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

描述(由申请人提供)：这项建议的总体目标是通过以新型粘液溶解剂靶向糖蛋白MUC5B来推进对临床前或轻度IPF的治疗干预，并开发与检测临床前/轻度IPF相关的生物标记物。这种方法基于以下基本原理。首先，MUC5B是IPF中经过验证的目标。在6项独立研究中，MUC5B启动子SNP rs35705950已被确认为IPF的风险变量，是家族性和散发性IPF发生的最强已知危险因素(优势比H6-8/等位基因)，并且代表至少一半的家族性或散发性IPF病例中观察到的风险变量。其次，MUC5B似乎参与了IPF的发病机制。MUC5B启动子SNP与MUC5B基因表达增强相关，IPF患者的MUC5B基因表达显著高于非IPF患者，MUC5B信息和蛋白在IPF的病理病变中表达，我们最近发现MUC5B基因缺陷小鼠对博莱霉素和石棉的纤维增殖模型都具有耐药性。第三，我们的结果表明，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IPF最强的已知危险因素，但我们已经证明，MUC5B启动子SNP可以识别临床前/轻度间质性肺疾病，提供了进一步的证据，表明过量粘液似乎与临床前/轻度疾病有关。基于这些观察，我们推测MUC5B启动子SNP通过慢性粘液高分泌和聚集在周围空隙而使个体处于发生IPF的风险中，从而损害粘液纤毛运输，导致粘液粘连在支气管肺泡区，从而诱导和加强慢性炎症和损伤。我们进一步推测，MUC5B引起的终末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少吸入的长效粘液类药物来克服，特别是在临床前/轻度疾病阶段。因此，我们假设吸入粘液剂将被证明在延缓临床前/轻度IPF的发生和发展方面有效。里程碑：在UH2阶段之后，我们将选择一种长效吸入型粘液溶解剂：1)减少肺粘液；2)减少小鼠的纤维增生性肺部疾病；以及3)具有可接受的抑制指数。第二个里程碑包括开发识别临床前/轻度IPF患者的生物标记物。在UH3阶段之后，我们将 为向FDA提交IND申请做好充分准备。这将需要我们：1)生产和扩大长效吸入型粘液剂的生产；2)在大鼠和狗身上进行完整的毒理学研究；3)确定临床前/轻度IPF的外周血液生物标志物的有效性；以及4)为对照和IPF患者制定临床配方/剂量策略。 (摘要结束)

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)