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: 9239277
• 负责人: Galina Florova
• 金额: $ 36.46万
• 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: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239277
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Alteplase; Antibiotics; Autopsy; Biochemical; Biological Assay; Biological Markers; Childhood; Chronic; Clinical; Companions; Complication; DNA; Data; Deoxyribonucleases; Development; Diagnostic; Diagnostic tests; Dose; Drainage procedure; Drug Formulations; Drug resistance; Effectiveness; Empyema; FDA approved; Fever; Fibrin; Fibrinolysis; Formulation; Fostering; Fright; Future; Half-Life; Hemorrhage; Hospitalization; Human; Imaging Techniques; Imaging technology; Immunologics; Incidence; Injury; Intervention; Knowledge; Label; Laboratories; Liquid substance; Lung; Modeling; Molecular; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Oryctolagus cuniculus; Outcome; Pathogenesis; Patient Care; Patients; Phase; Physiological; Plasmin; Plasminogen; Plasminogen Activator Inhibitor 1; Pleural; Pleural effusion disorder; Pre-Clinical Model; Protocols documentation; Pulmonary function tests; Regimen; Regulation; Risk; Role; Safety; Sampling; Severities; Streptococcus pneumoniae; Structure; Techniques; Testing; Tetracyclines; Therapeutic; Thrombolytic Therapy; Tissues; Treatment Cost; Ultrasonography; United States; Video-Assisted Thoracic Surgery; Work; X-Ray Computed Tomography; age group; aged; clinical development; clinical imaging; companion diagnostics; comparative efficacy; cost; design; diagnostic assay; drug development; efficacy testing; extracellular; improved; improved outcome; innovation; mortality; multidisciplinary; novel; outcome prediction; pre-clinical; predicting response; prevent; synergism; targeted delivery; therapeutic target; therapy outcome

Summary Approximately 65,000 patients in the United States alone develop empyema (EMP) or complicated parapneumonic pleural effusions each year. The incidence of EMP is increasing worldwide. EMP is associated with serious morbidity, a mortality of about 20%, and annual patient care costs of roughly $500 million. Intrapleural fibrinolytic therapy (IPFT) has been used for over sixty years to expedite pleural drainage and prevent lung restriction, but its efficacy and safety profile, especially in adults, remains uncertain. Bleeding occurs in up to 15% of patients. Current IPFT protocols use empirically dosed, off-label interventions and reflect rudimentary knowledge about the regulation of IPFT in EMP and its pathogenesis. These gaps have slowed the development of more reliable and safer IPFT for patients with EMP or other forms of loculated pleural injury and form the scientific premise for our project. Our preliminary data validates active plasminogen activator inhibitor 1 (PAI-1) as a biomarker and therapeutic target for IPFT. We provide proof of concept and show that three mechanistically different forms of PAI-1 targeted IPFT effectively reverse tetracycline-induced pleural organization in rabbits. These interventions allow for up to an 8-fold reduction of the dose of fibrinolysin in IPFT, thereby mitigating bleeding risk. We designed a companion diagnostic test; the Fibrinolytic Potential Assay (FPA), to monitor outcomes of PAI-1-targeted or other forms of IPFT. Our hypothesis is that PAI-1 targeted IPFT can effectively clear intrapleural organization in EMP. We also posit that FPA can predict outcomes of PAI-1-targeted IPFT and ultimately be used to select the subjects most likely to benefit. To test this hypothesis, we developed and characterized a new S. pneumoniae rabbit EMP model which simulates key features of human EMP from an acute (96h) to an organized chronic (7-21 days) phase with multiloculation-like organization and significant pleural thickening. Our objective is to test the efficacy and safety of PAI-1 targeted IPFT in the S. pneumoniae EMP model and determine if the FPA predicts pleural injury outcomes. This hypotheses will be tested in four Specific Aims, which are to: 1. Improve the efficacy of IPFT in rabbit EMP using PAI-1 targeted delivery; 2. Determine the molecular mechanisms governing intrapleural fibrinolysis in EMP and the effects of high levels of extracellular DNA on PAI-1 targeted IPFT; 3. Select the single most effective form of PAI-1 targeted IPFT in EMP, develop and validate the companion FPA test using EMP fluids from the model and patients; and 4. Optimize the structure and co-formulation of a novel IPFT for EMP and evaluate its safety and efficacy. A range of state-of-the-art biochemical, physiologic, tissue analysis, and imaging techniques will be used to accomplish the work. Our unique multidisciplinary team includes leading experts in the fields of fibrinolysis, pleural injury, as well as drug formulation and development. This project addresses current unmet needs: the identification and preclinical vetting of new, potentially more effective and safer IPFT candidates and FPA diagnostics for EMP that are clinically tractable and that could ultimately improve clinical outcomes.

