Mitigation of multi-organ delayed effects of acute radiation exposure (DEARE) with ACE2 agonist diminazene aceturate. - SUMMARY With the advent of hematopoietic growth factors for mitigation of acute radiation syndrome (ARS), victims of nuclear or radiological events will be more likely to survive ARS but also at greater risk for the development of a range of late multi-organ toxicities collectively referred to as the delayed effects of acute radiation exposure (DEARE). To date, there are no FDA-approved medical countermeasures (MCMs) for the treatment of DEARE. This application to RFA-AI-23-059 (Development of Candidate Radiation/Nuclear MCMs) proposes to address this unmet need and will focus on the unmet need for MCMs against two life-threatening subsyndromes of DEARE: radiation pneumonitis and nephropathy. Here, we propose to screen three candidate MCMs which target the non-canonical, alternative renin angiotensin system (RAS). As a counterbalance to the canonical RAS, the alternative RAS has broad tissue-protective function by promoting vasodilation, reducing inflammation, and reducing fibrosis. For these reasons, several recent and ongoing clinical trials are evaluating alternative RAS activators for the treatment of severe COVID-19. Data from our lab and others also supports the potential for alternative RAS activation in the treatment of radiation toxicities. Our laboratory has shown diminazene aceturate (DIZE) a small molecule agonist of the alternative RAS pathway promotes survival in rat models of ARS and DEARE. Important to this application, DIZE treatment also mitigated injury to the lung and kidney as evidenced by improved survival during the sub-syndromes of lung and kidney DEARE. Based on these data, we hypothesize the alternative RAS pathway can be targeted pharmacologically to mitigate radiation-induced multi-organ DEARE. Here, we propose a stepwise approach to targeting three key players in the alternative RAS pathway: angiotensin converting enzyme 2 (ACE2), Ang(1-7), and the Mas receptor (MasR). Each Aim of this application will target one of these players using the following lead candidate therapies: DIZE (ACE2 activator), TXA127 (synthetic Ang(1-7)), and BIO101 (MasR activator). We will evaluate the efficacy of the candidate MCMs in an established rat DEARE model which recapitulates the anticipated human sequelae of acute and delayed toxicities. For each candidate MCM, the primary outcome measure will be mitigation of all-cause mortality, which is the clinically relevant endpoint for FDA approval under the Animal Rule.
