Mitochondrial DNA repair agents for acute lung injury

描述(由申请人提供)：治疗急性肺损伤(ALI)的药物开发一直受到未能实现的期望的影响。也许最能说明这种不令人满意的情况的是 针对抑制活性氧物种(ROS)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ALI/ARDS的整个谱系中具有重要的致病作用，但抗氧化剂在临床试验中的有益效果并不令人印象深刻。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，部分原因是关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针对整合ROS细胞效应的关键哨兵分子(S)。许多证据支持线粒体DNA作为分子哨兵在氧化应激反应中控制细胞命运的观点。事实上，线粒体DNA修复的第一步也是限速步骤的基因调控--由Ogg1介导，DNA糖基酶去除氧化损伤的碱基--协调调节ROS诱导的线粒体DNA损伤和细胞死亡。基于这些具有挑衅性的发现，小型企业Exceren及其大学研究人员设计并申请了针对线粒体DNA修复糖基酶的新型融合蛋白结构，并在临床相关的啮齿动物模型中证明了新药物没有靶点外效应，防止氧化mtDNA损伤，并抑制肺损伤和死亡率。我们现在建议验证mt靶向DNA修复药物对肺移植中一种特定病因--缺血再灌注(IR)损伤的ALI的疗效。这一第一阶段提案的意义在于它侧重于移植相关的肺IR损伤，这应该会减少商业化所需的时间和费用。这一应用是创新的，因为拟议的实验将预示着一流的平台分子针对ALI中的一个新的药理靶点-mtDNA-以及许多其他疾病，在这些疾病中，氧化应激起致病作用。 公共卫生相关性：目前还没有治疗ALI的药物治疗干预措施。在一个相关的背景下，虽然活性氧物种在这些紊乱中发挥了作用，但非选择性抗氧化剂已被证明无效。在这里，我们将测试一个新概念--修复 氧化mtDNA损伤决定了ALI的细胞命运--如果有效，这将为治疗ALI和相关疾病指出一种全新的药理学策略。

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.