The Generative Brain

PrP-lowering divalent siRNA (PRiSM drug candidate 2439-s4 / exNA)

PrP-siRNA (2439-s4) is a divalent siRNA developed by the Broad and UMass Chan that lowers PrP; it is in the PRiSM first-in-human trial. The mouse results usually quoted (49 percent PrP lowering and 64 percent longer survival after one dose at symptom onset) were obtained with a separate mouse-targeting tool compound, not with the human candidate.

Key facts

  • The paper "Divalent siRNA for prion disease" (Gentile et al., Nucleic Acids Research 2026;54(8):gkag287; preprint December 2024) is by the Vallabh/Minikel and Khvorova groups and nominates 2439-s4 as the drug candidate for human prion disease.
  • Tool compound 1682-s4 (mouse Prnp): 49 percent residual brain PrP in wild-type mice; 2.7-fold longer survival with chronic pre-symptomatic treatment and 64 percent longer survival with a single dose after symptom onset in prion-infected mice.
  • Human candidate 2439-s4: a single 348 microgram dose lowered whole-hemisphere human PrP in transgenic mice to 17 percent residual at 30 days and 52 micrograms to 49 percent; scaffold s4 added 9.4 points (fixed UU tail) and 15.9 points (extended nucleic acid linkages) of knockdown versus other scaffolds.
  • The paper argues that about 50 percent lowering extends survival up to 3-fold but all mice still die, so halting or indefinitely delaying disease needs deeper than 50 percent lowering.
  • Good Laboratory Practice toxicology studies identified no significant liabilities, per the abstract; the NeuroNEXT page states the drug was manufactured and an IND filed.
  • PRiSM objectives: primary safety and tolerability; secondary CSF PrP lowering and drug concentration in CSF and blood; exploratory disease biomarkers and clinical endpoints; an observational arm of untreated newly diagnosed patients provides a comparator for this and future trials.
  • The siRNA platform silences targets for up to six months in rodents and non-human primates, and treated prion mice in an earlier study lived over a year versus about three months.
  • Collaboration: Khvorova (UMass Chan), Minikel and Vallabh have worked together since 2019 per the Broad and since 2020 per the Prion Alliance; funding came from NIH grants and community donations to the Broad and Prion Alliance.
  • Clinical use: single doses of 50, 100 and 200 mg are tested in PRiSM; the sponsor states one dose per participant, no expanded access and US sites only.

Timeline

  1. 2019Broad dates collaboration with Khvorova start.
  2. 2020Prion Alliance dates siRNA development start.
  3. 2024bioRxiv preprint posted.
  4. 2026Paper published in Nucleic Acids Research.
  5. 2026PRiSM launch announced.
  6. 2026PRiSM registry start date.
  7. 2026PRiSM pre-symptomatic arm announced.
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