Mitochondrial DNA repair agents for acute lung injury

线粒体DNA修复剂治疗急性肺损伤

• 批准号: 9111928
• 负责人: MARK N GILLESPIE
• 金额: $ 153.84万
• 依托单位: EXSCIEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111928
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Animal Model; Antioxidants; Biodistribution; Biological Preservation; Cell Survival; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Consult; Cryopreservation; DNA Repair; DNA Repair Enzymes; DNA Repair Gene; Development; Development Plans; Devices; Disease; Drug Targeting; Drug effect disorder; Drug usage; Employee Strikes; Failure; Family suidae; Functional disorder; Future; Goals; Human; Incidence; Infection; Intervention; Laboratories; Lung; Lung Inflammation; Lung Transplantation; Methods; Mitochondria; Mitochondrial DNA; Modeling; Molecular; New Agents; Organ; Outcome; Oxidants; Pathogenicity; Perfusion; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Pneumonia; Positioning Attribute; Procedures; Proteins; Pseudomonas aeruginosa; Rat Protein; Rattus; Reactive Oxygen Species; Reperfusion Injury; Research Personnel; Research Support; Respiratory physiology; Role; S Phase; Safety; Sentinel; Severities; Small Business Innovation Research Grant; Solid; Structure of parenchyma of lung; System; Testing; Therapeutic; Therapeutic Equivalency; Time; Transplantation; Transplanted Lung Complication; Uncertainty; United States National Institutes of Health; base; clinical application; clinical practice; cost; drug development; expectation; experimental study; improved; innovation; intravenous administration; lung ischemia; lung preservation; mitochondrial genome; molecular drug target; mortality; novel; oxidant stress; preclinical study; public health relevance; repair enzyme; repaired; research clinical testing; response; stress disorder; success; transplantation medicine; trend

 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.

 描述（由申请人提供）：开发急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）药物治疗的尝试因未实现的期望而受到损害。这些失败-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-结合起来，对这些目前无法治疗的疾病的未来药物开发工作产生了相当大的怀疑。在此背景下，Exscien的I期项目基于NIH支持的20年研究，该研究表明mtDNA作为一种独特的分子哨兵控制氧化应激的细胞毒性反应。为了将这一概念扩展到临床应用，我们构建了将DNA修复酶导向线粒体的融合蛋白，并在多种动物模型中发现，药物增强mtDNA修复抑制和逆转了ALI。我们的融合蛋白的临床引入计划-专注于其在肺移植中的首次使用-得到I期结果的坚实支持，并且在概念上得到两个相互关联的考虑的支持：首先，在采购期间向供体肺施用融合蛋白将消除对受体治疗的要求，并减少临床研究的成本和时间。其次，最重要的是，肺移植的常见并发症-与肺缺血-再灌注损伤相关的原发性移植物功能障碍（PGD）-与ALI/ARDS相似;融合蛋白对PGD的抑制将明确支持其在此类氧化应激障碍中的应用。我们现在提出了两个目标，旨在：（1）确定线粒体靶向DNA修复酶在肺移植和PGD猪模型中的安全性、处置和有效性;（2）在离体灌注的人肺中验证线粒体靶向DNA修复酶与已批准的肺保存方法相比的生物等效性、安全性和有效性。总的来说，这些研究将推动Exscien的线粒体靶向DNA修复酶作为用于肺移植的设备或药物获得FDA批准，预计将增加可用于移植的肺数量并降低PGD的发生率和严重程度。这些研究还将使Exscien能够在近期提交IND，以进行ALI /ARDS的测试。