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RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome
The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circul...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328615/ https://www.ncbi.nlm.nih.gov/pubmed/30631065 http://dx.doi.org/10.1038/s41467-018-08030-y |
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author | Urak, Kevin T. Blanco, Giselle N. Shubham, Shambhavi Lin, Li-Hsien Dassie, Justin P. Thiel, William H. Chen, Yani Sonkar, Vijay Kumar Lei, Beilei Murthy, Shubha Gutierrez, Wade R. Wilson, Mary E. Stiber, Jonathan A. Klesney-Tait, Julia Dayal, Sanjana Miller, Francis J. Giangrande, Paloma H. |
author_facet | Urak, Kevin T. Blanco, Giselle N. Shubham, Shambhavi Lin, Li-Hsien Dassie, Justin P. Thiel, William H. Chen, Yani Sonkar, Vijay Kumar Lei, Beilei Murthy, Shubha Gutierrez, Wade R. Wilson, Mary E. Stiber, Jonathan A. Klesney-Tait, Julia Dayal, Sanjana Miller, Francis J. Giangrande, Paloma H. |
author_sort | Urak, Kevin T. |
collection | PubMed |
description | The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe a therapeutic strategy for MODS based on the neutralization of histones by chemically stabilized nucleic acid bio-drugs (aptamers). Systematic evolution of ligands by exponential enrichment technology identified aptamers that selectively bind those histones responsible for MODS and do not bind to serum proteins. We demonstrate the efficacy of histone-specific aptamers in human cells and in a murine model of MODS. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS. |
format | Online Article Text |
id | pubmed-6328615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63286152019-01-15 RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome Urak, Kevin T. Blanco, Giselle N. Shubham, Shambhavi Lin, Li-Hsien Dassie, Justin P. Thiel, William H. Chen, Yani Sonkar, Vijay Kumar Lei, Beilei Murthy, Shubha Gutierrez, Wade R. Wilson, Mary E. Stiber, Jonathan A. Klesney-Tait, Julia Dayal, Sanjana Miller, Francis J. Giangrande, Paloma H. Nat Commun Article The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe a therapeutic strategy for MODS based on the neutralization of histones by chemically stabilized nucleic acid bio-drugs (aptamers). Systematic evolution of ligands by exponential enrichment technology identified aptamers that selectively bind those histones responsible for MODS and do not bind to serum proteins. We demonstrate the efficacy of histone-specific aptamers in human cells and in a murine model of MODS. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS. Nature Publishing Group UK 2019-01-10 /pmc/articles/PMC6328615/ /pubmed/30631065 http://dx.doi.org/10.1038/s41467-018-08030-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Urak, Kevin T. Blanco, Giselle N. Shubham, Shambhavi Lin, Li-Hsien Dassie, Justin P. Thiel, William H. Chen, Yani Sonkar, Vijay Kumar Lei, Beilei Murthy, Shubha Gutierrez, Wade R. Wilson, Mary E. Stiber, Jonathan A. Klesney-Tait, Julia Dayal, Sanjana Miller, Francis J. Giangrande, Paloma H. RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title | RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title_full | RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title_fullStr | RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title_full_unstemmed | RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title_short | RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
title_sort | rna inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328615/ https://www.ncbi.nlm.nih.gov/pubmed/30631065 http://dx.doi.org/10.1038/s41467-018-08030-y |
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