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National Institute of Environmental Health Sciences

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Publication Detail

Title: RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.

Authors: 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 Jr, Francis J; Giangrande, Paloma H

Published In Nat Commun, (2019 01 10)

Abstract: 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.

PubMed ID: 30631065 Exiting the NIEHS site

MeSH Terms: Animals; Aptamers, Nucleotide/genetics; Aptamers, Nucleotide/metabolism*; Aptamers, Nucleotide/pharmacology; Cell Line; Cell Survival/drug effects; Histones/antagonists & inhibitors; Histones/genetics; Histones/metabolism; Humans; Mice, Inbred BALB C; Multiple Organ Failure/genetics; Multiple Organ Failure/metabolism*; Multiple Organ Failure/prevention & control; Nuclear Proteins/genetics; Nuclear Proteins/metabolism*; Protein Binding; RNA/antagonists & inhibitors; RNA/genetics; RNA/metabolism*

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