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.

脓胸是胸膜空间的细菌感染，肺炎的严重并发症，带有A 死亡率高达20％，该事件在全球范围内继续增加。胸腔内纤维蛋白水解 涉及纤溶酶原激活剂递送的治疗（IPFT）已用于加快位置的排水 胸腔积液，包括脓肿。使用新的肺​​炎链球菌诱导的脓肿的模型 兔子我们开发了一种用纤溶酶原激活剂抑制剂1（PAI-1）靶向辅助的单剂量IPFT，该剂量 对于治疗急性毛细血管，比单独使用PA高出8倍。我们还验证了我们的能力 纤维蛋白水解潜力测定（FPA）预测脓肿患者IPFT的成功。有趣的是， IPFT在我们的高级脓肿模型中的功效降低了40-50％，类似于已经 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。到 减轻与PA剂量增加有关的出血并发症的风险，我们提出多个 注射低剂量PAI-1靶向IPFT以治疗晚期脓肿。我们的目标是确定 有效的PAI-1靶向IPFT，用于高级脓肿。我们的假设是成功的IPFT 晚期富裕症需要较长的时间和神经化的纤维蛋白水解活性 pai-1。该假设将以四个具体目的进行检验：1。最大化IPFT的效率 通过靶向纤维蛋白溶解的缓慢速率和PAI-1，2。 靶向肽以优化高级脓肿中的IPFT，3。确定导致导致的机制 在晚期富有肌瘤中对IPFT的阻力增加，4。 治疗前确定IPFT的候选人。我们将选择一个给药时间表，并使用两个经过验证的PAI-1 靶向辅助（单克隆抗体（mAb）和对接位点肽）以减少PA的剂量，测试 这些在PAI-1靶向中提高效率并测试PAI-1靶向效率的机制 使用噬菌体显示技术选择的肽。我们将使用FPA分析2阶段临床的样品 试验“一项评估受感染的，非胸腔积液患者的LTI-01的研究”（ClinicalTrials.gov； NCT04159831）。我们将使用最先进的生化技术来分析胸膜流体和血浆 人类患者和我们独特的富裕模型，以研究纤维蛋白溶解的分子相互作用 高级脓肿。我们的团队具有生化，肺和技术专业知识 完成拟议的工作。该项目解决了我们当前对发病机理的关键差距 胸膜组织，IPFT的优化以及一种新的诊断方法的开发来预测结果 IPFT。该项目的定位可以改变可用于广泛胸膜的患者可用的治疗范例 位置，排水失败和高级脓肿。