Novel Targeted Therapies for Pulmonary Fibrosis

描述(申请人提供)：肺纤维化的新靶向治疗(P01)。特发性肺纤维化(IPF)是一种主要的、进行性的、致死性的肺部疾病，病因不明。它缺乏任何有效的治疗方法。有希望的治疗可能会失败，因为糟糕的肺部输送和组织渗透使局部药物浓度不足，无法在没有全身毒性的情况下实现疗效。将治疗药物专门输送到肺组织的能力对患者护理具有巨大的优势。该方案项目赠款旨在协同整合3个项目和3个核心设施的活动，重点是为IPF创造和测试新疗法。我们将使用一种新的肺部给药平台，以降低毒性，增强知名抗纤维化生物制剂和介导IPF的关键促纤维化信号通路的小分子化疗抑制剂的靶向穿透和治疗效果。我们广泛的血管蛋白质组学图谱已经在肺内皮细胞表面确定了可访问的靶点，使快速和特定的肺靶向成为可能。更重要的是，我们还发现，靶向蛋白集中在EC表面的囊泡转运体中，称为小凹，使抗体能够克服通常限制性的EC屏障，方法是在静脉注射后几分钟内将抗体泵过血管壁，到达肺组织内部。根据这些基础发现，我们建议将我们的新的小窝靶向策略转化为新的、增强的治疗IPF的方法。项目1将测试这一策略在多大程度上能够快速传递和浓缩静脉注射的抗体及其附着的治疗货物(抗纤维蛋白或化学负载纳米凝胶)，特别是在啮齿类动物和人类的肺部。项目1确定的那些抗体和治疗剂被有效泵送，现在将在项目2和项目3中使用，以评估它们在纤维化肺中的靶向性和有效性。这两个项目都将评估来自IPF患者的人类临床标本，以评估纤维化的靶向表达、小窝功能和肺靶向。核心B将为每个项目生成并描述所有重定向疗法。Core C将为所有项目提供多种成像能力，以 全面跟踪静脉注射后每个重定向治疗剂的肺靶向和组织处理情况。行政和生物统计核心A将向所有项目提供行政和统计能力，以加强数据管理 以及P01研究的速度和质量。这一P01计划可能会启动肺部治疗方式的范式转变，为IPF和其他破坏性肺部疾病的患者带来希望。

DESCRIPTION (provided by applicant): Novel Targeted Therapies for Pulmonary Fibrosis (P01). Idiopathic pulmonary fibrosis (IPF) is a major, progressive, fatal lung disorder of unknown etiology. It lacks any effective treatment. Promising therapies likely fail because poor lung delivery and tissue penetration have prevented sufficient local drug concentration to achieve efficacy without systemic toxicity. The ability to specifically deliver therapies into the lung tisue has tremendous advantages for patient care. This program project grant is designed to integrate synergistically the activities of 3 projects and 3 core facilities focused on creating and testing novel therapies for IPF. We will use a novel lung delivery platform to reduce toxicity and enhance targeted penetration and therapeutic efficacy of well-known anti-fibrotic biologic agents and small chemotherapeutic inhibitors of key pro-fibrotic signaling pathways mediating IPF. Our extensive vascular proteomic mapping has identified accessible targets on the lung endothelial cell surface that enable rapid and specific lung targeting. More importantly, we also discovered that targeting proteins concentrated in vesicular transporters at the EC surface called caveolae enable antibodies to overcome the normally restrictive EC barrier by pumping them across the vascular wall to reach inside lung tissue within minutes of intravenous injection. From these fundamental discoveries, we are proposing to translate our novel caveolae-targeting strategy into new, enhanced treatments for IPF. Project 1 will test how well this strategy can rapidly deliver and concentrate intravenously injected antibodies and their attached therapeutic cargo (anti-fibrotic protein or chemo-loaded nanogels) specifically in rodent and human lungs. Those antibodies and therapeutic agents that Project 1 determines are pumped effectively will now be used in Projects 2 and 3 to evaluate their targeting and efficacy in fibrotic lungs. Both projects will evaluate human clinical specimens from IPF patients to assess target expression, caveolae function and lung targeting in fibrosis. Core B will generate and characterize all of the retargete therapeutics for each project. Core C will provide to all projects multiple imaging capabilities to comprehensively track the lung targeting and tissue processing of each retargeted therapeutic agent after intravenous injection. The Administrative and Biostatistical Core A will make both administrative and statistical capabilities available to all projects to potentiate data management and the pace and quality of the P01 research. This P01 program may initiate a paradigm shift in how pulmonary therapies are delivered, offering hope for patients with IPF and other devastating lung diseases.