Identification of Therapeutics for the Treatment of Sulfur Mustard Injury (U54)

Lovelace Biomedical & Environmental Research Institute, Albuquerque NM

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Abstract

[unreadable] Description (provided by applicant): The Center for Countermeasures Against Chemical Threat (CounterACT) at the Lovelace Biomedical Research Institute (LBERI-CC), a subsidiary of Lovelace Respiratory Research Institute, will focus on injury caused by the chemical agent, Sulfur Mustard (SM). For years now, analysts in the CIA, DOD and the Congressional Research Service (CRS) have ranked SM as the highest probability agent to be used in a chemical attack. The basis for this ranking is the overall ease of procurement of SM, its widespread public health impact, the lack of any current medical intervention, and the ease of dispersal of SM in either small-scale or larger-scale attacks. The LBERI-CC proposes to create a comprehensive program for the development of countermeasures to prevent and treat SM injury in the three most affected organs: the lungs, the skin and the eyes. To achieve this, the LBERI-CC center will first establish and validate animal models of SM aerosol/vapor exposure using mice, rats, hairless guinea pigs and rabbits as models for respiratory tract, dermal and ocular toxicity, respectively. The LBERI-CC has identified 2-4 existing therapeutics likely to be successful in treating SM-induced lesions based on their effectiveness in published reports and other preliminary data. One of these, ilomastat is the only drug to our knowledge that has been shown to prevent SM injury when administered after SM exposure an essential requirement for any SM therapeutic for civilians. These initial studies will focus on early efficacy evaluations against SM-induced lesions in the three animal models. Alternative formulations and routes of administration will be explored to enhance efficacy. Basic research will be conducted to identify additional likely therapeutics, based on the determined mechanisms of SM-induce injury. The LBERI-CC will be composed of 5 Projects, 3 scientific cores (exposure, chemistry, and pathology), and Administrative and Educational and Training cores. Project 1 will focus on identification of diagnostic markers and development of reliable simple tests for these markers. Projects 2-4 will focus on the molecular and cellular mechanisms of SM injury and pathology in the lung, eye and skin, in order to identify additional countermeasure therapeutics, to be evaluated in Project 5. Project 5 will establish and validate animal models and test and improve therapeutics for all target organs The Education and Training Core will provide educational opportunities for LBERI and outside scientists and create a Specimen Bank from SM exposed animals. This Center will identify efficacious Countermeasures and dose routes for the treatment of SM induced lesions for Investigative New Drug development.