Delivery of PAI-1-targeted intrapleural fibrinolytic therapy for empyema

PAI-1靶向胸腔内纤溶治疗脓胸

• 批准号: 10211268
• 负责人: Galina Florova
• 金额: $ 54.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211268
• 关键词: Acute; Address; Adult; Animals; Antibiotics; Bacterial Infections; Binding; Biochemical; Biological Assay; Biotechnology; Clinical; Clinical Research; Clinical Trials; Complication; Development; Diagnostic tests; Disease; Docking; Dose; Drainage procedure; Elderly; Empyema; FDA approved; Failure; Fibrin; Fibrinolysis; Gender; Hemorrhage; Human; Incidence; Injections; Injury; Legal patent; Liquid substance; Lung; Medicine; Meta-Analysis; Modeling; Molecular; Molecular Target; Monitor; Monoclonal Antibodies; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Patients; Peptides; Phage Display; Phase; Phase II Clinical Trials; Plasma; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Pleural; Pleural effusion disorder; Pneumonia; Positioning Attribute; Prior Therapy; Probability; Reagent; Research; Resistance; Resolution; Risk; Sampling; Schedule; Site; Solid; Streptococcus pneumoniae; Technical Expertise; Techniques; Technology; Testing; Therapeutic; Thoracentesis; Thrombolytic Therapy; Time; Translational Research; Translations; Treatment outcome; Ultrasonography; Uncertainty; Video-Assisted Thoracic Surgery; Work; aged; base; chest computed tomography; clinical decision-making; comorbidity; companion diagnostics; diagnostic assay; effective therapy; efficacy testing; effusion; improved; improved outcome; innovation; mortality; novel; novel diagnostics; outcome prediction; personalized approach; personalized medicine; prospective; research clinical testing; response; success; therapy development; therapy outcome; treatment optimization; treatment strategy

Empyema is a bacterial infection of the pleural space, a serious complication of pneumonia that carries a mortality rate of up to 20%, the incidence of which continues to increase worldwide. Intrapleural fibrinolytic therapy (IPFT) involving the delivery of plasminogen activators has been used to expedite drainage of loculated pleural effusions, including empyema. Using a new model of Streptococcus pneumoniae-induced empyema in rabbits we developed a single-dose IPFT with a plasminogen activator inhibitor 1 (PAI-1)-targeted adjunct, which is 8-fold more effective than PA alone for treatment acute empyema. We also validated the ability of our Fibrinolytic Potential Assay (FPA) to predict the success of IPFT in patients with empyema. Interestingly, the efficacy of IPFT in our model of advanced-stage empyema is decreased by 40-50%, similar to what has been observed in patients. This is, in part, due to a significant decrease in the rate of intrapleural fibrinolysis. To mitigate the risk of bleeding complications associated with an increase in the dose of PA, we propose multiple injections of low-dose PAI-1-targeted IPFT to treat advanced-stage empyema. Our objective is to identify effective PAI-1-targeted IPFT for advanced-stage empyema. Our hypothesis is that successful IPFT in advanced-stage empyema requires fibrinolytic activity sustained over a longer period of time and neutralization of PAI-1. The hypothesis will be tested in four Specific Aims: 1. Maximize the efficacy of IPFT in advanced- stage empyema in rabbits by targeting both the slow rate of fibrinolysis and PAI-1, 2. Develop novel PAI-1 targeting peptides to optimize IPFT in advanced-stage empyema, 3. Determine the mechanisms that result in increased resistance to IPFT in advanced-stage empyema, and 4. Using the Fibrinolytic Potential Assay to identify candidates for IPFT prior to treatment. We will select a dosing schedule and use two validated PAI-1 targeting adjuncts (monoclonal antibodies (mAbs), and a docking site peptide) to decrease the dose of PA, test these mechanisms for additivity in PAI-1 targeting to maximize efficacy, and test the efficacy of PAI-1 targeting peptides selected using phage display technology. We will use the FPA to analyze samples from Phase 2 Clinical Trial “A Study to Evaluate LTI-01 in Patients with Infected, Non-draining Pleural Effusions” (ClinicalTrials.gov; NCT04159831). We will use state of the art biochemical techniques to analyze pleural fluid and plasma from human patients and our unique model of empyema to investigate the molecular interactions of fibrinolysis of advanced-stage empyema. Our team has the biochemical, pulmonary and technical expertise to successfully accomplish the proposed work. The project addresses key gaps in our current understanding of the pathogenesis of pleural organization, optimization of IPFT and development of a new diagnostic approach to predict outcomes of IPFT. This project is positioned to shift the paradigm of treatments available for patients with extensive pleural loculation, failed drainage, and advanced-stage empyema.

脓胸是胸膜腔的细菌感染，是肺炎的一种严重并发症。 死亡率高达20%，其发病率在世界范围内持续增加。 治疗（IPFT）纤溶酶原激活剂的递送已被用于加速涉及闭锁的引流 使用肺炎链球菌引起的脓胸的新模型。 我们开发了一种带有纤溶酶原激活剂抑制剂 1 (PAI-1) 靶向辅助剂的单剂量 IPFT， 治疗急性脓胸的效果比单独使用 PA 有效 8 倍。我们还验证了我们的能力。 纤溶电位测定 (FPA) 可预测脓胸患者 IPFT 的成功。 在我们的晚期脓胸模型中，IPFT 的疗效下降了 40-50%，与之前的结果相似 在患者中观察到，这部分是由于胸膜内纤维蛋白溶解率显着降低。 为了减轻与增加 PA 剂量相关的出血并发症的风险，我们建议采取多种措施 注射低剂量 PAI-1 靶向 IPFT 来治疗晚期脓胸。 有效的 PAI-1 靶向 IPFT 治疗晚期脓胸我们的假设是 IPFT 能够成功治疗晚期脓胸。 晚期脓胸需要较长时间持续的纤溶活性和中和作用 PAI-1 的假设将在四个具体目标中得到检验： 1. 最大化 IPFT 在高级领域的功效。 通过针对纤溶速度缓慢和 PAI-1 来治疗兔子脓胸，2. 开发新型 PAI-1 靶向肽以优化晚期脓胸的 IPFT，3. 确定导致的机制 晚期脓胸对 IPFT 的抵抗力增加，以及 4. 使用纤溶电位测定法 在治疗前确定 IPFT 候选者，我们将选择给药方案并使用两种经过验证的 PAI-1。 靶向辅助剂（单克隆抗体 (mAb) 和对接位点肽）以减少 PA 剂量，测试 这些 PAI-1 靶向加和性机制可最大限度地提高功效，并测试 PAI-1 靶向的功效 使用噬菌体展示技术选择的肽我们将使用 FPA 分析来自 2 期临床的样品。 试验“一项评估 LTI-01 在感染、不引流性胸腔积液患者中的研究”（ClinicalTrials.gov； NCT04159831）。我们将使用最先进的生化技术来分析胸水和血浆。 人类患者和我们独特的脓胸模型来研究纤维蛋白溶解的分子相互作用 我们的团队拥有成功治疗晚期脓胸的生化、肺部和技术专业知识。 该项目解决了我们目前对发病机制理解的关键差距。 胸膜组织的优化、IPFT 的优化以及预测结果的新诊断方法的开发 该项目旨在改变广泛性胸膜炎患者的治疗模式。 脓胸、引流失败和晚期脓胸。