Raymond GJ et al. 2019, Antisense oligonucleotides extend survival of prion-infected mice (JCI Insight 4(16):e131175, PMID 31361599, doi 10.1172/jci.insight.131175)

This open access paper reported that antisense oligonucleotides (ASOs) that lower the prion protein (PrP) in the brain extended survival in mice infected with a mouse-adapted prion strain. It was written jointly by the NIAID Rocky Mountain Laboratories, Ionis Pharmaceuticals and the Broad Institute group, with Prion Alliance listed among the affiliations. It is the main published preclinical proof of concept behind the PrP-lowering ASO approach that later led to ION717. The authors presented the work as supporting further development, not as a clinical result. The full text was opened for the first part of the article only (see Open questions).

Key facts

  • The article is JCI Insight 2019, volume 4, issue 16, article e131175, DOI 10.1172/jci.insight.131175, PMID 31361599, PMCID PMC6777807, licensed CC BY.
  • It was received 19 June 2019, accepted 26 July 2019, published online 30 July 2019, with the issue dated 22 August 2019.
  • It has 22 authors, with Gregory J Raymond first and Sonia M Vallabh last; Eric Vallabh Minikel, Holly Kordasiewicz, Byron Caughey, Deborah Cabin and Jeffrey Carroll are among them.
  • Preventive ASO dosing in infected mice extended survival by 61 to 98 percent across two testing sites.
  • A single dose given 120 days after infection, close to the onset of clinical signs, extended survival by 55 percent (87 days) with one of two active ASOs.
  • A non-targeting control ASO gave no benefit, which the authors read as showing that PrP lowering, not a sequence-independent effect, drives the benefit.
  • PrP lowering in brain was partial and wore off between doses.
  • In mice that were still symptom-free when examined, treated animals had less PrP deposition, vacuolation and astrocyte reaction; animals that reached terminal disease looked similar to untreated animals.
  • Some mice died suddenly after injection, including some given the control ASO, and one of the two active ASOs was not tolerated at the late time point; the authors left the cause open.
  • CSF PrP was not measured; the authors propose it as a pharmacodynamic biomarker for later human work.
  • The authors listed limits themselves: only female wild-type mice, one ASO in the late-treatment experiment, research molecules rather than clinical candidates, and survival differences not tested statistically.
  • Funding named in the paper included CJD Foundation grants, Prion Alliance, Broad Institute funds, and NIH and NIAID intramural support; Ionis funded its own work and some authors are Ionis employees or hold equity.

Timeline

  1. 2019Manuscript received by JCI Insight.
  2. 2019Manuscript accepted.
  3. 2019Published online.
  4. 2019Issue 16 of volume 4 dated.

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Last checked 1 November 2026

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