Activation of lung myofibroblasts (LMF) is responsible for the development of lung fibrosis in chronic lung diseases of all causes and remarkably, LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury, and possibly allow recovery from reversal of lung fibrosis. There is full agreement among tissue fibrosis experts that inhibiting o reversing myofibroblast activation (the therapeutic target) is critical fr the treatment of lung fibrosis. Both preventing progression of lung fibrosis as well as possibly, regression of lung fibrosis in spite of continued lung injury, as we clearly documented in our pre-clinical studies, are considered important clinical targets for patients with chronic lung disease and lung fibrosis. Finally, blocking the progression of lung fibrosis may decrease development of lung cancer. The basis for our Research and Development is the development of novel humanized C/EBP? peptoids (not previously reported). We created a library using analog synthesis to improve potential pitfalls for human therapy. We have performed in a step-wise manner assays to select the safest and most efficient 'humanized'peptoids (including apoptosis assays in activated primary human myofibroblasts;cell-free caspase 8 activation assays;lung injury/fibrogenesis models;toxicology assays in mice). We have developed novel and effective anti-fibrotic peptoids with expected decreased immunogenicity and improved stability and bioavailability during clinical trials. The proposed compounds markedly inhibit activation of human and mouse myofibroblast in culture. These compounds were not toxic in the preliminary toxicology studies, including pilot toxicogenomics, to mice at least at 100-fold the therapeutic dose.
The aims that are proposed for completion by this STTR are: Chronic lung fibrogenesis assays in mouse models;Pharmacokinetics;In Vitro Metabolic Stability Studies;Pharmacokinetics;Potential off-target liabilities for Molecular Toxicology and Exploratory Toxicology. There is no medication for the treatment or prevention of lung fibrosis. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with lung fibrosis.
Chronic lung diseases, through inflammation and injury induce the development of scar tissue in the lung;this is called lung fibrosis. Excessive lung fibrosis can result in lung dysfunction, which accounts for the significant complications and mortality among the population with chronic lung diseases. The medical and financial burden of fibrotic lung diseases to the USA is substantial, as it is associated with emphysema, chronic bronchitis, pulmonary idiopathic fibrosis, and scleroderma and radiation therapy to the chest to treat lung and breast cancer. Additional knowledge gained by Xfibra with this work will facilitate the development of medication given by inhalation for the treatment of lung injury and fibrosis. Development of effective treatments for lung fibrosis may also facilitate future treatments for skin and kidney fibrosis.
| Buck, Martina; Solis-Herruzo, Jose; Chojkier, Mario (2016) C/EBP?-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury. Sci Rep 6:24268 |
