PAI-1 Targeted Intrapleural Fibronolytic Therapy

描述（由申请人提供）：每年有多达40，000例美国患者需要胸膜引流治疗复杂性胸膜旁积液和脓胸。胸膜内纤溶治疗（IPFT），增强胸膜腔的清除，以增加胸膜引流，仍然是一种治疗选择，避免了手术引流的需要。然而，目前的IPFT受到可变疗效、不确定剂量和安全性问题的限制，这些问题被最近临床试验的不同结果所强调。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（派-1）与胸膜腔形成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;目前用于IPFT的tPA和uPA。我们的假设，即胸膜内的派-1中和将进一步改善IPFT是强有力的支持发表的工作和初步的数据。我们的目的是改善治疗结果机化胸膜损伤使用新的派-1靶向干预。具体目标是：1）确定与纤溶酶竞争派-1的分子是否增强纤溶酶（tPA或单链尿激酶）清除胸膜腔的能力。2)确定通过潜伏期或底物途径重定向增强派-1失活的mAb是否增加纤溶酶的治疗潜力。3)测试派-1靶向干预增强人和兔原代间皮细胞和人胸腔液中的纤溶原反应的能力。我们还将测试派-1靶向干预在脓胸和四环素诱导的胸膜损伤的兔模型中的功效，所述模型通过腺病毒递送人派-1而增强。我们的方法是创新的，因为以前从未评价过派-1的胸膜内靶向。我们将在两年的资助期内完成我们的多学科团队可以完成的里程碑。在本项目结束时，我们将确定一个主要的干预性派-1靶向候选药物和一个或两个备用药物。我们将在CADET II中开发最有效的新型派-1靶向治疗药物，用于临床试验测试。该项目解决了医疗实践中的一个关键空白，并可以通过为胸膜腔形成患者确定更可靠，更有效和潜在更安全的治疗策略来推进IPFT领域。相关性（见说明书V）胸膜内纤维蛋白溶解疗法（IPFT）通常用作外科手术的微创替代疗法，用于治疗胸膜腔形成（瘢痕形成和积液）患者，但其疗效仍存在争议。我们推断，靶向派-1将改善IPFT的结局，这是一种解决胸膜损伤关键机制的新方法。最终，该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治疗结果。

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.