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

描述(申请人提供)：肺肌纤维母细胞(LMF)的激活导致各种原因慢性肺部疾病的肺纤维化的发展，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展，并可能使肺纤维化逆转恢复。组织纤维化专家一致认为，抑制或逆转肌成纤维细胞的激活(治疗靶点)是治疗肺纤维化的关键。正如我们在临床前研究中明确记录的那样，无论是预防肺纤维化的进展，还是可能在持续肺损伤的情况下肺纤维化的消退，都被认为是慢性肺病和肺纤维化患者的重要临床目标。最后，阻断肺纤维化的进展可能会减少肺癌的发生。我们研发的基础是开发新型人源化C/EBP类肽(此前未见报道)。我们使用模拟合成创建了一个库，以改进人类治疗的潜在陷阱。我们以循序渐进的方式进行分析，以选择最安全和最有效的人源化类肽(包括激活的原代人肌成纤维细胞的凋亡分析；无细胞的caspase 8激活分析；肺损伤/纤维化模型；小鼠的毒理学分析)。在临床试验中，我们已经开发出新的有效的抗纤维化肽类化合物，预期免疫原性降低，稳定性和生物利用度提高。所建议的化合物在培养中显著抑制人和小鼠肌成纤维细胞的激活。在包括试点毒理学基因组学在内的初步毒理学研究中，这些化合物对小鼠的毒性至少是治疗剂量的100倍。本研究拟完成的目标包括：小鼠模型的慢性肺纤维化分析；药代动力学；体外代谢稳定性研究；药代动力学；分子毒理学和探索性毒理学的潜在脱靶风险。目前还没有治疗或预防肺纤维化的药物。完成建议化合物的这些任务将使我们能够继续进行肺纤维化患者的第二阶段STTR和临床开发。

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.