Novel Mucolytic Agents

DESCRIPTION (provided by applicant): Mucus transport is the fundamental defense of the airways against inhaled particulates/infectious agents. Abnormalities in the mucus transport system characterize a complex of muco-obstructive airway diseases, such as cystic fibrosis (CF) and chronic bronchitis (CB). CB associated with CF affects 30,000 Americans, and the CB associated with environmental causes, e.g., COPD, affects more than 14,000,000 Americans. The pathogenesis of CB is multi-factorial, but we hypothesize that it includes a common, disease-initiating step, i.e., generation of excessively dehydrated mucus. The best known physical property of mucus that correlates with reduction of clearance in CF/COPD is the increased mucus concentration (from 2% solidsin normal to gt 8% solids in CF) as a result of abnormal ion/water transport coupled with mucin hypersecretion. We hypothesize that mucus concentration correlates with a series of other physical properties that determine the efficiency of mucus clearance.Further, we predict that for mild levels of dehydration, normal clearance can be restored by simple rehydration. However, we theorize that more severe mucus dehydration leads to increased mucus adhesion to the PCL that prevents restoration of clearance upon simple rehydration. Parion Science's goal is to develop therapies that provide major improvements in efficacy over current treatments for CF and COPD lung disease. Parion's focus has historically been the development of novel therapeutic agents to restore airways hydration. However, we recognize that there is an unmet medical need for mucolytic agents that alter the physical properties of mucus to improve clearance. The available agents (e.g. Mucomyst and Mucinex) are poorly characterized and modestly effective at best. The broad goal of this application is the development of new and efficacious mucolytic agents specifically optimized for pulmonary indications. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Chronic bronchitis affects more than 14,000,000 Americans and is characterized by the inability to effectively remove mucus from the lungs. The retention of thick, viscous mucus in the airways decreases lung function and leads to persistent infections. In this application, we propose to develop novel drugs specifically designed to help clear adherent mucus from the lungs.