概括 仅在美国就有约 65,000 名患者出现脓胸 (EMP) 或 每年都会发生复杂的肺炎旁胸腔积液。 EMP 的发生率正在增加 全世界。 EMP 与严重的发病率相关，死亡率约为 20%，并且每年 患者护理费用约为 5 亿美元。已使用胸膜内纤溶疗法（IPFT） 六十多年来一直致力于加速胸腔引流和防止肺受限，但其功效和作用 安全性，尤其是成人的安全性，仍然不确定。高达 15% 的患者会出现出血。 目前的 IPFT 方案使用经验剂量、标签外干预措施，反映了基本的 IPFT在EMP中的调控及其发病机制的认识。这些差距已经放缓 为 EMP 或其他形式的患者开发更可靠、更安全的 IPFT 局限性胸膜损伤并构成我们项目的科学前提。我们的初步数据 验证活性纤溶酶原激活剂抑制剂 1 (PAI-1) 作为生物标志物和治疗靶点 对于IPFT。我们提供了概念证明，并表明三种机械上不同的形式 PAI-1靶向IPFT可有效逆转四环素诱导的兔胸膜组织。 这些干预措施可将 IPFT 中纤溶素的剂量减少多达 8 倍，从而 降低出血风险。我们设计了一个伴随诊断测试；纤溶潜能 检测 (FPA)，用于监测 PAI-1 靶向或其他形式 IPFT 的结果。我们的假设是 表明PAI-1靶向IPFT可以有效清除EMP中的胸膜内组织。我们还假设 FPA 可以预测 PAI-1 靶向 IPFT 的结果，并最终用于选择 最有可能受益的对象。为了检验这一假设，我们开发并表征了一种新的 肺炎链球菌兔 EMP 模型，模拟急性感染时人类 EMP 的主要特征 （96小时）到有组织的慢性（7-21天）阶段，具有多房样组织和 胸膜显着增厚。我们的目标是测试 PAI-1 靶向药物的有效性和安全性 肺炎链球菌 EMP 模型中的 IPFT 并确定 FPA 是否预测胸膜损伤 结果。该假设将在四个具体目标中进行检验，这些目标是： 1. 改进 使用 PAI-1 靶向递送的 IPFT 对兔 EMP 的功效； 2. 确定分子 EMP 中控制胸膜内纤维蛋白溶解的机制以及高水平的影响 PAI-1 靶向 IPFT 上的细胞外 DNA； 3. 选择单一最有效的 PAI-1 形式 EMP 中的目标 IPFT，使用来自 EMP 液体开发并验证配套的 FPA 测试 模型和患者； 4. 优化用于 EMP 的新型 IPFT 的结构和联合配方 并评估其安全性和有效性。一系列最先进的生化、生理、组织 将使用分析和成像技术来完成这项工作。我们独特的 多学科团队包括纤溶、胸膜损伤领域的领先专家 如药物配方和开发。该项目解决了当前未满足的需求： 识别和临床前审查新的、可能更有效和更安全的 IPFT 候选药物 和 FPA 诊断 EMP，临床上易于处理，最终可以改善 临床结果。