New anti-fibrotic drugs are needed to treat Idiopathic Pulmonary Fibrosis (IPF). IPF is a progressive, chronically debilitating clinical syndrome with unknown etiology and a terminal outcome. IPF symptoms include persistent cough, progressive severe shortness of breath and decreased exercise capacity. Up to 200,000 Americans suffer from this disease with expected survival limited to 3-5 years. There are currently no approved US drugs leaving lung transplantation as the only option to extend life. IPF is initially characterized by alveolar epithelial cell injury followed by epithelial-mesenchymal transition (EMT) and exaggerated fibroblast migration, activation and proliferation with extracellular matrix deposition and tissue remodeling. When a sufficient proportion of the IPF lung becomes scarred respiratory failure and comorbidities occur. WNT1- Inducible Signaling Protein-1 (WISP1; also known as CCN4) is an autocrine and paracrine extracellular stimulus for EMT. Studies have shown that: 1. WISP1 is induced in human lung cells by TGF-¿; 2. WISP1 is upregulated at the alveolar epithelial surface in IPF; 3. WISP1 protein stimulates EMT and fibroblast ECM deposition in vitro; 4. depletion of WISP1 with neutralizing antibodies attenuates bleomycin-induced pulmonary fibrosis in vivo. Currently, no IPF drugs are in development that target WISP1 or the WNT pathway. Together with our collaborators we have outlined experiments that will harness a powerful combination of antibody discovery, fibrotic pathway expertise and aerosol drug development to provide a solid basis for the discovery, evaluation and development of an anti-WISP1 immunotherapy for IPF treatment.
Thesaurus Terms: Address;Aerosols;Affect;Alveolar;American;Analytical Method;Antibodies;Attenuated;Autocrine;Back;Base;Biophysical Properties;Bleomycin;Candidate Identification;Cell Injury;Cells;Cicatrix;Clinical;Collaborations;Comorbidity;Coughing;Data;Deposition;Design;Development;Disease;Drug Delivery Systems;Drug Development;Drug Kinetics;Epithelial;Epithelial Cells;Etiology;Evaluation;Event;Exercise;Extracellular;Extracellular Matrix;Fatal Outcome;Fda Approved;Fibroblasts;Fibrosis;Future;Growth Factor;Hamman-Rich Syndrome;Human;Human Wisp1 Protein;Hyperplasia;Immunotherapy;In Vitro;In Vivo;Intravenous;Kinetics;Left Lung;Libraries;Life;Life Expectancy;Lung;Lung Transplantation;Matrix Metalloproteinases;Mediating;Mesenchymal;Method Development;Migration;Modeling;Monoclonal Antibodies;Neutralizing Antibody;Novel;Outcome;Paracrine;Pathway Interactions;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Pre-Clinical;Process;Production;Public Health Relevance;Pulmonary Disease (Specialty);Pulmonary Fibrosis;Regulation;Research Study;Respiratory Failure;Risk;Route;Safety;Shortness Of Breath;Signal Transduction;Signaling Protein;Solid;Stimulus;Structure Of Parenchyma Of Lung;Surface;Symptoms;Syndrome;Therapeutic;Tissues;Universities;Wisp1 Gene;Wnt1 Gene;
