Targeting Extracellular Histones with Novel RNA Bio-Drugs for the Treatment of Acute Lung Injury
Abstract
Extracellular histones have been proposed as a causative agent of acute lung injury (ALI). The goal of this proposal was to develop a therapeutic to neutralize (inactivate) circulating histones and prevent the multiple organ dysfunction/acute respiratory distress syndrome (MODS/ARDS) occurring with ALI. To accomplish this goal, we developed synthetic oligonucleotides(RNA aptamers) that bind to extracellular histones known to cause MODS/ARDS but do not bind to other serum proteins. Invitro studies showed that selected RNA aptamers protected from histone-mediate cytotoxicity, platelet aggregation, inflammatory activation, and calcium influx. In a murine model of histone-mediated ALI, aptamers attenuated pulmonary toxicity and improved survival. In a smoke inhalation model of ALI, RNA aptamer protected mice from alveolar barrier disruption, decreased cytokine activation, and neutrophil infiltration. RNA aptamer attenuated weight loss, barrier disruption and inflammation in the lungs in a murine model of H1N1 influenza. The RNA aptamers did not activate innate immunity and caused no abnormalities of general clinical chemistries, or of liver and kidney function.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1108199
Entities
People
- Francis J. Miller
Organizations
- Duke University