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

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i Proceedings of the National Academy of Sciences of the United States of America
Volym 116
Nummer/häfte 16
Sidor 7793-7798
ISSN 0027-8424
Publiceringsår 2019
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 7793-7798
Språk en
Länkar dx.doi.org/10.1073/pnas.1901947116
Ämnesord Biomarker, Cerebrospinal fluid, Creutzfeldt-Jakob disease, Human prion disease, Prion protein
Ämneskategorier Neurovetenskaper

Sammanfattning

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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