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

MUC5B，特发性肺纤维化（IPF）的新治疗靶点

• 批准号: 9321207
• 负责人: David Albert Schwartz
• 金额: $ 157.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321207
• 关键词: Adhesions; Alleles; Alveolar; Asbestos; Biological Assay; Biological Markers; Bleomycin; Breathing; Canis familiaris; Cells; Chemistry; Chronic; Clinical; Data; Detection; Development; Diagnosis; Disease; Dose; Effectiveness; Epithelial; Family; Formulation; Gene Expression; Glycoproteins; Goals; Hamman-Rich syndrome; Impairment; In Vitro; Individual; Inflammation; Injury; Interstitial Lung Diseases; Knockout Mice; Lead; Lesion; Lung; Lung diseases; MUC5B gene; Modeling; Mucociliary Clearance; Mucolytics; Mucous body substance; Mus; Odds Ratio; Pathogenesis; Pathogenicity; Pathologic; Patients; Performance; Peripheral; Phase; Polymers; Production; Property; Proteins; Pulmonary Fibrosis; Rattus; Reducing Agents; Resistance; Risk; Risk Factors; Science; Series; Structure; Structure of respiratory bronchiole; Structure-Activity Relationship; Terminal Bronchiole; Testing; Therapeutic Index; Therapeutic Intervention; Time; Toxic effect; Toxicology; Triage; Variant; base; biomarker development; clinical development; design; genetic risk factor; improved; in vivo; man; manufacturing scale-up; mucus hypersecretion; new therapeutic target; novel; patient population; peripheral blood; pre-clinical; programs; promoter; risk variant; specific biomarkers

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)

描述（由申请人提供）：该提案的总体目标是通过使用新型粘液溶解剂靶向糖蛋白 MUC5B 来推进临床前或轻度 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。该方法基于以下原理。首先，MUC5B 是 IPF 中经过验证的靶点。 MUC5B 启动子 SNP rs35705950 已在六项独立研究中被验证为 IPF 的风险变异，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），并且代表在至少一半的家族性或散发性 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与未受影响受试者和IPF患者中MUC5B表达增强相关，IPF患者比未受影响受试者具有显着更多的MUC5B基因表达，MUC5B信息和蛋白在IPF病理病变中表达，并且我们最近发现Muc5b缺陷小鼠对博来霉素和石棉纤维增殖模型具有抵抗力。第三，我们的结果表明，过量的粘液似乎在 IPF 的临床前/轻度阶段具有致病性。虽然 MUC5B 启动子 SNP 是已知最强的 IPF 风险因素，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，从而进一步证明过多的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MUC5B启动子SNP通过慢性粘液过度分泌和在周围空腔中的积累而使个体面临发展IPF的风险，从而损害粘液纤毛运输，导致支气管肺泡区域粘液粘附，从而诱发和加剧慢性炎症和损伤。我们进一步假设，由MUC5B诱导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吸入长效粘液溶解剂等还原剂来克服，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可有效延缓临床前/轻度 IPF 的发病和进展。里程碑：UH2 阶段之后，我们将选择一种长效吸入性粘液溶解剂，它： 1) 减少肺部粘液； 2) 减少小鼠纤维增生性肺病； 3) 具有可接受的 TI。第二个里程碑包括开发识别患有临床前/轻度 IPF 个体的生物标志物。 UH3 阶段之后，我们将 做好向 FDA 提交 IND 申请的充分准备。这将要求我们：1）制造并扩大生产长效吸入性粘液溶解剂； 2）完成大鼠和狗的毒理学研究； 3) 确定临床前/轻度IPF外周血生物标志物的有效性； 4) 为对照组和 IPF 患者制定临床制剂/剂量策略。 （摘要结束）