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.
Highlights
The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality
Two parallel selections were performed using the in vitro systematic evolution of ligands by exponential enrichment (SELEX) protocol to isolate RNA aptamers (51 nucleotides in length) that selectively bind to human histones implicated in MODS (H3 and H4) (Fig. 1a)
To identify RNA sequences that bind to histones, but not to proteins in serum, we introduced a stringent negative selection step against bovine serum albumin (BSA) and human IgG (Fig. 1a; step 2)
Summary
The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS. Anti-histone treatments (e.g., histone neutralizing antibodies, activated protein C (APC), recombinant thrombomodulin and heparin) protect mice against secondary organ failure due to lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke and thrombosis[2,3,4,18,19]. Several other biologics that have demonstrated efficacy in animal models failed to provide therapeutic benefit in clinical trials (e.g., APC) and are associated with increased risk of bleeding (e.g., heparin and APC) or systemic toxicity (e.g., histone deacetylase inhibitors)[22,23].
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