Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

Prion diseases are
a group of neurodegenerative disorders characterized
by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of
the therapies developed until now are based on blocking this process.
Here, we propose a new drug strategy aimed at clearing prions without
any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation
during prion diseases, we have identified a small molecule, named
compound 5 (ARN1468), inhibiting the function of these serpins and
effectively reducing prion load in chronically infected cells. Although
the low bioavailability of this compound does not allow in
vivo studies in prion-infected mice, our strategy emerges
as a novel and effective approach to the treatment of prion disease.