C/EBP-beta PEPTIDES FOR THE TREATMENT OF LUNG INJURY AND FIBROSIS

用于治疗肺损伤和纤维化的 C/EBP-β 肽

基本信息

批准号：
8779048
负责人：
MARTINA BUCK
金额：
$ 31.18万
依托单位：
XFIBRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8779048
关键词：
Accounting Agreement Animals Apoptosis Apoptotic Area Autopsy Biological Assay Biological Availability Bleomycin Body Weight decreased Breathing Bronchoalveolar Lavage CCAAT-Enhancer-Binding Proteins Cell Death Cells Chest Chronic Chronic Bronchitis Chronic lung disease Cicatrix Clinical Clinical Trials DNA Damage Development Dose Drug Kinetics Endothelial Cells Epithelial Cells Excretory function Fibrosis Fluorescein-5-isothiocyanate Functional disorder Future Genes Genus Hippocampus Glycolysis Hamman-Rich syndrome Heat-Shock Response Human Hypoxia In Vitro Inflammation Inflammatory Response Injury Intravenous Kidney Knowledge Lead Libraries Lung Lung diseases Malignant neoplasm of lung Maximum Tolerated Dose Measurable Measurement Measures Medical Metabolic Metabolic Biotransformation Metabolism Microsomes Mitochondria Modeling Molecular Profiling Molecular Toxicology Morbidity - disease rate Mus Myofibroblast Oral Administration Oxidative Stress Oxygen Oxygen Consumption Pathway interactions Patients Peptides Peptoids Pharmaceutical Preparations Pharmacodynamics Phase Phosphorylation Plasma Play Population Prevention Procedures Proteins Protons Pulmonary Emphysema Radiation therapy Recovery Relative (related person)Reporting Respiration Reverse Transcriptase Polymerase Chain Reaction Role Route Schedule Scleroderma Skin Small Business Technology Transfer Research Stress Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Toxicogenomics Toxicokinetics Toxicology Work Xenobiotic Metabolism analog base caspase-8 cytokine effective therapy fibrogenesis immunogenicity improved in vivo inflammatory marker lung development lung injury malignant breast neoplasm mortality mouse model novel preclinical study prevent public health relevance research and development response sex therapeutic target urinary

项目摘要

DESCRIPTION (provided by applicant): Activation of lung myofibroblasts (LMF) is responsible for the development of lung fibrosis in chronic lung diseases of all causes and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. There is full agreement among tissue fibrosis experts that inhibiting o reversing myofibroblast activation (the therapeutic target) is critical fr the treatment of lung fibrosis. Both preventing progression of lung fibrosis as well as possibly, regression of lung fibrosis in spite of continued lung injury, as we clearly documented in our pre-clinical studies, are considered important clinical targets for patients with chronic lung disease and lung fibrosis. Finally, blocking the progression of lung fibrosis may decrease development of lung cancer. The basis for our Research and Development is the development of novel humanized C/EBP¿ peptoids (not previously reported). We created a library using analog synthesis to improve potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient 'humanized' peptoids (including apoptosis assays in activated primary human myofibroblasts; cell-free caspase 8 activation assays; lung injury/fibrogenesis models; toxicology assays in mice). We have developed novel and effective anti-fibrotic peptoids with expected decreased immunogenicity and improved stability and bioavailability during clinical trials. The proposed compounds markedly inhibit activation of human and mouse myofibroblast in culture. These compounds were not toxic in the preliminary toxicology studies, including pilot toxicogenomics, to mice at least at 100-fold the therapeutic dose. The aims that are proposed for completion by this STTR are: Chronic lung fibrogenesis assays in mouse models; Pharmacokinetics; In Vitro Metabolic Stability Studies; Pharmacokinetics; Potential off-target liabilities for Molecular Toxicology and Exploratory Toxicology. There is no medication for the treatment or prevention of lung fibrosis. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with lung fibrosis.

说明（由申请人提供）：肺肌成纤维细胞 (LMF) 的激活是各种原因导致的慢性肺病中肺纤维化的原因，且不常见，通过细胞凋亡清除 LMF 可以预防肺纤维化和肺损伤的发生，并可能实现康复组织纤维化专家一致认为，抑制或逆转肌成纤维细胞活化（治疗目标）对于治疗肺纤维化至关重要。正如我们在临床前研究中明确记录的那样，预防肺纤维化的进展以及尽管存在持续的肺损伤也可能使肺纤维化消退，被认为是慢性肺病和肺纤维化患者的重要临床目标。阻断肺纤维化的进展可能会减少肺癌的发展我们的研究和开发的基础是新型人源化 C/EBP 的开发。我们使用类似物合成创建了一个库，以改善人类治疗的潜在缺陷。我们以逐步的方式进行分析，以选择最安全和最有效的“人源化”类肽（包括活化初级中的细胞凋亡分析）。我们已经开发出新型有效的抗纤维化肽；所提出的化合物在临床试验中显着抑制人和小鼠肌成纤维细胞的活化，这些化合物在初步毒理学研究（包括试验毒物基因组学）中对小鼠至少在治疗剂量的 100 倍时没有毒性。该 STTR 拟完成的目标是：小鼠模型中的慢性肺纤维化测定；体外代谢稳定性研究；分子毒理学和探索性毒理学的责任目前尚无治疗或预防肺纤维化的药物。完成拟议化合物的这些任务将使我们能够继续进行 2 期 STTR 和肺纤维化患者的临床开发。