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

• 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
• 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

 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.

 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”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、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；小鼠的初步毒理学测定）。我们在动物模型中开发了新型高效的抗纤维化类肽，在最先进的 T 细胞测定中没有证据表明具有免疫原性，并且在小鼠微粒体系统和小鼠血液中具有出色的稳定性。先导类肽在水中具有极好的溶解度。这些功能应该有助于管理 在临床试验期间通过吸入增加 LMF 的生物利用度。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。为这一阶段 STTR 提出的目标是： 具体目标 1：先导类肽在肺纤维化小鼠模型中的功效。具体目标 2：小鼠药代动力学（单剂量和多剂量）以及人肺微粒体和人血浆的体外稳定性测定。目前尚无治疗 IPF 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 IPF 患者的临床开发。