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.