MUC5B, a novel therapeutic target for Idiopathic Pulmonary Fibrosis (IPF)

描述（由申请人提供）：本提案的总体目标是通过使用新型黏液溶解剂靶向糖蛋白MUC5B，推进临床前或轻度IPF的治疗干预，并开发与临床前/轻度IPF检测相关的生物标志物谱。这种方法基于以下基本原理。首先，MUC5B在IPF中是一个经过验证的靶点。MUC5B启动子SNP rs35705950已在六项独立研究中被证实为IPF的风险变异，是家族性和散发性IPF发展的已知最强风险因子（每个等位基因的优势比为H 6-8），并且代表至少一半家族性或散发性IPF病例中观察到的风险变异。其次，MUC5B似乎参与了IPF的发病机制。MUC5B启动子SNP在未受影响的受试者和IPF患者中均与MUC5B表达增强相关，IPF患者的MUC5B基因表达明显高于未受影响的受试者，MUC5B信息和蛋白在IPF的病理病变中表达，我们最近发现MUC5B缺陷小鼠对博来霉素和石棉纤维增殖模型均具有耐药性。第三，我们的研究结果表明，在IPF的临床前/轻度阶段，过量的粘液似乎是致病的。虽然MUC5B启动子SNP是已知IPF最强的危险因素，但我们已经证明MUC5B启动子SNP可以识别间质性肺疾病的临床前/轻度阶段，进一步证明过量粘液似乎与临床前/轻度阶段相关。基于这些观察结果，我们推测MUC5B启动子SNP通过慢性黏液高分泌和外周空气空间积聚使个体处于发生IPF的风险中，从而损害黏液纤毛运输，导致支气管肺泡区黏液粘连，从而诱导和增强慢性炎症和损伤。我们进一步假设，MUC5B诱导的终末期细支气管和可能的肺泡上皮炎症/损伤以及随后的纤维增殖可以部分地通过减减剂如吸入，长效黏液解药来克服，特别是在临床前/轻度疾病阶段。因此，我们假设吸入黏液溶解剂可以有效延缓临床前/轻度IPF的发生和进展。里程碑：在UH2期之后，我们将选择一种长效的吸入性黏液剂，它可以：1)减少肺黏液；2)减少小鼠纤维增生性肺病；3)具有可接受的TI。第二个里程碑包括识别临床前/轻度IPF个体的生物标志物的发展。在UH3阶段之后，我们将

DESCRIPTION (provided by applicant): The overall goals of this proposal are to advance a therapeutic intervention for preclinical or mild forms of IPF by targeting the glycoprotein MUC5B with a novel mucolytic agent and to develop a biomarker profile relevant to the detection of preclinical/mild IPF. This approach is based on the following rationale. First, MUC5B is a validated target in IPF. The MUC5B promoter SNP rs35705950 has been validated as a risk variant for IPF in six independent studies, is the strongest known risk factor for the development of both familial and sporadic forms of IPF (odds ratio H 6-8 per allele), and represents a risk variant observed in at least half of the cases of either familial or sporadic IPF. Second, MUC5B appears to be involved in the pathogenesis of IPF. The MUC5B promoter SNP is associated with enhanced MUC5B expression in both unaffected subjects and patients with IPF, IPF patients have significantly more MUC5B gene expression than unaffected subjects, MUC5B message and protein are expressed in the pathologic lesions of IPF, and we have recently found that Muc5b deficient mice are resistant to both bleomycin and asbestos models of fibroproliferation. Third, our results suggest that excess mucus appears to be pathogenic in the preclinical/mild stages of IPF. While the MUC5B promoter SNP is the strongest known risk factor for IPF, we have shown that the MUC5B promoter SNP may identify preclinical/mild stages of interstitial lung disease, providing further evidence that excess mucus appears to be relevant in the preclinical/mild stages of disease. Based on these observations, we speculate that the MUC5B promoter SNP places individuals at risk of developing IPF via chronic mucus hypersecretion and accumulation in the peripheral airspace that impairs mucociliary transport, results in mucus adhesion in the bronchoalveolar region, and consequently induces and potentiates chronic inflammation and injury. We further postulate that terminal bronchiolar and possibly alveolar epithelial inflammation/injury as well as subsequent fibroproliferation induced by MUC5B can be overcome, in part, by reducing agents such as inhaled, long-acting mucolytics, particularly in the preclinical/mild stages of disease. Thus, we hypothesize that an inhaled mucolytic agent will prove effective in delaying the onset and progression of preclinical/mild IPF. Milestones: Following the UH2 phase, we will select one long-acting, inhaled mucolytic agent that: 1) decreases lung mucus; 2) reduces fibroproliferative lung disease in mice; and 3) has an acceptable TI. A secondary milestone includes the development of biomarkers that identify individuals with preclinical/mild IPF. Following the UH3 phase, we will be fully prepared to submit an IND-application to the FDA. This will require that we: 1) manufacture and scale up production of the long-acting inhaled mucolytic agent; 2) complete toxicology studies in rats and dogs; 3) determine validity of peripheral blood biomarkers for preclinical/mild IPF; and 4) develop a clinical formulation/dosing strategy for controls and patients with IPF. (END OF ABSTRACT)