Pulmonary fibrosis is a leading cause of death worldwide. With a median survival of only 2.5 years after diagnosis, it is responsible for millions of deaths worldwide and billions in health care costs each year. Besides mortality, pulmonary fibrosis, of which the idiopathic type is most common, brings about tragic morbidity. Without a known cause of idiopathic pulmonary fibrosis, very few preventive strategies are practical and until recently no therapeutic options were available. The two drugs that were approved for this indication provide some attenuation of the disease, but despite this, clinical decline almost invariably occurs. The long-term goal of STXPC is to bring a drug to the clinic that can reverse the progression of pulmonary fibrosis with more complete results than the current standards of care with reduced or equally acceptable adverse effects. Phenotypic screens identified an FDA approved drug that blocks fibroblast activation in vitro and represses bleomycin-induced pulmonary fibrosis in vivo. In continuation of these efforts, three near term objectives are proposed to set the foundation for future IND-enabling studies. These objectives are: 1) to establish the mechanism of action for the drug, 2) to validate efficacy in additional animal models while also testing alternate routes of administration, and 3) to initiate feasibility studies for the development of an inhalable formulation of the drug. To address the mechanism of action, the hypothesis that the drug activates casein kinase 1 to promote the degradation of critical drivers of the myofibroblast phenotype including YAP/TAZ and/or ?-catenin will be tested. This will be accomplished using genetic and pharmacological techniques in cell culture assays. Two forms of the drug will be tested against in vivo models of pulmonary fibrosis, including bleomycin and asbestos-induced models, through multiple administration routes to establish minimum effective doses and to evaluate oral availability. The final aspect of this proposal includes a collaboration with a contract manufacturing organization to test feasibility of developing a stable nebulizable solution or suspension of the drug that could be used in future animal testing, and possibly lead to a clinical product. Development of this formulation would provide a direct topical medication for the lung, circumventing any inadequacies regarding GI absorption or liver metabolism and minimizing systemic side effects. Pulmonary fibrosis is a severe condition that warrants significant efforts to bring new therapeutics forward for clinical testing. The research team has identified a repurposable drug that holds early potential to reverse the effects of pulmonary fibrosis acting through a unique mechanism, but requires reformulation for an adequate means of administration.
Public Health Relevance Statement: PROJECT NARRATIVE Pulmonary fibrosis, including idiopathic pulmonary fibrosis, is a condition with severe morbidity, high mortality rates, and few therapeutic options for patients. Our research team has identified an FDA approved drug that suppresses fibrosis in in vitro and in vivo models and warrants further development to allow repurposing for pulmonary fibrosis patients. Our project consists of two aims to determine the drugs mechanism of action, validate efficacy in additional animal models, and reformulate for an optimal route of administration.
Project Terms: absorption; Address; Adverse effects; Agonist; American; animal efficacy; Animal Model; Animal Testing; Asbestos; attenuation; base; beta catenin; Biological Assay; Biotechnology; Bleomycin; Caring; casein kinase I; Cause of Death; Cell Culture Techniques; Cells; Cessation of life; Chicago; Clinic; Clinical; Clinical Trials; Collaborations; commercialization; Contracts; cost effective; Data; Development; Diagnosis; Disease; Dose; Down-Regulation; drug development; drug discovery; Drug effect disorder; Drug Formulations; drug mechanism; Drug Targeting; Drug usage; Enterobiasis; Enterobius; Enzymes; Evaluation; experimental study; Faculty; FDA approved; Feasibility Studies; Fibroblasts; Fibrosis; Formulation; Foundations; Funding; Future; Genetic; Goals; Health; Health Care Costs; Health Sciences; Heart; Human; idiopathic pulmonary fibrosis; In Vitro; in vivo; in vivo Model; Inhalation; inorganic phosphate; Intraperitoneal Injections; Kidney; knock-down; Lead; Left; Legal patent; Life Expectancy; Liver; liver metabolism; Louisiana; Lung; Lung diseases; Malignant neoplasm of pancreas; Malignant Neoplasms; Mediating; Medical; member; Modeling; Morbidity - disease rate; mortality; Myofibroblast; nanomolar; new therapeutic target; novel; novel therapeutics; off-patent; Oral; Oral Administration; Organ; Organ failure; Organ Size; overexpression; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Pirfenidone; Positioning Attribute; Preparation; prevent; Prevention strategy; Principal Investigator; programs; Protein Family; Proteins; Pulmonary Fibrosis; Research; research clinical testing; Research Support; Route; side effect; Signal Pathway; Small Business Innovation Research Grant; small hairpin RNA; Sodium Chloride; Solid; Suspensions; Symptoms; Techniques; Testing; Therapeutic; transcription factor; Transforming Growth Factor beta; tumor progression; Universities; Water; Work
