Development, Formulation and Inhalational Delivery of a New Peptide for ILD

ILD 新肽的开发、配制和吸入给药

• 批准号: 10318218
• 负责人: Sreerama Shetty
• 金额: $ 44.86万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318218
• 关键词: Affect; Apoptosis; Apoptotic; Architecture; Area; Binding; Biodistribution; Biological Availability; Bleomycin; Cell Aging; Cell Survival; Cell surface; Cells; Cicatrix; Clinical; Clinical Trials; Data; Deposition; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Dyspnea; Epithelial Cell Proliferation; Epithelial Cells; Extracellular Matrix; FDA approved; Fibroblasts; Formulation; Functional disorder; Future; Heterogeneity; In Vitro; Incidence; Individual; Inhalation; Inhalation Device; Interstitial Lung Diseases; Intervention; Lead; Lung; Lung Transplantation; Lung diseases; Maintenance; Measures; Mediating; Medical; Membrane; Minority; Modeling; Molecular; Molecular and Cellular Biology; Morphology; Mus; Myofibroblast; Nebulizer; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pirfenidone; Population; Powder dose form; Pre-Clinical Model; Probability; Prognosis; Proliferating; Property; Publications; Pulmonary Fibrosis; Refractory; Reporting; Resistance; Resolution; Safety; Signal Transduction; Silicon Dioxide; Structure; Structure of parenchyma of lung; TP53 gene; Tertiary Protein Structure; Toxicology; Transforming Growth Factor beta; Tumor Suppressor Proteins; Variant; Work; advanced disease; aged; alveolar epithelium; base; caveolin 1; cell type; connective tissue growth factor; crystallinity; drug candidate; drug discovery; effective therapy; efficacy testing; fibrotic lung; fibrotic lung disease; idiopathic pulmonary fibrosis; improved; in vivo; indium-bleomycin; injured; innovation; lung injury; lung lesion; migration; mouse model; nintedanib; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; preservation; pulmonary function; pulmonary function decline; repaired; scaffold; senescence; side effect; success; therapeutic candidate; therapeutic target; therapeutically effective

Interstitial lung diseases (ILDs) are characterized by progressive pulmonary scarring. Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of ILDs and is a fatal lung disease with an incidence of 60 cases/100,000 individuals in the US annually. IPF has a median five-year survival of only 20%. There is presently no cure. The pathogenesis of IPF is characterized by alveolar epithelial cell (AEC) senescence and apoptosis, proliferation and accumulation of activated myofibroblasts and fibrotic lung fibroblasts (fLfs) and extracellular matrix deposition. These features lead to progressive lung dysfunction. Morphologic changes include spatial and temporal heterogeneity incorporating areas of normal lung adjacent to diseased areas containing apoptotic AECs, and fLfs. Recently, pharmacotherapy has been shown to slow progression of IPF, suggest that even more effective treatment can be developed. We found that increased p53 contributes to AEC apoptosis and fibroblast activation, and that its decline in fLfs promotes myofibroblast expansion. We also found that caveolin-1 (Cav1) is increased in injured AECs while its level is markedly reduced in proliferating fLfs from the lungs of IPF patients and mice with established PF. We identified a 20-mer Cav1 scaffolding domain peptide (CSP), and its truncated 7-mer fragment, CSP7, that inhibits p53, TGF-β, CTGF, AEC apoptosis and fLf expansion. These peptides block PF in mice after single (1X) or multi-hit (8X) bleomycin (BLM), adenoviral TGF-β1 (Ad-TGF-β1)- and silica- induced lung injury. CSP7 inhibits degradation of p53 due to increased mdm2 expression in fLfs and blocks their proliferation. CSP7 also inhibits AEC senescence and apoptosis, which are otherwise increased in fibrotic lungs, including in IPF. CSP7 is well-tolerated in mice and can effectively be delivered via the airways. Our work validates Cav1 as a therapeutic target in PF. Our publications offer the premise for developing CSP7 for airway delivery by nebulization (neb) or dry power inhalation (DPI) as a new, safe and more effective therapy for PF. In Aim I, we will define cell surface binding/mode action of CSP7, optimize the structure of CSP7, identify the range of dosing for effective airway (neb or DPI) delivery and assess the tolerability and ability of CSP7 to resolve PF in 4 (1X BLM in young and aged mice, Ad-TGF-β1 and 8X BLM) models of PF. In Aim II, we will select the most effective, well-tolerated, optimized form CSP7s (CSP7OPs) identified in Aim I, then evaluate non-GLP pharmacokinetics, toxicology and evaluate systemic biodistribution after airway delivery. In Aim III, we will elucidate the molecular mechanisms by which CSP7OP combined with pirfenidone or nintedanib, affects injured AECs and fLfs to resolve existing PF. Targeting Cav1 with CSP7 represents a novel and promising approach for treatment of IPF via the airway. This project has a high probability of success and the data to be generated is a predicate for IND-enabling work. Our team has all the requisite expertise in cellular/molecular biology, preclinical modeling, drug discovery, formulation and airway drug delivery. This project will likely define novel and potentially more effective therapy for patients with IPF or other ILDs, for whom effective treatment options remain limited.

