451: Prion protein lowering is disease-modifying across stages and strains

Minikel EV et al., Nucleic Acids Research - This study uses antisense oligonucleotides (ASOs) to lower prion protein (PrP) RNA in mice and shows dose-dependent extension of survival, efficacy across multiple prion strains, reversal of molecular biomarkers, and benefit even when treatment is delayed into symptomatic stages. Key terms: prion protein, antisense oligonucleotide, neurodegeneration, biomarkers, survival. Study Highlights:Using ASOs to reduce PrP RNA in intracerebrally inoculated mice produced dose-dependent extension of survival in both prophylactic and delayed dosing paradigms. Less than 25% PrP suppression was sufficient to delay symptoms and extend survival. Treatment was effective across five distinct prion strains without evidence of drug-resistant prions. Biomarkers of neuronal injury (plasma NfL) and astrocytosis (GFAP bioluminescence) were reversed after ASO treatment, and chronic early dosing matched benefits seen in heterozygous PrP knockout animals. Conclusion:ASO-mediated PrP lowering is a robust, disease-modifying approach in mouse models of prion disease across strains and disease stages, supporting advancement of PrP-lowering therapeutics and use of CSF PrP and blood NfL as pharmacodynamic biomarkers. Music:Enjoy the music based on this article at the end of the episode. Article title:Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints First author:Minikel EV Journal:Nucleic Acids Research DOI:10.1093/nar/gkaa616 Reference:Minikel EV, Zhao HT, Le J, O’Moore J, Pitstick R, Graffam S, Carlson GA, Kavanaugh MP, Kriz J, Kim JB, Ma J, Wille H, Aiken J, McKenzie D, Doh-ura K, Beck M, O’Keefe R, Stathopoulos J, Caron T, Schreiber SL, Carroll JB, Kordasiewicz HB, Cabin DE, Vallabh SM. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Research. 2020;48(19):10615–10631. doi:10.1093/nar/gkaa616 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/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/prion-protein-lowering-stages-strains-endpoints QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-25. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections include PrP biology and PrP function; ASO mechanism and RNase H action; dose-response and minimal PrP knockdown; cross-strain efficacy across five mouse prion strains; biomarkers (plasma NfL and GFAP bioluminescence); therapeutic timing (prophylactic, early/delayed, late/symptomatic); resistance and tr- transcript topics: Prion protein biology and PrP function; ASO mechanism and RNase H action; Dose-response and minimal PrP knockdown; Cross-strain efficacy across five mouse prion strains; Biomarkers: plasma neurofilament light (NfL) and GFAP bioluminescence; Behavioral readouts: rotarod and nest-building QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata check...