Chronic intrapulmonary delivery of a novel small molecule Wnt/beta-catenin inhibitor for Idiopathic Pulmonary Fibrosis

Project Summary Idiopathic pulmonary fibrosisIPFis a devastatingprogressive disease with no known cure and no treatment that convincingly alters the disease course or significantly improves mortalityThe objective of this proposal is the development of nebulized delivery of the small molecule inhibitor of Wntcatenin signalingBCfor Idiopathic Pulmonary FibrosisPre clinical studies in rodentsdogsand minipigs show that BChas favorable pharmacokinetics and safety data with intravenous administrationwhich provides support for short term useHoweverin a chronic diseasesuch as IPFwhich requires prolonged treatmentintravenous administration is undesirable for patientsNebulization of BCwould achieve high local levels of the drugwhile minimizing off target side effects in other critical organswhich is key for the chronic treatment of patients with pulmonary fibrosisIn Specific Aima respiratory formulation of BCwill be optimized to generate particle sizesm to allow for maximal distribution into the alveolar spacesIn Specific Aimthe efficacy and pharmacodynamics of nebulized administration of BCwill be determined in vivo using two mouse models of chronic pulmonary fibrosisusing intratracheally administered asbestos and repetitive intratracheal administration of bleomycinboth of which create non resolving fibrosisNebulized BCwill be administered after the establishment of pulmonary fibrosisin order to determine whether the drug improves the resolution of fibrosiswhich would increase its translational potential and make a clinically meaningful impact for patientsThe overall goal for this Phaseapplication is the generation of high quality pre clinical data that will provide a highly compelling rationale for clinical trials for the treatment of IPF and potentially other fibrotic lung diseases Project Narrative The goal of this proposal is the development of nebulized delivery of the small molecule inhibitor of Wntcatenin signalingBCfor Idiopathic Pulmonary FibrosisThis approach would achieve high local levels of the drugwhile minimizing off target side effects in other critical organsfor the chronic treatment of patients with pulmonary fibrosisThe findings from these studies will provide a highly compelling rationale for clinical trials using nebulized BCfor the treatment of IPF and potentially other fibrotic lung diseases