Targeting Synaptotagmin to Prevent Airway Mucus Obstruction

PROJECT SUMMARY Mucus dysfunction underlies the pathophysiology of a number of common respiratory diseases including asthma cystic fibrosis and chronic obstructive pulmonary disease COPD Asthma alone impacts of the US population resulting in considerable cost morbidity and occasional mortality caused by mucus hypersecretion Recently it was discovered that Synaptotagmin Syt regulates fast exocytosis of mucin granules in the lungs and that Syt is limiting with respect to stimulated mucus secretion These findings suggest that small molecule inhibitors of Syt may comprise a new class of therapeutic agents allowing the clinical modulation of stimulated mucus secretion We have developed a number of early lead inhibitors of Syt capable of inhibiting mucus secretion in airways of mice with IL induced mucous metaplasia These include Exo our early lead compound Phase I studies will focus on the derivatization of the Exo compound and success would advance a new drug class likely to improve quality of life for patients with a number of life threatening chronic respiratory conditions including asthma cystic fibrosis and COPD Phase II work would include formulation and delivery studies followed by pre IND studies including GLP toxicology and animal efficacy studies in accordance with the most recent CDER guidance PROJECT NARRATIVE In this Phase I project inhibitors against Syt are pursued as potential clinical therapeutic agents targeting mucus hypersecretion Mucus dysfunction is at the heart of major respiratory diseases including asthma cystic fibrosis and chronic obstructive pulmonary disease Following up on recent findings that Syt plays a limiting role in mucus hypersecretion in the lungs this project proposes optimization of lead compound Exo