Inhibition of Mucin Secretion in Murine Model of Asthma

DESCRIPTION (provided by applicant): Hypersecretion of mucus into the respiratory airways is a major factor in several lung diseases, including chronic bronchitis, asthma, cystic fibrosis, and bronchiectasis. Despite the obvious medical importance, mechanisms that regulate production and secretion of airway mucus have not been elucidated fully, and, relatedly, there presently are no effective therapies to control excess mucus secretion in disease, and very few potential therapeutic targets. In previous NIH-funded research from the laboratories of the scientific consultants, a key molecule in the secretory pathway in human airway goblet cells was described. This molecule, MARCKS protein (Myristoylated Alanine-Rich C Kinase Substrate) plays a major role in regulating secretion of mucus in well-differentiated human airway epithelial cells in vitro. In the course of these studies, we developed a peptide to inhibit the function of MARCKS. The peptide corresponds to the N-terminal region of the MARCKS molecule. The peptide, named the MANS peptide, inhibits secretion of mucus by normal human bronchial epithelial (NHBE) cells in tissue culture in response to exogenous stimulation. A control peptide, consisting of the same N-terminal amino acids, but arranged in random order, has no effect. In the present application, we wish to determine if this peptide, instilled intratracheally into asthmatic mice that secrete excessive amounts of mucus can, similar to its effects in vitro, inhibit mucus secretion in vivo. If successful, these studies will be expanded in Phase II to include additional species, efficacy and toxicity studies, and research to optimize peptide solubility and stability; steps necessary for commercial development. The long-term goal is to develop a novel treatment that reduces mucus hypersecretion in the respiratory tract by directly blocking a step in the intracellular secretory pathway.