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Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development
Sonia M. Vallabh (Broad Institute, Harvard University), Chloe K. Nobuhara (Massachusetts General Hospital), Franc Llorens (Biomedical Research Networking Center on Neurodegenerative Diseases, University of Göttingen), Inga Zerr (University of Göttingen), Piero Parchi (Istituto delle Scienze Neurologiche di Bologna, University of Bologna), Sabina Capellari (Istituto delle Scienze Neurologiche di Bologna, University of Bologna), Eric W. Kuhn (Broad Institute), Jacob Aaron Klickstein (Massachusetts General Hospital), Jiri Safar (Case Western Reserve University), Flávia C. Nery (Massachusetts General Hospital), Kathryn J. Swoboda (Massachusetts General Hospital), Michael D. Geschwind (University of California, San Francisco), Henrik Zetterberg (Sahlgrenska University Hospital, UK Dementia Research Institute), Steven Edward Arnold (Massachusetts General Hospital), Eric Vallabh Minikel (Broad Institute, Harvard University), Stuart L. Schreiber (Broad Institute)
Résumé : 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.