Mitochondrial DNA repair agents for acute lung injury
Principal Investigator: Mark N Gillespie
Abstract: DESCRIPTION (provided by applicant): Drug development for acute lung injury (ALI) has been marred by unfulfilled expectations. Perhaps best illustrating this unsatisfactory situation is the history of therapeutic strategies directed at inhibition of reactive oxygen species (ROS). While decades of laboratory and clinical studies make it clear that ROS are pathogenically important across the entire spectrum of ALI/ARDS, beneficial effects of anti-oxidants in clinical trials have been unimpressive. These negative outcomes may be attributed in part to the heterogeneous nature and onset of ALI/ARDS which tends to obfuscate design and interpretation of clinical trials, and partly to the scientific uncertainty about molecular targetsof anti-oxidant drug action. Currently available strategies may not target the key sentinel molecule(s) integrating cellular effects of ROS. Multiple lines of evidence support the idea that mtDNA serves as a molecular sentinel controlling cell fate in response to oxidant stress. Indeed, genetic modulation of the first and rate-limiting step in mtDNA repair - mediated by Ogg1, a DNA glycosylase excises oxidatively damaged bases - coordinately regulates ROS-induced mtDNA damage and cell death in all cultured cell populations so far studied. Based on these provocative findings, the small business concern, Exscien, and its university investigators devised and patented novel fusion protein constructs targeting DNA repair glycosylases to mitochondria and demonstrated in clinically-relevant rodent models that the new agents exert no off-target effects, prevent oxidative mtDNA damage, and suppress lung injury and mortality. We now propose to verify the efficacy of mt-targeted DNA repair "drugs" in ALI of a specific etiology - Ischemia-Reperfusion (IR) injury in the setting of lung transplant. The significance of this Phase I proposal lies in its focus on transplant-related lung IR injury which should reduce the time and expense required for commercialization. This application is innovative because the proposed experiment will herald first-in-class, platform molecules directed against a novel pharmacologic target in ALI - mtDNA - and many other disorders wherein oxidant stress plays a pathogenic role. PUBLIC HEALTH RELEVANCE: There are currently no pharmacotherapeutic interventions to treat ALI. In a related context, while reactive oxygen species play a role in these disorders, non-selective anti-oxidants have proven ineffective. Herein we will test a new concept - that repair of oxidative mtDNA damage directs cell fate decisions in ALI - which, if valid, will point to an entirely new pharmacologic strategy for treating ALI and related disorders.
Funding Period: 2012-07-15 - 2014-07-14
more information: NIH RePORT