Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development
Year: 2019
Type: article
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.
Institutions: Broad Institute, Harvard University, Prion Alliance, Massachusetts General Hospital, Biomedical Research Networking Center on Neurodegenerative Diseases, University of Göttingen, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Case Western Reserve University, University of California, San Francisco, Sahlgrenska University Hospital, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, University of Gothenburg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Broad Institute, Bundesministerium für Gesundheit, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities
Awards: G1222096957, G1632916191, Clinical and Translational Science Institute, G1778344677, G1859882300, G2058173175, G2240379263, G3058368938, G3486798699, New Clinical Approaches to Creutzfeldt-Jakob Disease, G4337430293, G5589164507, G6041155856, G611802359, G613912715, G6781161026, G723466177, G7532129822, G758528517, G7913889536, G8223734540, G9000007463, G9000032698, G9000058261, G9000103430, G9000166495, G9000208643, G9000325434, Massachusetts Alzheimer's Disease Research Center (MADRC)
OpenAlex ID: W2796074293