PAI-1 Targeted Intrapleural Fibronolytic Therapy

描述(由申请人提供)：每年有多达40,000名美国患者需要胸腔引流治疗复杂的肺炎旁积液和脓胸。胸膜腔内纤溶治疗(IPFT)是一种不需要手术引流的治疗选择，它可以增强胸膜腔内积液的清除，从而增加胸膜引流。然而，目前的IPFT受到疗效可变、剂量不确定和安全性问题的限制，最近临床试验的不同结果突显了这些问题。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物-1(PAI-1)与胸腔积液的发病机制密切相关，可抑制组织纤溶酶原激活物和尿激酶型纤溶酶原激活物，目前用于IPFT。我们的假设是胸膜腔内中和PAI-1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的PAI-1靶向干预来改善组织性胸膜损伤的治疗结果。具体目的是：1)确定与纤溶酶竞争PAI-1的分子是否能增强纤溶酶(tPA或单链尿激酶)清除胸腔积液的能力。2)检测9株通过潜伏期或底物通路重定向增强PAI-1失活的IF单抗，增加纤溶酶的治疗潜力。3)检测PAI-1靶向干预对人和兔原代胸膜间皮细胞及人胸水纤溶原反应的影响。我们还将测试PAI-1靶向干预在兔脓胸和四环素诱导的胸膜损伤模型中的有效性，并通过腺病毒递送人PAI-1来增强其疗效。我们的方法是创新的，因为胸腔内靶向PAI-1以前从未被评估过。我们将在两年的资金期限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PAI-1目标候选对象和一个或两个备份。我们将在CADET II中开发最有效的新型PAI-1靶向治疗药物进行临床试验。该项目解决了医疗实践中的一个关键空白，并可能通过为胸腔积液患者确定更可靠、更有效和潜在更安全的治疗策略来推动IPFT领域的发展。相关性(见说明V)胸膜腔内纤溶治疗(IPFT)通常被用作手术治疗胸膜积液(疤痕形成和积液)患者的一种侵入性较小的替代方案，但其疗效仍存在争议。我们推断，通过PAI-1靶向治疗，IPFT的结果将得到改善，这是一种解决胸膜损伤的关键机制的新方法。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.