间质性肺疾病（ILD）的特点是进行性肺部疤痕形成。特发性肺病 纤维化 (IPF) 是最常见的 ILD 形式之一，是一种致命的肺部疾病，发病率为 60 美国每年有病例/100,000 人。 IPF 的中位五年生存率仅为 20%。目前有 无法治愈。 IPF的发病机制以肺泡上皮细胞（AEC）衰老和凋亡为特征， 活化的肌成纤维细胞和纤维化肺成纤维细胞（fLfs）和细胞外的增殖和积累 基质沉积。这些特征导致进行性肺功能障碍。形态变化包括空间和 时间异质性包括与包含细胞凋亡的患病区域相邻的正常肺区域 AEC 和 fLfs。最近，药物治疗已被证明可以减缓 IPF 的进展，这表明更多 可以开发出有效的治疗方法。我们发现 p53 增加有助于 AEC 凋亡和成纤维细胞 激活，并且 fLfs 的下降促进肌成纤维细胞扩张。我们还发现 Caveolin-1 (Cav1) 在受伤的 AEC 中增加，而在 IPF 患者肺部增殖的 fLf 中其水平显着降低 和已确定 PF 的小鼠。我们鉴定了 20 聚体 Cav1 支架结构域肽 (CSP)，及其截短的 7 聚体片段 CSP7，可抑制 p53、TGF-β、CTGF、AEC 细胞凋亡和 fLf 扩增。这些肽可以阻断 单次 (1X) 或多次 (8X) 博来霉素 (BLM)、腺病毒 TGF-β1 (Ad-TGF-β1)- 和二氧化硅- 后小鼠的 PF 诱发肺损伤。 CSP7 由于 fLfs 中 mdm2 表达增加而抑制 p53 降解，并阻断其降解 增殖。 CSP7 还抑制 AEC 衰老和细胞凋亡，而这些在纤维化肺中会增加， 包括IPF。 CSP7 在小鼠体内具有良好的耐受性，并且可以通过气道有效输送。我们的工作 验证 Cav1 作为 PF 的治疗靶点。我们的出版物为开发气道 CSP7 提供了前提 雾化 (neb) 或干粉吸入 (DPI) 是一种新的、安全且更有效的 PF 治疗方法。在 目标一，我们将定义CSP7的细胞表面结合/模式作用，优化CSP7的结构，确定范围 确定有效气道（neb 或 DPI）输送的剂量，并评估 CSP7 解决 PF 的耐受性和能力 在 4 个 PF 模型中（年轻和老年小鼠为 1X BLM，Ad-TGF-β1 和 8X BLM）。在《目标 II》中，我们将选择最多的 目标 I 中确定的有效、耐受性良好、优化形式的 CSP7 (CSP7OP)，然后评估非 GLP 药代动力学、毒理学并评估气道输送后的全身生物分布。在目标 III 中，我们将 阐明 CSP7OP 与吡非尼酮或尼达尼布联合影响损伤的分子机制 AEC 和 fLfs 用于解决现有 PF。用 CSP7 靶向 Cav1 代表了一种新颖且有前途的方法 通过气道治疗IPF。该项目成功的可能性很高，并且要生成的数据是 IND 支持工作的谓词。我们的团队拥有细胞/分子生物学、临床前研究等方面所有必要的专业知识 建模、药物发现、配方和气道药物输送。该项目可能会定义新颖且潜在的 对于 IPF 或其他 ILD 患者来说，更有效的治疗方法对他们来说有效的治疗选择仍然有限。