期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 16, 页码 7793-7798出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1901947116
关键词
prion protein; cerebrospinal fluid; biomarker; human prion disease; Creutzfeldt-Jakob disease
资金
- NIH [P50 AG005134]
- National Institute of General Medical Sciences [R35GM127045]
- National Science Foundation (GRFP Award) [2015214731]
- National Institutes of Health [AI122592]
- BroadIgnite and the Next Generation Fund at the Broad Institute of MIT and Harvard, Prion Alliance
- Federal Ministry of Health [1369-341]
- Spanish Ministry of Health-Instituto Carlos III University of California, San Francisco [Miguel Servet-CP16/00041]
- NIH/National Institute on Aging [R01 AG-031189, R01 AG-032289]
- National Center for Advancing Translational Sciences [NIH UCSF-CTSI UL1 RR024131]
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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