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

描述(申请人提供)：特发性肺纤维化(IPF)是一种间质性肺疾病，以正常上皮结构破坏、成纤维细胞增殖和结缔组织基质蛋白沉积为特征。大多数患者都经历了呼吸衰竭和死亡的无情进展。最近在解剖疾病进展过程中的关键分子机制方面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。根据我们已报道的观察和初步研究，我们已经证实，低浓度吸入CO通过靶向与IPF发病相关的多个分子途径，在博莱霉素诱导的小鼠肺纤维化模型中起到保护作用。假设：吸入低浓度一氧化碳可以减缓或阻止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：调查在IPF患者中，低剂量吸入CO治疗3个月是否导致外周血中MMP7水平的相对下降和疾病进展的二级指标的稳定性。具体目的#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作为治疗剂来治疗人类的IPF。为此，我们召集了一批在IPF发病机制、CO生物学、生物标记物开发、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，以调查一种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一氧化碳的作用机制，并验证能够预测个体对一氧化碳治疗反应的外周血液基因组特征。这项研究的成功完成将为设计更明确的低剂量吸入CO在IPF中的III期临床试验提供基础。相关性：这项临床试验将验证我们的假设，即低剂量吸入一氧化碳将减缓IPF患者的疾病进展。我们召集了一批在IPF发病机制、CO生物学、生物标记物开发、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，以调查一种新型吸入疗法对这种毁灭性疾病的有效性。这项研究的成功完成将为设计更明确的低剂量吸入CO在IPF中的III期临床试验提供基础。(摘要结束)

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)