PAI-1 Targeted Intrapleural Fibronolytic Therapy

描述（由申请人提供）：每年有多达40,000名美国患者需要胸膜引流治疗复杂的肺旁积液和肺气肿。胸膜内纤溶治疗（IPFT），增强胸膜定位的清除，以增加胸膜引流，仍然是一种治疗选择，消除了手术引流的需要。然而，目前的IPFT受到不同疗效、不确定剂量和安全问题的限制，最近临床试验的不同结果强调了这一点。这些都是重要的临床问题，要求寻找更好的IPFT。纤溶酶原激活物抑制剂-1 （PAI-1）与胸膜定位的发病机制密切相关，并抑制组织和尿激酶纤溶酶原激活物；tPA和uPA，目前用于IPFT。我们的假设是，胸膜内中和PAI-1将进一步改善IPFT，这得到了已发表的工作和初步数据的有力支持。我们的目标是利用新型pai -1靶向干预措施改善组织胸膜损伤的治疗效果。具体目的是：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）清除胸膜定位的能力。2)确定通过潜伏期或底物通路重定向增强PAI-1失活的单克隆抗体是否增加了纤维蛋白溶素的治疗潜力。3)测试PAI-1靶向干预增强人和兔原代间皮细胞和人胸膜液中纤原蛋白溶解反应的能力。我们还将在兔胸膜脓肿和四环素引起的胸膜损伤模型中测试PAI-1靶向干预的效果，这些胸膜损伤是由腺病毒递送人PAI-1增强的。我们的方法是创新的，因为胸膜内靶向PAI-1从未被评估过。我们将达到里程碑，可以由我们的多学科团队在两年的资助期内完成。在本项目结束时，我们将确定一个主要的介入性PAI-1靶向候选方案和一个或两个备用方案。我们将在CADET II中开发最有效的新型PAI-1靶向治疗方法进行临床试验。该项目解决了医疗实践中的一个关键空白，并可以通过确定更可靠、更有效和潜在更安全的胸膜定位患者治疗策略来推进IPFT领域。相关性（见说明书）胸膜内纤溶治疗（IPFT）常被用作手术治疗胸膜定位（瘢痕形成和积液）患者的微创替代方法，但其疗效仍存在争议。我们推断，pai -1靶向治疗将改善IPFT的预后，这是一种解决胸膜损伤关键机制的新方法。最终，在这个项目中确定的新干预措施可以改善每年数千名美国患者的预后。

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.