TY - JOUR
T1 - Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development
AU - Vallabh, Sonia M.
AU - Nobuhara, Chloe K.
AU - Llorens, Franc
AU - Zerr, Inga
AU - Parchi, Piero
AU - Capellari, Sabina
AU - Kuhn, Eric
AU - Klickstein, Jacob
AU - Safar, Jiri G.
AU - Nery, Flavia C.
AU - Swoboda, Kathryn J.
AU - Geschwind, Michael D.
AU - Zetterberg, Henrik
AU - Arnold, Steven E.
AU - Minikel, Eric Vallabh
AU - Schreiber, Stuart L.
N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Parchi Piero, Capellari Sabina).
PY - 2019/4/16
Y1 - 2019/4/16
N2 - 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.
AB - 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.
KW - Biomarker
KW - Cerebrospinal fluid
KW - Creutzfeldt-Jakob disease
KW - Human prion disease
KW - Prion protein
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U2 - 10.1073/pnas.1901947116
DO - 10.1073/pnas.1901947116
M3 - Article
C2 - 30936307
AN - SCOPUS:85064342914
VL - 116
SP - 7793
EP - 7798
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 16
ER -