Anti-Fibrotic Therapy for Pulmonary Fibrosis

肺纤维化的抗纤维化治疗

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：肺纤维化是一种弥漫性间质性肺疾病，其特征是慢性炎症和病因不明的进行性纤维化。肺纤维化影响着全世界 500 万人，在美国有超过 200,000 名肺纤维化患者。其中每年有超过 40,000 个到期。通常，患者被诊断时年龄在四五十岁左右。从诊断时起的中位生存期为 5.5 年。肺纤维化与显着的发病率和死亡率相关，并且对目前可用的治疗反应不佳。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够的，并且具有有害的副作用。最近的研究已确定肝细胞生长因子 (HGF) 作为一种抗纤维化剂，可防止动物模型中肝、肾和肺纤维化中的上皮细胞和细胞外基质积累受到转化生长因子 (TGFbeta) 介导的凋亡作用。为了克服蛋白质疗法的缺点和费用，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HGF活性的小分子模拟物。在体外，我们的主要 HGF 模拟物 Ang1170 激活 HGF 受体 c-Met，并诱导其生物学功能，包括激活内皮和支气管上皮细胞增殖，而不刺激 SMC/成纤维细胞，并与 HGF 类似地抑制 TGF β 表达。在体内，Ang1170 抑制胶原蛋白合成并减少肝脏和肾脏纤维化。我们最近的初步第一阶段研究表明，Ang1170 治疗可降低博来霉素诱导的体内肺纤维化中的胶原蛋白含量。定量组织学评估表明，与媒介物处理组相比，Ang1170处理的小鼠肺切片减少了间质纤维化、肺泡细胞凋亡和组织损伤。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）对肺纤维化的保护作用。本申请的目的是在临床相关的肺纤维化模型中评估我们的主要小分子化合物 Ang1170，以开发足够的数据，以成功向 FDA 提交研究性新药 (IND) 申请，以对我们的主要小分子进行临床试验肺纤维化的抗纤维化治疗。肺纤维化影响着全世界 500 万人，以及美国超过 200,000 名患者。从诊断时起的中位生存期为 5.5 年。本申请的目的是评估临床相关肺纤维化模型中的主要小分子候选药物，以开发足够的数据，以成功向 FDA 提交研究性新药 (IND) 申请以进行临床试验。