Abstract
Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
Highlights
Prion disease is a fatal neurodegenerative disease caused by misfolding of the prion protein (PrP) leading to a gain of toxic function [1]
Given the pivotal role of PrP in prion biology, it is reasonable to ask whether any known risk factors for prion disease, including age, sex, and genotype, are mediated by differences in PrP expression
Two previous studies observed suggestive associations between cerebrospinal fluid (CSF) PrP concentration and age [10, 13], but only in historical cohorts where preanalytical variables were not well-controlled and/or samples were not well-matched on other variables
Summary
Prion disease is a fatal neurodegenerative disease caused by misfolding of the prion protein (PrP) leading to a gain of toxic function [1]. Antisense oligonucleotides that lower PrP extend survival by up to three-fold in prion-infected mice [4,5,6], supporting the further development of PrP-lowering drugs This motivates a need to accurately measure the degree to which PrP has been lowered upon drug treatment, across a variety of species and matrices. Such quantification of target engagement — a drug’s impact on its intended molecular target — is critical throughout the life cycle of any drug development program, from therapeutic candidate screening and lead optimization, to in vitro and in vivo pharmacology studies in animals, to dose selection and confirmation of drug activity in human clinical trials. Quantification of PrP may play an even larger role: lowering of cerebrospinal fluid (CSF) PrP in presymptomatic individuals at high risk for genetic prion disease could be employed as a surrogate biomarker endpoint in support of provisional drug approval [3]
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