Wednesday, April 2, 2025
4/2/2025
Biomarkers and Mechanisms of PrP Misfolding, Mutation, and Deficiency - PROJECT SUMMARY Prion disease is an incurable and uniformly fatal neurodegenerative disease of humans and other mammals. PrP lowering is a pharmacologically validated therapeutic strategy for prion disease, and antisense oligonucleotides (ASOs) with this mechanism of action are currently advancing toward the clinic. The promise of this progress, and indeed our ability to advance any therapy for prion disease, will critically depend on our capacity to leverage molecular biomarkers as windows into the brain. To date the molecular states of the brain during lifelong genetic risk prior to disease, first prion formation, and early phases of prion replication all remain elusive, and yet, it is precisely these upstream disease stages that have shown themselves most amenable to PrP-lowering intervention. To become a clinical reality, early treatment paradigms will require biomarkers to report on drug safety and efficacy but also the earliest molecular stages of risk and disease; critical decisions about trial eligibility, timing of treatment, and advancement or termination of whole experimental drug programs will rest on our ability to accurately interpret and mechanistically contextualize these molecular readouts. The goal of the present proposal is to discover and illuminate biomarkers across three key categories. 1) Markers of PrP misfolding. Using CSF and plasma samples from healthy at-risk humans and from prion-infected rats and hamsters at pre-symptomatic stages, we will track the earliest molecular changes resulting from prion replication. We will characterize new markers as well as determine the temporal sequence and prognostic value of existing markers. 2) Markers of PrP mutation. In a mouse model of a common human prion disease mutation, we will dissect the mechanism by which a pathogenic missense variant results in under-expression of not only mutant PrP but also wild-type PrP and other bystander proteins. We will determine whether resulting changes will confound other biomarker readouts, and whether the under-expression reflects a host protective mechanism or a harmful pathological consequence of PrP mutation. 3) Markers of PrP deficiency. Leveraging new PrP knockout rats and hamsters as well as PrP knockout mice, we will perform experiments to gain a mechanistic understanding of the molecular changes resulting from PrP’s reduction or absence. Taken together, these studies will on one hand illuminate core mechanisms of prion biology, from the early consequences of PrP mutation and misfolding to the native function of PrP. On the other hand, these studies will facilitate informed clinical development of PrP-lowering therapies by allowing biomarkers to be correctly interpreted so that harmful therapies are halted while promising therapies are advanced.
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