Phase II Study of Inhales Carbon Monoxide for the Treatment of Idiopathic Pulmona

吸入一氧化碳治疗特发性肺病的二期研究

• 批准号: 8149936
• 负责人: Augustine M Choi
• 金额: $ 190.02万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149936
• 关键词: Address; Biochemical; Biological Markers; Biology; Bleomycin; Breathing; Carbon Monoxide; Cell Death; Cell Proliferation; Cessation of life; Clinical; Clinical Trials; Connective Tissue; Deposition; Development; Disease; Disease Progression; Dose; Effectiveness; Epithelial; Epithelial Cells; Fibroblasts; Fibrosis; Gene Expression Profile; Genes; Genomics; Goals; Hamman-Rich syndrome; Human; Individual; Inhalation Exposure; Interstitial Lung Diseases; Lung; Mesenchymal; Modeling; Molecular; Mononuclear; Mus; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase III Clinical Trials; Physiological; Prognostic Marker; Proteins; Relative (related person); Reporting; Research Personnel; Respiratory Failure; Role; Staging; Structure; Testing; Therapeutic Agents; abstracting; base; clinically relevant; design; experience; novel; peripheral blood; phase 2 study; prevent; response

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by destruction of normal epithelial structure, proliferation of fibroblasts, and deposition of connective-tissue matrix proteins. Most patients experience a relentless progression to respiratory failure and death. Recent progress in dissecting key molecular mechanisms involved in disease progression has set the stage for implementation of novel therapies that prevent epithelial cell death, inhibit matrix deposition and deter mesenchymal cell proliferation. We have established with our reported observations and preliminary studies that low concentration inhaled CO provides protection in a murine model of bleomycin-induced lung fibrosis by targeting multiple molecular pathways relevant to the pathogenesis of IPF. Hypothesis: Inhaled low concentration carbon monoxide will slow or arrest the progression of lung fibrosis in patients with IPF. We will test the hypothesis by addressing the following specific aims: Specific Aim #1: To investigate whether, in IPF patients, 3 months of therapy with low dose inhaled CO results in a relative decrease in peripheral blood levels of MMP7 and stability in secondary indicators of disease progression. Specific Aim #2: To investigate the potential role of an IPF specific peripheral blood mononuclear gene expression signature to predict rates of disease progression and determine responsiveness to inhaled CO. Our goal is to study the use of low-dose inhaled CO as a therapeutic agent to treat IPF in humans. For this purpose we have assembled a remarkable group of basic and clinical researchers with expertise in the pathogenesis of IPF, CO biology, biomarker development, large-scale genomics and IPF clinical trials to investigate the effectiveness of a novel inhaled therapy in this devastating disease. Our ancillary proposals will clarify mechanisms of action of CO and validate a peripheral blood genomic signature capable of predicting individual response to CO treatment. The successful completion of this study will provide the basis for the design of a more definitive phase III clinical trial of low dose inhaled CO in IPF. RELEVANCE: This clinical trial will test our hypothesis that low-dose inhaled carbon monoxide will slow disease progression in IPF patients. We have assembled a group of researchers with expertise in the pathogenesis of IPF, CO biology, biomarker development, large-scale genomics and IPF clinical trials to investigate the effectiveness of a novel inhaled therapy in this devastating disease. Successful completion of this study will provide the basis for the design of a more definitive phase III clinical trial of low dose inhaled CO in IPF. (End of Abstract)

描述（由申请人提供）：特发性肺纤维化（IPF）是一种间质性肺疾病，其特征为正常上皮结构破坏、成纤维细胞增殖和结缔组织基质蛋白沉积。大多数患者都会经历持续的呼吸衰竭和死亡。最近在剖析疾病进展中涉及的关键分子机制方面取得的进展，为实施防止上皮细胞死亡、抑制基质沉积和阻止间充质细胞增殖的新疗法奠定了基础。根据我们报告的观察结果和初步研究，我们已经确定，低浓度吸入 CO 通过针对与 IPF 发病机制相关的多个分子途径，可以在博莱霉素诱导的肺纤维化小鼠模型中提供保护。假设：吸入低浓度一氧化碳会减缓或阻止 IPF 患者肺纤维化的进展。我们将通过解决以下具体目标来检验这一假设： 具体目标#1：调查 IPF 患者接受 3 个月的低剂量吸入 CO 治疗是否会导致外周血 MMP7 水平相对下降以及疾病进展次要指标的稳定性。具体目标#2：研究 IPF 特异性外周血单核基因表达特征在预测疾病进展速率并确定对吸入 CO 的反应性方面的潜在作用。我们的目标是研究使用低剂量吸入 CO 作为治疗剂来治疗人类 IPF。为此，我们聚集了一批出色的基础和临床研究人员，他们在 IPF 发病机制、CO 生物学、生物标志物开发、大规模基因组学和 IPF 临床试验方面拥有专业知识，以研究新型吸入疗法对这种破坏性疾病的有效性。我们的辅助提案将阐明 CO 的作用机制，并验证能够预测个体对 CO 治疗反应的外周血基因组特征。这项研究的成功完成将为设计更明确的低剂量吸入CO治疗IPF的III期临床试验提供基础。相关性：这项临床试验将检验我们的假设，即低剂量吸入一氧化碳将减缓 IPF 患者的疾病进展。我们聚集了一组在 IPF 发病机制、CO 生物学、生物标志物开发、大规模基因组学和 IPF 临床试验方面具有专业知识的研究人员，以研究新型吸入疗法对这种破坏性疾病的有效性。这项研究的成功完成将为设计更明确的低剂量吸入CO治疗IPF的III期临床试验奠定基础。 （摘要完）