Anti-Fibrotic Therapy for Pulmonary Fibrosis

肺纤维化的抗纤维化治疗

• 批准号: 7157091
• 负责人: LATHA PAKA
• 金额: $ 97.38万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157091
• 关键词: biomimetics; biotechnology; disease /disorder model; dosage; drug administration rate /duration; drug screening /evaluation; genetically modified animals; hepatocyte growth factor; histology; intraperitoneal injections; laboratory mouse; nonhuman therapy evaluation; oral administration; pharmacokinetics; pulmonary fibrosis /granuloma; respiratory disorder chemotherapy; respiratory function; small molecule

DESCRIPTION (provided by applicant): Pulmonary Fibrosis is a diffuse interstitial lung disease characterized by chronic inflammation and progressive fibrosis of unknown etiology. Pulmonary fibrosis affects five million people worldwide and in the United States there are over 200,000 patients with pulmonary fibrosis. Of these more than 40,000 expire annually. Typically, patients are in their forties and fifties when diagnosed. Median survival from time of diagnosis is 5.5 years. Pulmonary fibrosis is associated with pronounced morbidity and mortality and responds poorly to currently available therapy. While steroids and other immunosuppressive agents serve as the standard treatment for pulmonary fibrosis, these agents have proved inadequate and have deleterious side effects. Recent studies have identified hepatocyte growth factor (HGF) as an antifibrogenic agent that protects against transforming growth factor (TGFbeta) mediated apoptotic effects on epithelial cells and extracellular matrix accumulation in liver, kidney and lung fibrosis in animal models. In order to overcome the shortcomings and expense of protein therapy, we have developed a small molecule mimetic of HGF activity that was rationally designed through a novel combination of phage display and molecular modeling technology. In vitro, our lead HGF mimetic, Ang1170, activates the HGF receptor, c-Met, and induces its biological functions including activation of endothelial and bronchial epithelial cell proliferation, without stimulating SMC/fibroblasts and suppresses TGF beta expression similar to HGF. In vivo, Ang1170 inhibits collagen synthesis and decreases the liver and kidney fibrosis. Our recent preliminary PHASE-I studies suggest that Ang1170 treatment decreases collagen content in bleomycin induced pulmonary fibrosis in vivo. Quantitative histological evaluation demonstrated that Ang1170 treated mouse lung sections have reduced interstitial fibrosis, alveolar apoptosis, and damaged tissue compared with the vehicle-treated group. In the proposed studies, we will further evaluate the protective effects of Ang1170 (via delayed treatment and oral route) on lung from lung fibrosis in three different pre- clinical animal models of lung fibrosis. The objective of this application is the evaluation of our lead small molecule compound, Ang1170 in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials of our lead small molecule antifibrotic therapy for pulmonary fibrosis. Pulmonary fibrosis affects five million people worldwide and over 200,000 patients in the United States. Median survival from time of diagnosis is 5.5 years. The objective of this application is to evaluate a lead small-molecule drug candidate in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials.

描述（申请人提供）：肺纤维化是一种弥漫性间质性肺疾病，以慢性炎症和进行性纤维化为特征，病因不明。肺纤维化影响着全世界500万人，在美国有超过20万患者患有肺纤维化。其中每年有4万多个到期。确诊时，患者通常在四五十岁左右。诊断后的中位生存期为5.5年。肺纤维化与明显的发病率和死亡率相关，并且对目前可用的治疗反应较差。虽然类固醇和其他免疫抑制剂是肺纤维化的标准治疗方法，但这些药物已被证明是不充分的，并且有有害的副作用。最近的研究发现，肝细胞生长因子（HGF）是一种抗纤维化药物，在动物模型中可以防止转化生长因子（tgf β）介导的上皮细胞凋亡效应和肝、肾和肺纤维化的细胞外基质积累。为了克服蛋白质治疗的缺点和费用，我们通过噬菌体展示和分子建模技术的新颖结合，合理设计了一种模拟HGF活性的小分子。在体外，我们的主要HGF模拟物Ang1170激活HGF受体c-Met，诱导其生物学功能，包括激活内皮细胞和支气管上皮细胞增殖，而不刺激SMC/成纤维细胞，并抑制TGF β表达，类似于HGF。在体内，Ang1170抑制胶原合成，减少肝、肾纤维化。我们最近的初步i期研究表明，Ang1170治疗降低了博来霉素诱导的肺纤维化的体内胶原含量。定量组织学评价表明，与载药组相比，Ang1170处理的小鼠肺切片间质纤维化、肺泡凋亡和损伤组织减少。在拟议的研究中，我们将在三种不同的肺纤维化临床前动物模型中进一步评估Ang1170（通过延迟治疗和口服途径）对肺纤维化肺的保护作用。此次申请的目的是评估我们的先导小分子化合物Ang1170在临床相关肺纤维化模型中的应用，以获得足够的数据，成功向FDA提交新药（IND）申请，以开展我们的先导小分子抗纤维化治疗肺纤维化的临床试验。