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

描述（由申请方提供）：本提案的总体目标是通过新型粘液溶解剂靶向糖蛋白MUC 5 B，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。这一做法基于以下理由。首先，MUC 5 B是IPF中经验证的靶标。MUC 5 B启动子SNP rs35705950已在6项独立研究中被验证为IPF的风险变体，是家族性和散发性IPF发展的最强已知风险因素（每个等位基因的比值比H 6-8），代表了在至少一半的家族性或散发性IPF病例中观察到的风险变体。其次，MUC 5 B似乎参与IPF的发病机制。MUC 5 B启动子SNP与未受影响的受试者和IPF患者中MUC 5 B表达增强相关，IPF患者比未受影响的受试者具有显著更多的MUC 5 B基因表达，MUC 5 B信息和蛋白质在IPF的病理损伤中表达，并且我们最近发现Muc 5 b缺陷小鼠对博莱霉素和石棉纤维增生模型均具有抗性。第三，我们的研究结果表明，在IPF的临床前/轻度阶段，过多的粘液似乎是致病的。虽然MUC 5 B启动子SNP是IPF最强的已知风险因素，但我们已经证明MUC 5 B启动子SNP可以识别间质性肺病的临床前/轻度阶段，进一步证明过量粘液似乎与疾病的临床前/轻度阶段相关。 基于这些观察结果，我们推测MUC 5 B启动子SNP使个体处于通过外周空气中的慢性粘液分泌过多和积累而发展IPF的风险中，所述外周空气中的慢性粘液分泌过多和积累损害粘液纤毛转运，导致支气管肺泡区域中的粘液粘附，并因此诱导和增强慢性炎症和损伤。我们进一步假设，终末细支气管和可能的肺泡上皮炎症/损伤以及随后由MUC 5 B诱导的纤维增生可以部分地通过还原剂如吸入的长效粘液溶解剂来克服，特别是在疾病的临床前/轻度阶段。因此，我们假设吸入性粘液溶解剂将被证明可有效延迟临床前/轻度IPF的发作和进展。Military：在UH 2阶段之后，我们将选择一种长效吸入粘液溶解剂，其：1）减少肺粘液; 2）减少小鼠中的纤维增生性肺病;和3）具有可接受的TI。次要里程碑包括开发可识别临床前/轻度IPF个体的生物标志物。在UH 3阶段之后，我们将 充分准备向FDA提交IND申请。这将要求我们：1）制造和扩大长效吸入粘液溶解剂的生产; 2）完成大鼠和犬的毒理学研究; 3）确定外周血生物标志物对临床前/轻度IPF的有效性;以及4）开发用于对照和IPF患者的临床制剂/给药策略。 (END（见摘要）

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)