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

描述（由申请人提供）：肺肌成纤维细胞（LMF）的激活与各种原因的慢性肺部疾病的肺纤维化发展有关，值得注意的是，通过细胞凋亡清除LMF可能阻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活化（治疗靶点）对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载的那样，预防肺纤维化的进展以及可能的肺纤维化的消退，被认为是慢性肺病和肺纤维化患者的重要临床靶点。最后，阻断肺纤维化的进展可能会减少肺癌的发生。我们的研究和开发的基础是开发新的人源C/EBP¿类肽（以前没有报道）。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。我们进行了分步分析，以选择最安全、最有效的“人源化”类肽（包括活化的原代人肌成纤维细胞的细胞凋亡试验、无细胞caspase 8活化试验、肺损伤/纤维形成模型、小鼠毒理学试验）。在临床试验中，我们开发了新型有效的抗纤维化肽，预期免疫原性降低，稳定性和生物利用度提高。所提化合物可显著抑制培养的人和小鼠肌成纤维细胞的活化。在初步毒理学研究中，包括初步毒理学基因组学研究，这些化合物对小鼠的毒性至少为治疗剂量的100倍。该STTR拟完成的目标是：在小鼠模型中进行慢性肺纤维化测定；药物动力学;体外代谢稳定性研究；药物动力学;分子毒理学和探索性毒理学的潜在脱靶责任。目前还没有治疗或预防肺纤维化的药物。这些任务的完成将使我们能够进行肺纤维化患者的2期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.