Minikel et al. 2020, Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints (Nucleic Acids Research)

A 24-author preclinical study in prion-infected mice testing antisense oligonucleotides (ASOs) that lower prion protein (PrP). It examined five mouse-adapted prion strains, different doses, different start times including near symptom onset, and survival and biomarker endpoints. The authors conclude that PrP lowering is a promising disease-modifying approach, with the largest benefit when started early and a smaller, partial benefit when started around symptom onset. It is mouse data only. The queue entry gave the right journal (Nucleic Acids Research, not Science Translational Medicine). Read depth: registry records plus a partial full-text read through a summarising tool, not a complete read.

Key facts

  • Bibliographic record: Nucleic Acids Research, volume 48, issue 19, pages 10615-10631, 2020; DOI 10.1093/nar/gkaa616; PMID 32776089; PMCID PMC7641729. Published online 10 August 2020 and in the November 2020 issue.
  • The article is open access under a CC BY 4.0 licence.
  • The author list has 24 names, with Eric Vallabh Minikel first and Sonia M. Vallabh last; Holly Kordasiewicz and Deborah Cabin are among the co-authors.
  • Funders named in the records are Ionis Pharmaceuticals, the Broad Institute, Prion Alliance, the NIH (including an NIGMS R35 grant and an F31 fellowship) and the National Science Foundation.
  • Prophylactic ASO dosing extended survival by 24% to 46% across five mouse-adapted strains (RML, 22L, ME7, Fukuoka-1, OSU), against 57% to 184% for mice genetically lacking one copy of the PrP gene.
  • Survival benefit tracked the degree of PrP RNA reduction with no clear threshold; the authors report that under 25% suppression was enough to extend survival in a prophylactic setting.
  • Benefit depended on timing: chronic dosing begun at or before 78 days after infection gave about a three-fold survival increase, while starting at 105 to 120 days gave about 19%.
  • Treatment begun around symptom onset (132 and 143 days) helped about one third of treated animals, who lived roughly 85 days longer without recovery of weight loss or nesting deficits; treatment at 156 days had no effect.
  • Prions recovered from ASO-treated animals were still delayed by treatment, which the authors read as no sign of drug-resistant strains.
  • Plasma neurofilament light chain rose in infected mice and fell after a single late dose, rebounding about 90 days later, supporting its use as a pharmacodynamic marker in mice.
  • Stated limitations: uneven response between animals and repeat experiments, poor tolerability of some ASOs at late timepoints, PrP RNA used in place of protein, no CSF PrP readout, unblinded raters at one site, uncorrected p-values, and no clinical testing.

Timeline

  1. 2020Paper published online (10 August 2020) in Nucleic Acids Research.
  2. 2020Appears in the November 2020 print issue (volume 48, issue 19).

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Last checked 1 November 2026

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