448: PrP‑lowering ASOs prolong survival in prion‑infected mice

Raymond GJ et al., JCI Insight - This study tests antisense oligonucleotides (ASOs) targeting Prnp in wild‑type mice infected with RML prions and shows that sequence‑specific PrP lowering by bolus i.c.v. ASO dosing delays disease and extends survival, even when given near clinical onset. Key terms: prion disease, antisense oligonucleotide, PrP lowering, mouse model, intracerebroventricular delivery.

Study Highlights:
Two sequence‑specific ASOs targeting mouse Prnp lowered Prnp mRNA and PrP protein in brain and delayed neuropathology compared with a non‑targeting control. Prophylactic bolus i.c.v. dosing given every 2–3 months extended survival by 61%–98%. A single ASO dose at 120 days post‑infection, near expected symptom onset, extended survival by 55% and slowed symptomatic progression. Control ASO showed no benefit, supporting RNA‑lowering as the mechanism of action.

Conclusion:
Bolus intracerebroventricular delivery of PrP‑targeting ASOs lowers PrP via RNase H–mediated mRNA degradation, slows accumulation of misfolded PrP, and substantially extends survival in prion‑infected mice, including when treatment is initiated near clinical onset.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Antisense oligonucleotides extend survival of prion‑infected mice

First author:
Raymond GJ

Journal:
JCI Insight

DOI:
10.1172/jci.insight.131175

Reference:
Raymond GJ, Tran Zhao H, Race B, Raymond LD, Williams K, Swayze EE, Graffam S, Le J, Caron T, Stathopoulos J, O’Keefe R, Lubke LDL, Reidenbach AG, Kraus A, Schreiber SL, Mazur C, Cabin DE, Carroll JB, Minikel EV, Kordasiewicz H, Caughey B, Vallabh SM. Antisense oligonucleotides extend survival of prion‑infected mice. JCI Insight. 2019;4(16):e131175. https://doi.org/10.1172/jci.insight.131175.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/prp-lowering-asos-prolong-survival-ep448

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing PrP biology, ASO mechanism (RNA lowering vs aptameric), delivery strategy, prophylactic and late-stage efficacy, control experiments, neuropathology, and translational implications.
- transcript topics: Prion biology and PrP involvement; ASO mechanism: RNA lowering vs aptameric effects; Delivery methods: bolus i.c.v. vs osmotic pumps; Prophylactic ASO efficacy in mice (onset delay, survival extension); scrambled control ASO vs active ASOs; Late-stage (120 dpi) ASO efficacy and ASO2 toxicity

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ASOs lowered Prnp mRNA and reduced PrP protein in brain regions
- Prophylactic ASO...

Chapters

• (00:00:00) - The genetic silencing approach to Creutzfeldt-Jak
• (00:02:27) - What is Prion Disease?
• (00:06:16) - How to Turn off prion disease's spread
• (00:11:54) - AsO 1, the scrambled ASO
• (00:12:47) - ASO2 delays the RML prion progression by nearly three
• (00:17:14) - The neuroscience of prion disease
• (00:21:11) - Thanks for listening to Prion Disease Podcasts
• (00:22:35) - Silence the Spark