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Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development

Journal article
Authors S. M. Vallabh
C. K. Nobuhara
F. Llorens
I. Zerr
P. Parchi
S. Capellari
E. Kuhn
J. Klickstein
J. G. Safar
F. C. Nery
K. J. Swoboda
M. D. Geschwind
Henrik Zetterberg
S. E. Arnold
E. V. Minikel
S. L. Schreiber
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 116
Issue 16
Pages 7793-7798
ISSN 0027-8424
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 7793-7798
Language en
Keywords Biomarker, Cerebrospinal fluid, Creutzfeldt-Jakob disease, Human prion disease, Prion protein
Subject categories Neurosciences


Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test–retest reliability (mean coefficient of variation, 13% in samples collected 8–11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action. © 2019 National Academy of Sciences. All rights reserved.

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