Targeting C/EBP-beta Phosphorylation for the Treatment of Lung Fibrosis

靶向 C/EBP-β 磷酸化治疗肺纤维化

基本信息

批准号：
8904981
负责人：
MARTINA BUCK
金额：
$ 31.61万
依托单位：
XFIBRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-25 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904981
关键词：
Accounting Adverse event Affect Agreement Alveolar American Animal Model Animals Apoptosis Apoptotic Binding Biochemistry Biological Assay Biological Availability Bleomycin Blood Breathing CCAAT-Enhancer-Binding Proteins Cancer Center Cells Chemistry Chronic lung disease Cicatrix Clinical Clinical Research Clinical Trials Core Facility Development Dose Drug Formulations Drug Kinetics Embryonic Development Fibrosis Functional disorder Hamman-Rich syndrome Histocompatibility Antigens Class II Histology Histone Acetylation Human Immune Induction of Apoptosis Inflammation Inhalation Drug Administration Inhalation Toxicology Injury Interferons Interleukin-12 Interleukin-4 Interleukin-6 International Investigational Drugs Knowledge Lead Libraries Lung Malignant neoplasm of lung Medical Microscopy Microsomes Modeling Molecular Biology Mus Myofibroblast Particle Size Pathology Patients Peptides Peptoids Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorylation Plasma Population Production Proteins Reaction Recovery Regulatory Affairs Reporting Resistance Route Signal Transduction Small Business Technology Transfer Research Solubility System T-Cell Proliferation T-Lymphocyte Testing Therapeutic Tissues Toxicogenomics Toxicology Transgenic Organisms Treatment Efficacy Water Work aerosolized analog base cancer research center director caspase-8 commercialization cytokine drug development expectation fibrogenesis histone modification immunogenic immunogenicity improved in vitro Assay in vivo lung development lung injury mortality mouse model novel outcome forecast postnatal pre-clinical pre-clinical research preclinical study prevent professor promoter public health relevance research and development therapeutic target tissue culture translational medicine

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 documented in our pre-clinical studies, are considered important clinical targets for patients with Idiopathic Pulmonary Fibrosis (IPF). 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' 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; preliminary toxicology assays in mice). We have developed novel and highly effective anti-fibrotic peptoids in animal models, with no evidences of immunogenicity in state-of-the-art T-cell assays and with exceptional stability in mouse microsomal systems and mouse blood. The lead peptoid has excellent solubility in water. These features should facilitate administration by inhalation with increased bioavailability to the LMF 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 this Phase-1 STTR are: Specific Aim 1: Efficacy of the Lead Peptoid in Lung Fibrosis Mouse Models. Specific Aim 2: Pharmacokinetics (Single and Multiple doses) in Mice and Stability Assays in vitro in Human Lung Microsomes and Human Plasma. There is no medication for the treatment of lung fibrosis in IPF. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with IPF.

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所记录的，尽管存在持续的肺损伤，但两者都可以防止肺纤维化的进展，并且可能使肺纤维化消退研究被认为是特发性肺纤维化（IPF）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展。我们的研究和开发的基础是开发新型“人源化”类肽。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测定，以选择最安全、最有效的“人源化”类肽（包括细胞凋亡测定）。激活的原代人肌成纤维细胞；无细胞 caspase 8 激活试验；小鼠肺损伤/纤维发生模型；我们在动物模型中开发了新型高效的抗纤维化肽，没有证据表明其具有免疫原性。先进的 T 细胞，在小鼠微粒体系统和小鼠血液中具有出色的稳定性，这些特性应有利于给药。在临床试验中，通过吸入增加 LMF 的生物利用度，这些化合物在初步毒理学研究（包括试验毒物基因组学）中对小鼠没有毒性，其毒性至少是其 100 倍。为这一阶段 STTR 提出的目标是：具体目标 1：先导肽在肺纤维化小鼠模型中的功效。图 2：小鼠体内的药代动力学（单剂量和多剂量）以及人肺微粒体和人血浆中的体外稳定性测定目前还没有用于治疗 IPF 肺纤维化的药物。完成所提出的化合物的这些任务将使我们能够继续进行。 a IPF 患者的 2 期 STTR 和临床开发。