RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome

Kevin T. Urak, Giselle N. Blanco, Shambhavi Shubham, Li-Hsien Lin, Justin P. Dassie, William H. Thiel, Yani Chen, Vijay Kumar Sonkar, Beilei Lei, Shubha Murthy, Wade R. Gutierrez, Mary E. Wilson, Jonathan A. Stiber, Julia Klesney-Tait, Sanjana Dayal, Francis J. Miller () and Paloma H. Giangrande ()
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Kevin T. Urak: University of Iowa
Giselle N. Blanco: University of Iowa
Shambhavi Shubham: University of Iowa
Li-Hsien Lin: University of Iowa
Justin P. Dassie: University of Iowa
William H. Thiel: University of Iowa
Yani Chen: University of Iowa
Vijay Kumar Sonkar: University of Iowa
Beilei Lei: Duke University
Shubha Murthy: University of Iowa
Wade R. Gutierrez: University of Iowa
Mary E. Wilson: University of Iowa
Jonathan A. Stiber: Duke University
Julia Klesney-Tait: University of Iowa
Sanjana Dayal: University of Iowa
Francis J. Miller: Duke University
Paloma H. Giangrande: University of Iowa

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08030-y

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