Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.

Autor: Mortberg MA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Zhao HT; Ionis Pharmaceuticals Inc., Carlsbad, California, USA., Reidenbach AG; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Gentile JE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Kuhn E; Proteomics Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA., O'Moore J; McLaughlin Research Institute, Great Falls, Montana, USA., Dooley PM; Massachusetts Alzheimer's Disease Research Center, and., Connors TR; Massachusetts Alzheimer's Disease Research Center, and., Mazur C; Ionis Pharmaceuticals Inc., Carlsbad, California, USA., Allen SW; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Trombetta BA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., McManus A; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Moore MR; Bioagilytix, Boston, Massachusetts, USA., Liu J; Bioagilytix, Boston, Massachusetts, USA., Cabin DE; McLaughlin Research Institute, Great Falls, Montana, USA., Kordasiewicz HB; Ionis Pharmaceuticals Inc., Carlsbad, California, USA., Mathews J; Ionis Pharmaceuticals Inc., Carlsbad, California, USA., Arnold SE; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Vallabh SM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Prion Alliance, Cambridge, Massachusetts, USA., Minikel EV; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Prion Alliance, Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2022 Mar 22; Vol. 7 (6). Date of Electronic Publication: 2022 Mar 22.
DOI: 10.1172/jci.insight.156532
Abstrakt: Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
Databáze: MEDLINE