Human prion disease is a rare, exceptionally rapid, universally fatal neurodegenerative disease. Though
currently untreatable, all prion disease follows a single well-characterized molecular mechanism by which the
native prion protein (PrP), encoded by the prion protein gene (PRNP), misfolds into a pathogenic conformation.
These so-called prions template the conformational corruption of healthy PrP molecules, propelling the spread
of prions and prion-induced neurotoxicity across the brain. As the necessary substrate for prion conversion,
native PrP has emerged as an attractive therapeutic target in prion disease. Decades of evidence indicate that
reduction of native PrP is dose-dependently protective against prion disease. Full knockout confers total
protection against disease, with animal and human evidence indicating that PrP reduction should be well
tolerated. In light of these promising proofs of concept, we are collaborating with Ionis Pharmaceuticals to
develop PrP-lowering antisense oligonucleotides (ASOs) that reduce PrP in the brain by targeting PrP RNA for
degradation. Preliminary preclinical studies suggest that ASOs against prion protein potently extend survival of
prion-infected animals, with prophylactic treatment conferring the greatest benefit. Our preliminary engagement
with the FDA indicates that primary prevention trials in pre-symptomatic prion disease mutation carriers could
be feasible, and that lowering PrP in cerebrospinal fluid (CSF) may be a viable surrogate endpoint for Accelerated
Approval of a PrP-lowering therapeutic. Informed by FDA engagement, the following three aims will gather critical
and time-sensitive data to enable this clinical path. 1) Assess short-term within-subject test-retest stability
of CSF PrP in pre-symptomatic genetic prion disease mutation carriers and non-carrier controls. We will
use a technically validated ELISA to determine short-term stability of PrP levels in repeat CSF samples donated
by genetic prion disease carriers and controls over 2-4 month intervals. 2) Determine the correlation between
brain and CSF PrP knockdown in rats, and between brain PrP knockdown and survival in mice. We will
analyze ASO-treated rodent tissues to model the relationship between brain and CSF PrP levels, as well as the
relationship between brain PrP knockdown and extension of survival. 3) Gather pathological biomarker data
to assess presence of a biochemically detectable prodromal phase of prion disease in pre-symptomatic
human carriers. We will analyze pre-symptomatic human plasma and/or CSF samples for markers of neuronal
damage and presence of prion seeds, biomarkers known to be associated with symptomatic prion disease, to
understand for purposes of trial design and stratification whether pre-symptomatic carriers show evidence of a
biochemically detectable pathological prodromal phase prior to symptom onset.