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

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          Significance

          Human prion disease is a rapidly fatal and incurable neurodegenerative disease. Reduction of prion protein in the brain is a well-supported therapeutic hypothesis, and antisense oligonucleotides with this mechanism of action are currently in development. To facilitate clinical testing of prion protein-lowering drugs in prion disease, we show that with proper sample handling, brain prion protein levels can be monitored in cerebrospinal fluid, using existing tools, and exhibit suitable short-term stability for drug-dependent decreases to be reliably measured. Cerebrospinal fluid prion protein levels thus may usefully serve as a pharmacodynamic biomarker. This biomarker may open new paths for informative clinical trials in presymptomatic individuals who harbor high-risk mutations for genetic prion disease.

          Abstract

          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.

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          Most cited references52

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          Is Open Access

          PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT

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            Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

            PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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              Nobel Lecture: Prions

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                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                Proceedings of the National Academy of Sciences
                Proc. Natl. Acad. Sci. U.S.A.
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                April 16 2019
                April 2019
                April 16 2019
                : 116
                : 16
                : 7793-7798
                Affiliations
                [1 ]Chemical Biology and Therapeutics Science, Broad Institute of Harvard and MIT, Cambridge, MA 02142;
                [2 ]Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115;
                [3 ]Prion Alliance, Cambridge, MA 02139;
                [4 ]Department of Neurology, Massachusetts General Hospital, Boston, MA 02114;
                [5 ]National Reference Center for TSE, Georg-August University, 37073 Göttingen, Germany;
                [6 ]Biomedical Research Networking Center on Neurodegenerative Diseases, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;
                [7 ]IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Laboratorio di Neuropatologia, 40139 Bologna, Italy;
                [8 ]Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40123 Bologna, Italy;
                [9 ]Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy;
                [10 ]Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142;
                [11 ]Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106;
                [12 ]Department of Neurology, Case Western Reserve University, Cleveland, OH 44106;
                [13 ]Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114;
                [14 ]Memory and Aging Center, University of California, San Francisco, CA 94158;
                [15 ]Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden;
                [16 ]Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden;
                [17 ]UK Dementia Research Institute, University College London, WC1N 3BG London, United Kingdom;
                [18 ]Department of Molecular Neuroscience, University College London Institute of Neurology, WC1N 3BG London, United Kingdom
                Article
                10.1073/pnas.1901947116
                6475435
                30936307
                9c3ff5b3-8ad8-493e-bc69-c28a1f1d28ed
                © 2019

                Free to read

                https://www.pnas.org/site/aboutpnas/licenses.xhtml

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