Mitochondrial DNA repair agents for acute lung injury

描述（由申请人提供）：急性肺损伤（ALI）的药物开发因未实现的预期而受到损害。也许最能说明这种不令人满意的情况的是 针对活性氧（ROS）抑制的治疗策略的历史。虽然数十年的实验室和临床研究清楚地表明，ROS在整个ALI/ARDS谱中具有重要的致病性，但抗氧化剂在临床试验中的有益作用并不令人印象深刻。这些负面结果可能部分归因于ALI/ARDS的异质性和发病，这往往会混淆临床试验的设计和解释，部分归因于抗氧化药物作用的分子靶点的科学不确定性。目前可用的策略可能不靶向整合ROS的细胞效应的关键哨兵分子。 多种证据支持线粒体DNA作为一个分子哨兵控制细胞命运的氧化应激反应的想法。事实上，mtDNA修复的第一步和限速步骤的遗传调节-由Ogg 1介导，DNA糖基化酶切除氧化损伤的碱基-协调调节ROS诱导的mtDNA损伤和细胞死亡，在所有培养的细胞群体中，迄今为止研究。基于这些挑衅性的发现，小企业关注，Exscien及其大学研究人员设计并申请了新型融合蛋白结构的专利，靶向线粒体的DNA修复糖基化酶，并在临床相关的啮齿动物模型中证明了新药物不会产生脱靶效应，防止氧化性mtDNA损伤，并抑制肺损伤和死亡率。我们现在建议验证线粒体靶向DNA修复“药物”在特定病因-肺移植中的缺血再灌注（IR）损伤的ALI中的疗效。该I期提案的重要性在于其关注移植相关的肺IR损伤，这将减少商业化所需的时间和费用。这种应用是创新的，因为所提出的实验将预示着一流的平台分子针对一个新的药理学靶点在急性肺损伤- mtDNA -和许多其他疾病，其中氧化应激发挥致病作用。 公共卫生相关性：目前尚无药物干预治疗ALI。在相关的背景下，虽然活性氧在这些疾病中发挥作用，但非选择性抗氧化剂已被证明无效。在此，我们将测试一个新概念--修复 氧化性mtDNA损伤指导ALI中的细胞命运决定-如果有效，将指出治疗ALI和相关疾病的全新药理学策略。

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.