PAI-1 Targeted Intrapleural Fibronolytic Therapy

PAI-1靶向胸膜内纤溶治疗

• 批准号: 8073711
• 负责人: Steven Idell
• 金额: $ 44.33万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073711
• 关键词: Address; Alteplase; Biological Availability; Cicatrix; Clinical; Clinical Trials; Collection; Data; Deposition; Development; Disease; Docking; Dose; Drainage procedure; Empyema; Enzyme Precursors; Europe; Fibrin; Funding; Goals; Human; Injury; Intervention; Liquid substance; Lung; Medical; Mesothelial Cell; Modeling; Molecular Conformation; Molecular Target; Monoclonal Antibodies; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Plasma; Plasmin; Plasminogen Activator Inhibitor 1; Pleural; Pre-Clinical Model; Production; Publishing; Refractory; Research Personnel; Safety; Serpins; Testing; Tetracyclines; Therapeutic; Therapeutic Clinical Trial; Thrombolytic Therapy; Tissues; Toxicology; Treatment Efficacy; Treatment outcome; United States National Institutes of Health; Urokinase; Work; efficacy testing; effusion; improved; in vivo; innovation; meetings; multidisciplinary; novel; novel strategies; response; therapeutic target; treatment strategy; urokinase inhibitor

DESCRIPTION (provided by applicant): Pleural drainage is required for complicated parapneumonic effusions and empyema in up to 40,000 US patients annually. Intrapleural fibrinolytic therapy (IPFT), which enhances clearance of pleural loculation to augment pleural drainage, remains a therapeutic option that obviates the need for surgical drainage. However, current IPFT is limited by variable efficacy, uncertain dosing and safety concerns that are underscored by ttie disparate results of recent clinical trials. These are important clinical problems that mandate the search for better IPFT. Plasminogen activator inhibitor-1 (PAI-1) is strongly implicated in the pathogenesis of pleural loculation and inhibits tissue and urokinase plasminogen activators; tPA and uPA, which are currently used for IPFT. Our hypothesis that intrapleural neutralization of PAI-1 will further improve IPFT is strongly supported by published work and preliminary data. Our objective is to improve outcomes of treatment for organizing pleural injury using novel PAI-1-targeted interventions. The Specific Aims are: 1) To determine if molecules that compete with fibrinolysins for PAI-1 enhance the ability of fibrinolysins (tPA or single chain urokinase) to clear pleural loculations. 2) To detennine if mAbs that potentiate inactivation of PAI-1 via latency or substrate pathway redirection increase the therapeutic potential of fibrinolysins. 3) To test the ability of PAI-1 targeted interventions to potentiate profibrinolytic responses of human and rabbit primary mesothelial cells and in human pleural fluids. We will also test the efficacy of PAI-1 targeted interventions in rabbit models of empyema and tetracycline- induced pleural injury enhanced with adenoviral delivery of human PAI-1. Our approach is innovative as intrapleural targeting of PAI-1 has never before been evaluated. We will meet milestones that can be accomplished by our multidisciplinary team within the two year funding period. At the end of this project, we will identify a prime interventional PAI-1 -targeted candidate and one or two backups. We will develop the most effective novel PAI-1- targeted therapeutics in CADET II for clinical trial testing. This project addresses a key gap in medical practice and could advance the field of IPFT through identification of more reliable, more effective and potentially safer treatment strategies for patients with pleural loculation. RELEVANCE (See instructionsV Intrapleural fibrinolytic therapy (IPFT) is often used as a less invasive alternative to surgery to treat patients with pleural loculation (scarring and fluid collections), but its efficacy remains controversial. We infer that outcomes of IPFT will be improved by PAI-1-targeting, a novel approach that addresses a critical mechanism of pleural injury. Ultimately, new interventions identified in this project could improve outcomes for thousands of afflicted US patients annually.

描述（由申请人提供）：美国每年有多达 40,000 名患者因复杂的肺炎旁胸腔积液和脓胸而需要胸腔引流。胸膜内纤溶治疗（IPFT）可增强胸膜腔的清除以增强胸腔引流，仍然是一种无需手术引流的治疗选择。然而，目前的 IPFT 受到疗效可变、剂量不确定和安全问题的限制，最近临床试验的不同结果强调了这些问题。这些都是重要的临床问题，需要寻找更好的 IPFT。纤溶酶原激活剂抑制剂-1 (PAI-1) 与胸膜腔的发病机制密切相关，并抑制组织和尿激酶纤溶酶原激活剂； tPA和uPA，目前用于IPFT。我们的假设是，PAI-1 的胸膜内中和将进一步改善 IPFT，这一假设得到了已发表的工作和初步数据的有力支持。我们的目标是使用新型 PAI-1 靶向干预措施来改善组织性胸膜损伤的治疗效果。具体目标是： 1) 确定与纤溶素竞争 PAI-1 的分子是否增强纤溶素（tPA 或单链尿激酶）清除胸膜腔的能力。 2) 确定通过潜伏或底物途径重定向增强 PAI-1 失活的 mAb 是否会增加纤溶酶的治疗潜力。 3) 测试 PAI-1 靶向干预措施增强人和兔原代间皮细胞以及人胸膜液中纤溶酶原反应的能力。我们还将测试 PAI-1 在兔脓胸和四环素诱导的胸膜损伤模型中的靶向干预效果，并通过腺病毒递送人 PAI-1 增强。我们的方法是创新的，因为之前从未评估过 PAI-1 的胸膜内靶向。我们将在两年的资助期内实现我们的多学科团队可以实现的里程碑。在该项目结束时，我们将确定一个主要的干预性 PAI-1 靶向候选药物和一两个备用药物。我们将在 CADET II 中开发最有效的新型 PAI-1 靶向疗法进行临床试验测试。该项目填补了医疗实践中的一个关键空白，并可以通过为胸膜腔患者确定更可靠、更有效和可能更安全的治疗策略来推进 IPFT 领域。相关性（参见说明V 胸膜内纤溶治疗 (IPFT) 通常用作手术的侵入性较小的替代方案来治疗胸膜腔（疤痕和积液）患者，但其疗效仍存在争议。我们推断，IPFT 的结果将通过 PAI-1 靶向得到改善，PAI-1 靶向是一种解决胸膜损伤关键机制的新方法。最终，本项目中确定的新干预措施可以 每年改善数以千计的美国患者的治疗结果。