Mitochondrial DNA repair agents for acute lung injury

 描述(由申请人提供)：开发治疗急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的药物疗法的尝试因未实现预期而受到影响。这种失败--通常归因于ALI/ARDS的异质性病理生理学和药物作用的分子靶点的不确定性--加在一起，引发了人们对这些目前无法治疗的疾病未来药物开发努力的相当大的怀疑。在此背景下，Exceren的第一阶段项目是基于NIH支持的20年来的研究，该研究表明mtDNA作为一种独特的分子哨兵功能，控制细胞对氧化应激的反应。为了将这一概念扩展到临床应用，我们构建了将DNA修复酶定向到线粒体的融合蛋白，并在多种动物模型中发现，药物增强的mtDNA修复抑制和逆转了ALI。我们的融合蛋白临床引入计划--侧重于它们在肺移植中的初步应用--得到了第一阶段结果的坚定支持，并在概念上得到了两个相互关联的考虑：首先，在采购期间将融合蛋白注入供体肺将消除对受者治疗的要求，并减少临床研究的成本和时间。第二，也是最重要的是，肺移植的一个常见并发症-与肺缺血-再灌注损伤相关的原发移植物功能障碍(PGD)-类似于ALI/ARDS；融合蛋白抑制PGD将明确支持它们在此类氧化应激障碍中的应用。我们现在提出两个目标：(1)在猪肺移植和PGD模型中确定mt靶向DNA修复酶的安全性、配置和有效性；(2)在体外灌流的人肺中验证mt靶向DNA修复酶与已批准的肺保存方法的生物等效性、安全性和有效性。总而言之，这些研究将推动Extisen的mt靶向DNA修复酶作为肺移植设备或药物获得FDA的批准，预计它将增加可用于移植的肺的数量，并降低PGD的发生率和严重程度。这些研究还将为近期提交IND以在ALI/ARDS中进行测试做好准备。

 DESCRIPTION (provided by applicant): Attempts to develop drug treatments for acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have been marred by unfulfilled expectations. Such failures - often attributed to the heterogeneous pathophysiology of ALI/ARDS and uncertainty about molecular targets of drug action - have combined to fuel considerable skepticism about future drug development efforts for these currently untreatable disorders. Against this background, Exscien's Phase I project was based on two decades of NIH-supported research showing that mtDNA functions as a unique molecular sentinel controlling cytoxic response to oxidant stress. To extend this concept to the point of clinical application, we constructed fusion proteins directing DNA repair enzymes to mitochondria and found in multiple animal models that pharmacologic enhancement of mtDNA repair suppressed and reversed ALI. Our plan for clinical introduction of the fusion proteins - focusing on their inaugural use in lung transplant - is solidly supported by Phase I results and conceptually buttressed by two interrelated considerations: First, administration of the fusion proteins to donor lungs during procurement will eliminate the requirement for treatment of the recipient and reduce the cost and time for clinical studies. And second and most importantly, a common complication of lung transplant - primary graft dysfunction (PGD) related to lung ischemia-reperfusion injury - is similar to ALI/ARDS; suppression of PGD by the fusion proteins will unambiguously support their use in such oxidant stress disorders. We now propose two aims intended to: (1) Determine the safety, disposition, and efficacy of mt-targeted DNA repair enzyme in a porcine model of lung transplant and PGD; and (2)Verify in ex vivo perfused human lungs the bioequivalence, safety, and efficacy of the mt-targeted DNA repair enzyme in comparison to approved methods of lung preservation. Collectively, these studies will advance Exscien's mt-targeted DNA repair enzymes towards FDA clearance as a device or drug for use in lung transplant, where it is expected to increase the number of lungs available for transplant and reduce the incidence and severity of PGD. These studies also will position Exscien for a near- term submission of IND to pursue testing in ALI /ARDS.