Development of ACE Inhibitor as Countermeasure for Radiation-Induced Lung Injury

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DESCRIPTION (provided by applicant): Our goals for this Project will be to develop countermeasures to effectively mitigate and treat radiation-induced pneumonitis and pulmonary fibrosis in rodents. Specifically we propose to accelerate development of FDA-approved Angiotensin Converting Enzyme inhibitors (ACEi), captopril, enalapril or fosinopril for safe and effective mitigation and treatment. Additionally we will test one selected ACEi in combination with either a free radical scavenger EUK-207 or an anti-inflammatory soluble epoxide hydrolase inhibitor (sEHi), 1471. We will use 2 relevant models of injury to test countermeasures: a single dose of 10 Gy total body irradiation (TBI) for pneumonitis; and >12 Gy localized thoracic irradiation for pulmonary fibrosis. The doses and models we propose simulate conditions that may be survivable with supportive care following exposure to a radiological or nuclear attack. Our product development milestones are to: 1) Identify a safe and effective ACEi with optimal duration of administration for mitigation and treatment of pneumonitis - timeline by 6-8 months from start; 2) Determine efficacy of agents EUK-207 or sEHi1471 in combination with the ACE inhibitor for mitigation and treatment of pneumonitis - timeline 6-12 months from start; 3) Determine the effect of ACEi on mitigation of radiation-induced fibrosis in the lung - 12 months from start; 4) Confirm the most effective mitigating regimen in juvenile animals and rats of both sexes - timeline 13-15 months from start; 5) Determine the dose modification factor (DMF) of the most effective mitigating regimen - timeline 13-15 months from start; and 6) Test the most effective mitigating regimen in a second rodent species, mice (in collaboration). Our aims are designed to satisfy the goal of this RFA to accelerate research and development of promising medical products, for mitigation and treatment of radiation-induced pulmonary injury.