Inhibition of runt related transcription factor 1 with Ro24-7429 improves lung function in experimental models of...

Idiopathic Pulmonary Fibrosis (IPF) is a life limiting disease with debilitating symptoms and limited therapeutic options. The development of IPF is a chronic process involving epithelial-to-mesenchymal transition (EMT), perpetuated by fibroblast proliferation and abnormal wound healing during which normal lung tissue is replaced with collagen impairing lung expansion and aeration. We targeted Runt-related transcription factor 1 (RUNX1), a transcription factor that coordinates EMT upon stimulation by key inflammatory mediators, such as TGF-β and TNF-α. In a previous investigation performed during the COVID19 pandemic, inhibiting RUNX1 with the small molecule inhibitor Ro24-7429 (Ro24), which has undergone testing in humans with a favorable side effect profile, was linked to a robust amelioration of lung fibrosis and decreased markers of fibrosis. In prior work utilizing Ro24, no studies of pulmonary function were performed and investigation of RUNX1 in human lung tissue was limited. Herein, we identified abnormally elevated RUNX1 in diseased human lung tissue of seven patients with IPF, implicating the transcription factor in the progression of the disease. Targeting RUNX1 with the small molecule inhibitor, Ro24 improved lung function and exercise tolerance in a murine model of bleomycin-induced pulmonary fibrosis. In comparison to the currently used clinical standards nintedanib and pirfenidone, Ro24 improved exercise tolerance in bleomycin-challenged mice. Thus, Ro24 has strong translational potential as a preventative therapy for patients with IPF.