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

• 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
• 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

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.

描述（由申请人提供）：肺肌成纤维细胞（LMF）的激活是所有原因引起的慢性肺部疾病中肺纤维化的发生的原因，值得注意的是，通过细胞凋亡清除LMF可以防止肺纤维化和肺损伤的发生，并可能允许从肺纤维化的逆转中恢复。组织纤维化专家一致认为，抑制或逆转肌成纤维细胞活化（治疗靶点）对于肺纤维化的治疗至关重要。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在持续肺损伤的情况下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。最后，阻止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开发新型人源化 C/EBP¿ 类肽（之前未报道过）。我们使用模拟合成创建了一个库，以改善人类治疗的潜在缺陷。我们以逐步的方式进行测定，以选择最安全和最有效的“人源化”类肽（包括激活的原代人肌成纤维细胞的细胞凋亡测定；无细胞 caspase 8 激活测定；肺损伤/纤维发生模型；小鼠毒理学测定）。我们开发了新型有效的抗纤维化类肽，预计在临床试验期间可降低免疫原性并提高稳定性和生物利用度。所提出的化合物显着抑制培养物中人和小鼠肌成纤维细胞的活化。在初步毒理学研究（包括试验性毒物基因组学）中，这些化合物在至少 100 倍治疗剂量下对小鼠没有毒性。该 STTR 建议完成的目标是： 小鼠模型中的慢性肺纤维发生测定；药代动力学；体外代谢稳定性研究；药代动力学；分子毒理学和探索毒理学的潜在脱靶责任。没有药物可以治疗或预防肺纤维化。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。