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

描述（由申请方提供）：特发性肺纤维化（IPF）是一种间质性肺病，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。大多数患者经历了呼吸衰竭和死亡的无情进展。在剖析疾病进展中涉及的关键分子机制方面的最新进展为实施预防上皮细胞死亡、抑制基质沉积和阻止间充质细胞增殖的新型疗法奠定了基础。我们通过报告的观察结果和初步研究确定，低浓度吸入CO通过靶向与IPF发病机制相关的多个分子途径，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将减缓或阻止IPF患者的肺纤维化进展。我们将通过解决以下具体目标来检验该假设：具体目标#1：研究在IPF患者中，3个月的低剂量吸入CO治疗是否导致MMP7外周血水平的相对降低和疾病进展的次要指标的稳定性。具体目标#2：研究IPF特异性外周血单核细胞基因表达特征在预测疾病进展率和确定对吸入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作为治疗剂治疗人类IPF。为此，我们召集了一组在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基础和临床研究人员，以研究新型吸入疗法在这种毁灭性疾病中的有效性。我们的辅助建议将阐明CO的作用机制，并验证外周血基因组特征能够预测CO治疗的个体反应。本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。我们召集了一组在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在这种毁灭性疾病中的有效性。本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。(End摘要）

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)