Targeting Extracellular Histones with Novel RNA Bio drugs for the Treatment of Acute Lung Injury
Abstract
Extracellular histones have been proposed as the 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 morbidity and mortality associated with multiple organ dysfunction/acute respiratory distress syndrome (MODS/ARDS) occurring with ALI. To accomplish this goal, we developed novel bio-reagents (RNA aptamers) that bind to histones known to cause MODS/ARDS and ALI but do not bind to other serum proteins. The RNA aptamers were evaluated for their ability to inhibit histone-mediate 1. cytotoxicity, 2. platelet aggregation, 3. TLR activation and 4. calcium influx. In this report, we show that RNA aptamers protect from histone-mediated pulmonary cell toxicity and attenuate mortality and lung inflammation and tissue destruction in mice. Pulmonary delivery results in diffuse distribution and prolonged retention of aptamers in the lungs. Ongoing studies are evaluating the protective effects of aptamers in murine models of inhalation injury.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1095451
Entities
People
- Francis Miller
Organizations
- Duke University