447: Divalent siRNA for prion disease

Gentile JE et al., Nucleic Acids Research - This study develops and tests divalent siRNA molecules that lower prion protein (PrP) in the brain, identifies a potent human-targeting candidate (2439-s4), demonstrates survival benefit in prion-infected mice with a mouse-targeting tool compound, and reports IND-enabling toxicology supporting clinical testing. Key terms: prion disease, PrP lowering, divalent siRNA, 2439-s4, transgenic mouse. Study Highlights:The authors identify a mouse Prnp-targeting divalent siRNA (1682-s4) that lowers brain PrP to ~49% residual and extends survival in RML prion–infected mice (2.7-fold when dosed presymptomatically, 64% increase after a single symptomatic dose). They generate two transgenic mouse lines expressing full human PRNP (Tg25109, Tg26372) and use them to discover human-targeting siRNA 2439, optimized as 2439-s4, which lowers whole-hemisphere human PrP to 17% residual at 348 μg and to 49% at 52 μg. Chemical features—an exNA terminal linkage and a fixed 3' UU tail—each contribute substantially to potency, and a single dose shows durability out to months while 1–2% of CSF dose is retained in brain. GLP toxicology in rats and dogs identified no major liabilities and the FDA cleared an IND to advance 2439-s4 to human trials. Conclusion:Divalent siRNA can achieve deep, durable PrP lowering in the CNS, confer disease-modifying benefit in a mouse prion model, and yield a clinical candidate (2439-s4) with supportive nonclinical toxicology and regulatory clearance for a first-in-human study. Music:Enjoy the music based on this article at the end of the episode. Article title:Divalent siRNA for prion disease First author:Gentile JE Journal:Nucleic Acids Research DOI:10.1093/nar/gkag287 Reference:Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, et al. Divalent siRNA for prion disease. Nucleic Acids Research. 2026;54:gkag287. doi:10.1093/nar/gkag287 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/divalent-sirna-prion-disease 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 sections covering: divalent siRNA mechanism and CNS delivery; mouse Prnp knockdown and survival data for 1682-s4; human PRNP targeting with 2439-s4 in transgenic mice; scaffold optimization (exNA, fixed tail, PS); PK/PD and IND-enabling GLP tox; and FDA IND clearance.- transcript topics: Divalent siRNA mechanism and CNS delivery; Mouse Prnp knockdown and survival in prion model with 1682-s4; Human PRNP transgenic mouse models Tg25109/Tg26372 and lead candidate 2439-s4; Chemical scaffold optimization (PS reductions, exNA, fixed UU tail); IND-enabling GLP toxicology and FDA IND clearance; PK/PD metrics (IC50 ~1.2 μg/g; tissue retention 1–2% dose) QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata is... Chapters (00:00:02) - Basses by Bass(00:00:28) - The science of Creutzfeldt Jakob Disease(00:05:56) - Turning off the prion protein(00:13:13) - Quantum therapy for prion disease(00:20:18) - CJD Foundation on Lito Sousa(00:21:32) - Cut the Thread