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; 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用新型的粘液溶解剂靶向糖蛋白MUC5B来推进临床前或轻度IPF的治疗干预措施，并开发与检测到抗蛋plinical/温和IPF的生物标志物相关的生物标志物。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。 MUC5B启动子SNP RS35705950在六项独立研究中已被确认为IPF的风险变体，是家庭和零星形式的IPF形式发展的最强风险因素（每个等位基因H 6-8），代表至少在两种家庭或sporadic ipf的案例中观察到的风险变体。其次，MUC5B似乎参与IPF的发病机理。 MUC5B启动子SNP与未受影响的受试者和IPF患者的MUC5B表达增强有关，IPF患者的MUC5B基因表达明显高于未受影响的受试者，MUC5B消息和蛋白质在IPF的病理病变中表达，并且我们最近构建了MuC5B对bleymersif and bleymersif and blemorysif and asbleStif and Blesomefif and asbemifif and asbemifif and asblestif。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性的。虽然MUC5B启动子SNP是IPF的最强危险因素，但我们已经表明，MUC5B启动子SNP可能会识别间质肺疾病的临床前/轻度阶段，提供了进一步的证据，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使个人面临通过慢性粘液高出分泌和损害粘膜纤毛运输的慢性粘液分泌和积累的风险，从而导致粘液粘附在粘膜粘附，从而导致粘膜粘附，从而诱导和增强炎症和损伤。我们进一步假设，可以通过减少吸入，长效的粘液液（尤其是在疾病的预性痛苦/轻度阶段）来克服末端支气管和可能的肺泡上皮炎症/损伤以及MUC5B诱导的随后的纤维蛋白增殖。因此，我们假设吸入的粘液溶解剂将有效地延迟临床前/轻度IPF的发作和进展。里程碑：遵循UH2相，我们将选择一种长效，吸入的粘液溶解剂：1）降低肺粘液； 2）减少小鼠纤维增生性肺部疾病； 3）有一个可接受的ti。第二个里程碑包括开发生物标志物，这些生物标志物识别具有临床前/轻度IPF的个体。遵循UH3阶段，我们将 要充分准备向FDA提交索引。这将要求我们：1）生产和扩大长效吸入的粘液溶剂的生产； 2）在大鼠和狗中进行完整的毒理学研究； 3）确定外周血生物标志物对临床前/轻度IPF的有效性； 4）为对照和IPF患者制定临床配方/剂量策略。 （抽象的结尾）