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

Sonia M Vallabh, Chloe K Nobuhara, Franc Llorens, Inga Zerr, Piero Parchi, Sabina Capellari, Eric Kuhn, Jacob Klickstein, Jiri Safar, Flavia Nery, Kathryn Swoboda, Stuart L Schreiber, Michael D Geschwind, Henrik Zetterberg, Steven E Arnold, Eric Vallabh Minikel
doi: https://doi.org/10.1101/295063
Sonia M Vallabh
1Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
3Prion Alliance, Cambridge, MA, 02139, USA
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  • For correspondence: svallabh@broadinstitute.org
Chloe K Nobuhara
4Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
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Franc Llorens
5National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
6Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), L’Hospitalet de Llobregat, Barcelona, Spain
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Inga Zerr
5National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
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Piero Parchi
7IRCCS - Institute of Neurological Sciences, Bologna, 40139, Italy
8Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 40123, Italy
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Sabina Capellari
7IRCCS - Institute of Neurological Sciences, Bologna, 40139, Italy
9Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40138, Italy
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Eric Kuhn
10Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
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Jacob Klickstein
4Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
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Jiri Safar
11Department of Pathology, Neurology, and National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, 44106, USA
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Flavia Nery
4Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
12Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
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Kathryn Swoboda
4Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
12Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
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Stuart L Schreiber
1Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
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Michael D Geschwind
13Memory and Aging Center, University of California San Francisco, San Francisco, CA, 94158, USA
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Henrik Zetterberg
14Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden
15Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, S-431 80, Sweden
16UK Dementia Research Institute, University College London, London, WC1N 3BG, UK
17Department of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK
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Steven E Arnold
4Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
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Eric Vallabh Minikel
1Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
3Prion Alliance, Cambridge, MA, 02139, USA
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Abstract

Reduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, 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 enzyme-linked immunosorbent assay (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 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 weeks 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, enabling the development of prion disease therapeutics with this mechanism of action.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 04, 2018.
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Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development
Sonia M Vallabh, Chloe K Nobuhara, Franc Llorens, Inga Zerr, Piero Parchi, Sabina Capellari, Eric Kuhn, Jacob Klickstein, Jiri Safar, Flavia Nery, Kathryn Swoboda, Stuart L Schreiber, Michael D Geschwind, Henrik Zetterberg, Steven E Arnold, Eric Vallabh Minikel
bioRxiv 295063; doi: https://doi.org/10.1101/295063
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Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development
Sonia M Vallabh, Chloe K Nobuhara, Franc Llorens, Inga Zerr, Piero Parchi, Sabina Capellari, Eric Kuhn, Jacob Klickstein, Jiri Safar, Flavia Nery, Kathryn Swoboda, Stuart L Schreiber, Michael D Geschwind, Henrik Zetterberg, Steven E Arnold, Eric Vallabh Minikel
bioRxiv 295063; doi: https://doi.org/10.1101/295063

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