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: 10524032
• 负责人: Sreerama Shetty
• 金额: $ 44.84万
• 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/10524032
• 关键词: Acceleration; 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; Disparity; Dose; Drug Delivery Systems; Drug Kinetics; Dryness; Dyspnea; Epithelial Cells; Extracellular Matrix; FDA approved; Fibroblasts; Formulation; Functional disorder; Future; Heterogeneity; In Vitro; Incidence; Individual; Inhalation; Inhalation Device; Interstitial Lung Diseases; Intervention; Invaded; 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; 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; caveolin 1; cell type; connective tissue growth factor; drug candidate; drug discovery; effective therapy; efficacy evaluation; efficacy testing; fibrotic lung; fibrotic lung disease; idiopathic pulmonary fibrosis; improved; in vivo; injured; innovation; lung injury; lung lesion; migration; mouse model; nintedanib; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; pre-clinical assessment; 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）的特征是进行性肺部疤痕。特发性肺 纤维化（IPF）是最常见的ILD形式之一，是一种致命的肺部疾病，有60例 案件/100,000人在美国年度。 IPF的中位数五年生存仅20％。目前有 无法治愈。 IPF的发病机理的特征是肺泡上皮细胞（AEC）感应和凋亡， 激活的肌纤维细胞和纤维化肺成纤维细胞（FLFS）和细胞外肺成纤维细胞的增殖和积累 基质沉积。这些功能导致肺部功能障碍。形态学变化包括空间和 临时异质性结合了正常肺的区域，毗邻含有凋亡的孤立区域 AEC和FLFS。最近，药物治疗已显示出降低IPF的进展，这表明更多 可以开发有效的治疗方法。我们发现p53增加有助于AEC凋亡和成纤维细胞 激活，FLFS的下降会促进肌纤维细胞的扩张。我们还发现Caveolin-1（Cav1） 受伤的AEC的增加，而其水平显着降低了IPF患者肺的增殖FLF 和既定PF的小鼠。我们确定了一个20-Mer Cav1脚手架肽（CSP），其截断 7-mer片段CSP7，抑制p53，TGF-β，CTGF，AEC凋亡和FLF扩张。这些肽阻塞 在单个（1x）或多命中（8x）博来霉素（BLM），腺病毒TGF-β1（AD-TGF-β1）和二氧化硅 - 诱发肺损伤。 CSP7抑制p53的降解，因为FLF中的MDM2表达增加并阻止其阻塞 增殖。 CSP7还抑制AEC的感应和凋亡，否则在纤维化肺中会增加 包括在IPF中。 CSP7在小鼠中耐受性良好，可以通过气道有效地传递。我们的工作 验证CAV1为PF中的治疗靶标。我们的出版物提供了开发Airway CSP7的前提 通过雾化（NEB）或干功率吸入（DPI）作为PF进行新的，安全，更有效的治疗方法。 AIM I，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 有效气道（NEB或DPI）的剂量交付和评估CSP7解决PF的能力和能力 在4（年轻小鼠和年龄小鼠中的1x BLM中，AD-TGF-β1和8X BLM的PF）中。在AIM II中，我们将选择最多 在AIM I中确定的有效，耐受性良好，优化的形式CSP7S（CSP7OPS），然后评估了非GLP 药代动力学，毒理学和评估呼吸道输送后的全身生物分布。在AIM III中，我们将 阐明CSP7OP与吡啶酮或nyntedanib结合的分子机制会影响受伤 AEC和FLF可以解决现有的PF。用CSP7靶向CAV1代表了一种新颖而有希望的方法 通过气道处理IPF。该项目的成功可能性很高，要生成的数据是 谓词的谓词。我们的团队拥有蜂窝/分子生物学的所有必要专业知识，临床前 建模，药物发现，配方和气道药物输送。这个项目可能会定义小说，并有可能 对于IPF或其他ILD患者，有效治疗方案仍然有限的患者更有效的疗法。