The Generative Brain

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, home of Gerold Schmitt-Ulms's brain-penetrant cardiac glycoside program (KDC203) lowering PrPC.

Key facts

  • The lead compound was earlier reported to cut cell-surface PrPC by 84 percent in differentiated human cells; mice are refractory to cardiac glycosides so guinea pigs were used, whose cells and slices responded at about 30-fold higher concentrations.
  • 2024 grants: Kong (NPDPSC) ADAM8-based gene therapy; Schmitz (Goettingen) tear fluid diagnostic; Schmitt-Ulms (Toronto) small brain-penetrant molecule that reduces PrPC and mouse models of spontaneous prion emergence; Castilla (CIC bioGUNE) dominant-negative protein-based gene therapy; Aguzzi and Caredio (Zurich) GPNMB as therapeutic target; organoids from sporadic CJD donors (RML postdoc).
  • A 2024 CJD Foundation grant funds testing whether an orally dosed lead compound extends survival in a prion model and whether brain lowering can be tracked by PrPC in blood white cells.
  • The 2024 PLOS ONE update reports KDC203 lowering cell-surface PrPC in human cells but brain PrPC not lowered in guinea pigs because brain compound levels were too low.
  • 2025 slides report most oral KDC203 is converted by gut bacteria to a weaker compound that does not cross the blood-brain barrier.

Timeline

  1. 2024Grant awarded.
  2. 2024PLOS ONE update published.
  3. 2025Slides report gut conversion problem.
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