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

Publication ,  Journal Article
Urak, KT; Blanco, GN; Shubham, S; Lin, L-H; Dassie, JP; Thiel, WH; Chen, Y; Sonkar, VK; Lei, B; Murthy, S; Gutierrez, WR; Wilson, ME ...
Published in: Nat Commun
January 10, 2019
Published version (DOI) Link to item

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.

Duke Scholars

Jonathan Andrew Stiber
Author Jonathan Andrew Stiber Medicine, Cardiology
Francis Joseph Miller Jr.
Author Francis Joseph Miller Jr. Medicine, Cardiology
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Published In

Nat Commun

DOI

10.1038/s41467-018-08030-y

EISSN

2041-1723

Publication Date

January 10, 2019

Volume

10

Issue

1

Start / End Page

116

Location

England

Related Subject Headings

  • RNA
  • Protein Binding
  • Nuclear Proteins
  • Multiple Organ Failure
  • Mice, Inbred BALB C
  • Humans
  • Histones
  • Cell Survival
  • Cell Line
  • Aptamers, Nucleotide
 

Citation

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Urak, K. T., Blanco, G. N., Shubham, S., Lin, L.-H., Dassie, J. P., Thiel, W. H., … Giangrande, P. H. (2019). RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome. Nat Commun, 10(1), 116. https://doi.org/10.1038/s41467-018-08030-y
Urak, Kevin T., Giselle N. Blanco, Shambhavi Shubham, Li-Hsien Lin, Justin P. Dassie, William H. Thiel, Yani Chen, et al. “RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.” Nat Commun 10, no. 1 (January 10, 2019): 116. https://doi.org/10.1038/s41467-018-08030-y.
Urak KT, Blanco GN, Shubham S, Lin L-H, Dassie JP, Thiel WH, et al. RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome. Nat Commun. 2019 Jan 10;10(1):116.
Urak, Kevin T., et al. “RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.” Nat Commun, vol. 10, no. 1, Jan. 2019, p. 116. Pubmed, doi:10.1038/s41467-018-08030-y.
Urak KT, Blanco GN, Shubham S, Lin L-H, Dassie JP, Thiel WH, Chen Y, Sonkar VK, Lei B, Murthy S, Gutierrez WR, Wilson ME, Stiber JA, Klesney-Tait J, Dayal S, Miller FJ, Giangrande PH. RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome. Nat Commun. 2019 Jan 10;10(1):116.

Published In

Nat Commun

DOI

10.1038/s41467-018-08030-y

EISSN

2041-1723

Publication Date

January 10, 2019

Volume

10

Issue

1

Start / End Page

116

Location

England

Related Subject Headings

  • RNA
  • Protein Binding
  • Nuclear Proteins
  • Multiple Organ Failure
  • Mice, Inbred BALB C
  • Humans
  • Histones
  • Cell Survival
  • Cell Line
  • Aptamers, Nucleotide