Novel Targeted Therapies for Pulmonary Fibrosis

描述（由申请人提供）：肺纤维化的新型靶向治疗（p0.01）。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，因为肺部输送和组织渗透不良，阻碍了足够的局部药物浓度，以达到无全身毒性的疗效。这种将治疗方法特异地输送到肺组织的能力对病人的护理有着巨大的优势。该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给药平台来降低毒性，增强已知的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化疗抑制剂的靶向渗透和治疗效果。我们广泛的血管蛋白质组学图谱已经确定了肺内皮细胞表面可接近的靶标，使快速和特异性肺靶向成为可能。更重要的是，我们还发现，在静脉注射的几分钟内，抗体通过泵送它们穿过血管壁到达肺组织内部，从而克服通常限制性的EC屏障，这种靶向蛋白集中在EC表面的囊泡转运体中，称为小泡。基于这些基础发现，我们建议将我们的新小泡靶向策略转化为新的、增强的IPF治疗方法。项目1将测试该策略在啮齿动物和人类肺部快速递送和集中静脉注射抗体及其附加治疗货物（抗纤维化蛋白或化学负载纳米凝胶）的效果。项目1确定的有效泵送抗体和治疗剂现在将用于项目2和项目3，以评估其在纤维化肺中的靶向性和有效性。这两个项目将评估来自IPF患者的人类临床标本，以评估纤维化中的靶表达、小泡功能和肺靶向性。核心B将为每个项目生成和描述所有的重靶向治疗方法。Core C将为所有项目提供多种成像功能

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.