The Generative Brain

Brain-penetrant small molecule lowering PrPC (Toronto)

This approach tries to lower the cell-surface prion protein with a tablet instead of an injected drug. The lead compound, a modified cardiac glycoside called KDC203, binds the sodium-potassium pump that sits next to the prion protein, and when cells clear the pump the prion protein is cleared with it. It works in human cells and in guinea pig brain slices, but in 2024 and 2025 the group reported that the compound did not reach the brain in enough amounts in animals and that gut bacteria inactivate much of the oral dose. No survival data in prion-infected animals and no human data. Information only.

Key facts

  • Mechanism in the lead's words: PrPC sits next to Na+,K+ pumps; cardiac glycosides inhibit the pumps, cells internalize and degrade them, and PrPC is co-degraded.
  • Rationale for lowering PrPC: knockout is tolerated in mice and cattle, a goat with a natural null mutation exists, and heterozygous Prnp roughly doubles prion survival in mice; ASOs give proof of concept but need periodic intrathecal dosing.
  • Lead compound: KDC203 (C4'-dehydro-oleandrin), a semi-synthetic derivative of oleandrin selected for brain access; reported to cut PrPC by 84 to 85 percent in human cell models at low nanomolar levels.
  • Funding: a 2024 CJD Foundation grant at the Tanz Centre, University of Toronto, to test whether oral dosing extends survival in an animal prion model and whether brain effect can be tracked by PrPC in blood white cells.
  • 2024 peer-reviewed update: effect seen in several human cell models (cell-surface PrPC), with some cell types raising total PrPC while the surface pool still fell.
  • Model problem: mice are refractory to cardiac glycosides; guinea pig cells, primary cells and brain slices responded but at about 30-fold higher concentrations than human cells.
  • Feedback biology: cells raise prion gene expression to compensate and PrPC overshoots after withdrawal, so daily dosing is needed for sustained lowering.
  • In vivo result: in an 8-animal subcutaneous guinea pig study heart and lung PrPC fell but brain PrPC did not because brain compound levels were too low; the authors say the main goal of finding a survival-testing rodent model was not met.
  • 2025 grantee slides: most oral KDC203 was converted by gut bacteria into a weaker substance that does not cross the blood-brain barrier and oral dosing in a mammalian model did not consistently lower PrPC; proposed fixes are a gut-stable version or blood-based dosing; unpublished and unreviewed.
  • Safety statements by the grantee: cardiac glycosides have long human clinical use for heart disease and are described as not toxic at PrPC-lowering concentrations, with a possible cost near 1 US dollar per day; the 2024 paper notes long-term effects of PrPC build-up in slow-degrading cells are unknown; these are grantee claims, not trial data.
  • Human data: none.

Timeline

  1. 2022Identification of the brain-penetrant lead KDC203 (preprint read here).
  2. 2024CJD Foundation grant page published; 2024 grant awarded for the preclinical bridge.
  3. 2024PLOS ONE update: in vitro and brain slice lowering, guinea pig brain exposure insufficient.
  4. 2025Grantee slides (2025 CJD Foundation meeting) report gut conversion of KDC203 and inconsistent oral PrPC lowering.
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