Prion Clearance and Treatment of Recalcitrant Prion Strains Through Deep PrP Suppression

PROJECT SUMMARY/ABSTRACT Prion disease is a fatal neurodegenerative disease caused by misfolding of the prion protein (PrP). Lowering PrP by genetic deletion or pharmacologic means both delays onset and slows progression of prion disease. A PrP-lowering medicine is now in clinical trials in prion disease patients. Yet despite ample support for PrP lowering as a therapeutic hypothesis, key questions have remained unanswered due to the lack of potent PrP-lowering reagents for the whole brain. First, what threshold percentage of PrP lowering is required in order to halt prion replication entirely, and tip the kinetics towards prion clearance? Second, will ultra deep PrP lowering prove effective against recalcitrant prion strains that show only limited response to 50% PrP lowering? In this proposal we will use highly potent PrP-lowering reagents to probe the following questions. 1) Quantify the depth of PrP suppression achievable under a repeated dosing regimen. 2) Determine the trajectory of prion replication with and without treatment. We will infect mice with prions and harvest brains at timepoints before and after treatment to determine whether the treatment slows, halts, or reverses replication of prions. 3) Compare the efficacy of deep PrP suppression to only 50% suppression for a recalcitrant prion strain. Using a prion strain for which the benefit of 50% PrP lowering is less pronounced, we will ask whether deeper suppression with chronic treatment confers additional benefit and whether it is capable of keeping animals alive until end of study at 500 days post-inoculation. Our findings will inform the design of clinical trials in prion disease by delineating the requirements for efficacy against recalcitrant prion strains and quantifying a threshold of PrP lowering required to achieve prion clearance.