Targeting Extracellular Histones with Novel RNA Biodrugs for the Treatment of Acute Lung Injury
Abstract
The studies outlined in this proposal the Fiscal Year 2015 Peer Review Medical Research Program Acute Lung Injury Topic Area. A challenging medical problem often observed in critically ill patients is that following a severe injury or illness, even those organs not directly affected by the original problem subsequently become dysfunctional. For example, patients with major trauma can survive the initial damage of the injury but soon afterwards will develop problems with their breathing, requiring a ventilator; the kidneys will stop working, requiring dialysis; the liver will not function normally; and they will bleed from every orifice. This condition, known as multiple organ dysfunction syndrome (MODS) may be reversible, but there is no treatment to prevent it from happening and of those that develop MODS, the risk of death is 40%. The most common organ involved in MODS is the lungs (referred to as acute respiratory distress syndrome or ARDS), resulting in acute lung injury (ALI). Trauma (blast and explosive) has obvious relevance to the military; however, other equally relevant causes of MODS/ARDS and ALI include smoke/chlorine gas inhalation, burns, radiation, influenza, and severe infection. Only recently have investigators recognized that each of these various injury conditions are caused by the damaged tissues releasing histones into the circulation. Histones normally reside in the nucleus and partner with the DNA, but when extracellular, researchers have found that histones have toxic effects to the lungs and other organs. For example, when injected, a high dose of histones kill mice within a few minutes, whereas lower doses kill mice within a few hours. The goal of this proposal is to develop a therapeutic to neutralize (inactivate) circulating histones and prevent the morbidity and mortality associated with MODS/ARDS and ALI that can be easily delivered in combat and field situations. To accomplish this goal, novel bioreagents (RNA aptamers) bind to those histones known to cause MODS/ARDS and ALI but not bind to other circulating proteins or cells will be tested in human cultured cells and then in mice for their ability to prevent histone-mediated toxicity and ALI. Since histones are highly conserved across species from yeast to humans, the bioreagents developed and validated in this proposal can be immediately tested in preclinical animal models and human clinical trials. Furthermore, as a drug to prevent the development of MODS/ARDS and ALI in high-risk patients, these bioreagents have significant advantages as compared to other possible therapeutics because they are very stable and not as susceptible to fluctuations in temperature, do not require special handling conditions, do not cause allergic responses, and will be easy to deliver. Once this study identifies and validates bioreagents that target histones, future studies will test their protective effect in other lung injury models, radiation, sepsis, and blast wave injury. Future studies will also evaluate the possibility of aerosolizing the histone-targeting bioreagents to facilitate respiratory delivery via inhalers. In addition to having relevance to military situations, the therapeutics derived from this application would have wide benefit to the general population in reducing morbidity and mortality associated with MODS/ARDS and ALI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610179
Entities
People
- Jr. Francis Miller
Organizations
- Duke University
- United States Army