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.
Our recent discovery that MUC5B is a highly significant and common genetic risk factor for established IPF and early interstitial lung disease suggests that the MUC5B variant has the potential to detect preclinical or mild disease. Furthermore, our colleagues at Parion Sciences have developed novel soluble mucolytic agents that reduce MUC5B polymers with high potency and efficacy, and are well-suited as inhaled therapies. The studies we propose have the potential to improve the preclinical diagnosis and treatment of pulmonary fibrosis, and thus could have a highly significant overall impact on what is now essentially an incurable disease.
|Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6|
|Mathai, Susan K; Pedersen, Brent S; Smith, Keith et al. (2016) Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1151-60|
|Evans, Christopher M; Raclawska, Dorota S; Ttofali, Fani et al. (2015) The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun 6:6281|
|Mathai, Susan K; Schwartz, David A (2015) Taking the ""I"" out of IPF. Eur Respir J 45:1539-41|