Anti-Fibrotic Therapy for Pulmonary Fibrosis

肺纤维化的抗纤维化治疗

基本信息

批准号：
7286694
负责人：
LATHA PAKA
金额：
$ 90.06万
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 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7286694
关键词：
3-Dimensional Accounting Acute Address Adverse effects Affect Alveolar Animal Model Animals Apoptosis Apoptotic Appendix Architecture Area Asses Attenuated Biological Availability Biological Process Biology Bleomycin California Chemicals Chest Chronic Chronic Disease Clinical Clinical Trials Collaborations Collagen Cytochrome P450 Daily Data Data Analyses Development Diagnosis Diffuse Disease Disease Progression Dose Doxycycline Dropout Drug Industry Drug Interactions Drug Kinetics Elements Endpoint Determination Ensure Epithelial Epithelial Cell Proliferation Epithelial Cells Etiology Evaluation Experimental Designs Extracellular Matrix Fibroblasts Fibrosis Free Radicals Functional disorder Gene Proteins Genes Half-Life Hepatocyte Growth Factor Histopathology Immune Immunosuppressive Agents In Vitro Inflammation Inflammatory Response Injury Intellectual Property International Interstitial Lung Diseases Investigation Investigational Drugs Investigational New Drug Application Ionizing radiation Kidney Laboratories Lawyers Lead Legal patent Letters Liver Lung Lung diseases Lymphoma Marketing Mechanics Mediating Medicine Mesenchyme Metabolic Metabolism Methodology Micronucleus Tests Mitogens Modeling Molecular Weight Monitor Morbidity - disease rate Morphogenesis Mus Mutagenicity Tests Mutation Myofibroblast Oral Oral Administration Patients Phage Display Pharmaceutical Preparations Phase I Clinical Trials Play Pre-Clinical Model Principal Investigator Process Production Protein Chemistry Proteins Proteomics Proto-Oncogene Protein c-met Protocols documentation Publications Pulmonary Fibrosis Radiation Radiation Oncologist Recruitment Activity Research Design Resources Respiratory Failure Respiratory physiology Rodent Model Role Route Safety Seminal Series Services Signal Transduction Smooth Muscle Myocytes Solutions Standards of Weights and Measures Steroids Techniques Technology Testing Therapeutic Time Tissues Transforming Growth Factor beta Transforming Growth Factors Transgenes Treatment Cost Treatment Efficacy United States United States Food and Drug Administration Universities University Hospitals Vermont Week Work absorption base clinically relevant cost cytokine day design expectation experience fibrosing agent human MET protein in vivo indium-bleomycin innovation interstitial intraperitoneal irradiation microbial migration mimetics molecular modeling mortality novel pre-clinical preclinical study professor programs prophylactic prospective protective effect pulmonary function receptor repaired research study small molecule success

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肺疾病，其特征是慢性炎症和未知病因的进行性纤维化。肺纤维化影响全球500万人，在美国，有超过200,000例肺纤维化患者。其中有40,000多个每年过期。通常，诊断为四十多岁的患者。诊断时间的中位生存期为5。5年。肺纤维化与明显的发病率和死亡率有关，并且对当前可用的治疗反应不佳。尽管类固醇和其他免疫抑制剂是肺纤维化的标准治疗方法，但这些药物已证明不足，并且具有有害的副作用。最近的研究已将肝细胞生长因子（HGF）鉴定为一种抗纤维化剂，可防止转化生长因子（TGFBETA）介导的凋亡对上皮细胞和细胞外基质在动物模型中肝，肾脏和肺纤维化中的积累的影响。为了克服蛋白质治疗的缺点和费用，我们开发了一种小分子模拟于HGF活性，该分子是通过噬菌体显示和分子建模技术的新型组合合理设计的。在体外，我们的铅HGF Mimetic，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，而无需刺激SMC/成纤维细胞和抑制类似于HGF的TGFβ表达。在体内，ANG1170抑制胶原蛋白合成并降低肝脏和肾脏纤维化。我们最近的初步I期研究表明，ANG1170治疗可降低博来霉素诱导的体内肺纤维化的胶原蛋白含量。定量组织学评估表明，与媒介物处理的组相比，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受损的组织。在拟议的研究中，我们将进一步评估ANG1170（通过延迟治疗和口服途径）对肺纤维化中肺肺部的保护作用。该应用的目的是评估我们铅的小分子化合物，ANG1170在临床上相关的肺纤维化模型中，以开发足够的数据，以成功地向FDA提出研究新药物（IND），以对我们的铅小分子抗纤维化治疗进行肺纤维化的临床试验。在美国，肺纤维化影响全球500万人，超过20万名患者。诊断时间的中位生存期为5。5年。该应用的目的是评估临床相关模型的肺纤维化模型中的铅小分子候选药物，以开发足够的数据，以成功地向FDA提出研究新药（IND）以进行临床试验。