay rigour, including inter-laboratory reproducibility as development proceeds, efficacy in two animal models unless one is justified, and showing the minimum lowering that predicts benefit.

Timeline

  1. 2019FDA Type C meeting on CSF PrP as a surrogate.
  2. 2019PNAS paper validating the CSF PrP ELISA.
  3. 2020MGH pre-symptomatic biomarker cohort reported.
  4. 2022Regional variability and genotype effects on PrP concentration published.
  5. 2024OBSERVE paper reports four conversions.
  6. 2024PrProfile fully enrolled; CSF PrP data pending.
  7. 2026PRiSM statement lists CSF PrP lowering as an aim of the single dose.
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