RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 01 2019
10 01 2019
Historique:
received:
07
03
2018
accepted:
12
12
2018
entrez:
12
1
2019
pubmed:
12
1
2019
medline:
21
3
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30631065
doi: 10.1038/s41467-018-08030-y
pii: 10.1038/s41467-018-08030-y
pmc: PMC6328615
doi:
Substances chimiques
Aptamers, Nucleotide
0
Histones
0
Nuclear Proteins
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
116Subventions
Organisme : NIA NIH HHS
ID : R01 AG049784
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES005605
Pays : United States
Organisme : BLRD VA
ID : I01 BX001729
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007337
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121105
Pays : United States
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