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

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 factor...

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Autores principales: Mortberg, Meredith A., Zhao, Hien T., Reidenbach, Andrew G., Gentile, Juliana E., Kuhn, Eric, O’Moore, Jill, Dooley, Patrick M., Connors, Theresa R., Mazur, Curt, Allen, Shona W., Trombetta, Bianca A., McManus, Alison, Moore, Matthew R., Liu, Jiewu, Cabin, Deborah E., Kordasiewicz, Holly B., Mathews, Joel, Arnold, Steven E., Vallabh, Sonia M., Minikel, Eric Vallabh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986079/
https://www.ncbi.nlm.nih.gov/pubmed/35133987
http://dx.doi.org/10.1172/jci.insight.156532
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author Mortberg, Meredith A.
Zhao, Hien T.
Reidenbach, Andrew G.
Gentile, Juliana E.
Kuhn, Eric
O’Moore, Jill
Dooley, Patrick M.
Connors, Theresa R.
Mazur, Curt
Allen, Shona W.
Trombetta, Bianca A.
McManus, Alison
Moore, Matthew R.
Liu, Jiewu
Cabin, Deborah E.
Kordasiewicz, Holly B.
Mathews, Joel
Arnold, Steven E.
Vallabh, Sonia M.
Minikel, Eric Vallabh
author_facet Mortberg, Meredith A.
Zhao, Hien T.
Reidenbach, Andrew G.
Gentile, Juliana E.
Kuhn, Eric
O’Moore, Jill
Dooley, Patrick M.
Connors, Theresa R.
Mazur, Curt
Allen, Shona W.
Trombetta, Bianca A.
McManus, Alison
Moore, Matthew R.
Liu, Jiewu
Cabin, Deborah E.
Kordasiewicz, Holly B.
Mathews, Joel
Arnold, Steven E.
Vallabh, Sonia M.
Minikel, Eric Vallabh
author_sort Mortberg, Meredith A.
collection PubMed
description 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.
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spelling pubmed-89860792022-04-07 Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS Mortberg, Meredith A. Zhao, Hien T. Reidenbach, Andrew G. Gentile, Juliana E. Kuhn, Eric O’Moore, Jill Dooley, Patrick M. Connors, Theresa R. Mazur, Curt Allen, Shona W. Trombetta, Bianca A. McManus, Alison Moore, Matthew R. Liu, Jiewu Cabin, Deborah E. Kordasiewicz, Holly B. Mathews, Joel Arnold, Steven E. Vallabh, Sonia M. Minikel, Eric Vallabh JCI Insight Research Article 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. American Society for Clinical Investigation 2022-03-22 /pmc/articles/PMC8986079/ /pubmed/35133987 http://dx.doi.org/10.1172/jci.insight.156532 Text en © 2022 Mortberg et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Mortberg, Meredith A.
Zhao, Hien T.
Reidenbach, Andrew G.
Gentile, Juliana E.
Kuhn, Eric
O’Moore, Jill
Dooley, Patrick M.
Connors, Theresa R.
Mazur, Curt
Allen, Shona W.
Trombetta, Bianca A.
McManus, Alison
Moore, Matthew R.
Liu, Jiewu
Cabin, Deborah E.
Kordasiewicz, Holly B.
Mathews, Joel
Arnold, Steven E.
Vallabh, Sonia M.
Minikel, Eric Vallabh
Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title_full Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title_fullStr Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title_full_unstemmed Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title_short Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS
title_sort regional variability and genotypic and pharmacodynamic effects on prp concentration in the cns
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986079/
https://www.ncbi.nlm.nih.gov/pubmed/35133987
http://dx.doi.org/10.1172/jci.insight.156532
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