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Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7793-7798. doi: 10.1073/pnas.1901947116. Epub 2019 Apr 1.

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

Author information

Chemical Biology and Therapeutics Science, Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115.
Prion Alliance, Cambridge, MA 02139.
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114.
National Reference Center for TSE, Georg-August University, 37073 Göttingen, Germany.
Biomedical Research Networking Center on Neurodegenerative Diseases, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Laboratorio di Neuropatologia, 40139 Bologna, Italy.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40123 Bologna, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy.
Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106.
Department of Neurology, Case Western Reserve University, Cleveland, OH 44106.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114.
Memory and Aging Center, University of California, San Francisco, CA 94158.
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden.
UK Dementia Research Institute, University College London, WC1N 3BG London, United Kingdom.
Department of Molecular Neuroscience, University College London Institute of Neurology, WC1N 3BG London, United Kingdom.


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.


Creutzfeldt-Jakob disease; biomarker; cerebrospinal fluid; human prion disease; prion protein

[Available on 2019-10-01]

Conflict of interest statement

Conflict of interest statement: S.L.S. is a member of the Board of Directors of the Genomics Institute of the Novartis Research Foundation ("GNF"); a shareholder and member of the Board of Directors of Jnana Therapeutics; a shareholder of Forma Therapeutics; a shareholder of and adviser to Decibel Therapeutics and Eikonizo Therapeutics; an adviser to Eisai, Inc., the Ono Pharma Foundation, and F-Prime Capital Partners; and a Novartis Faculty Scholar.

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