Targeting Extracellular Histones with Novel RNA Bio drugs for the Treatment of Acute Lung Injury
Technical Report,15 Sep 2017,14 Sep 2018
Duke University Durham United States
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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 dysfunctionacute respiratory distress syndrome MODSARDS occurring with ALI. To accomplish this goal, we developed novel bio-reagents RNA aptamers that bind to histones known to cause MODSARDS 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.
- Medicine and Medical Research