Targeting Extracellular Histones with Novel RNA Bio-drugs for the Treatment of Acute Lung Injury
Abstract
Extracellular histones are proposed as a causative agent of acute lung injury (ALI). The goal of this proposal is 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. Our in vitro 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. Ongoing studies are evaluating the efficacy of the RNA aptamer in a murine model of H1N1 influenza. Safety data are underway to test if the RNA aptamers activate innate immunity or cause abnormalities of general organ function. A six month no cost extension has been requested to allow for completion of studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1108200
Entities
People
- Francis J. Miller
Organizations
- Duke University