Abstract. Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder affecting ∼3 million people worldwide with function-limiting progressive symptoms and a 2-3 year median survival time from diagnosis. While the etiology of IPF is not clear, genetic factors, environmental exposures and microbial pathogens have been identified as IPF risk factors. Pirfenidone and nintedanib currently are two orally administrated fibrosis inhibitors. However, both are accompanied by a wide adverse effect profile, limiting utility. Thus, a high unmet need exists for tolerable and effective treatment options. Based on a discovery in the academic partner Yale university laboratory, TargetSite Therapeutics Corporation is developing a novel class of oligonucleotide therapeutic agents that selectively interfere with the binding interaction of an “enhancing microRNA” (e-miRNA), miR466l-3p, to specific target sites within an mRNA’s 3’UTR. These “target site blocking” (TSB) oligonucleotides effectively and specifically interfere with the production of individual pro-inflammatory cytokines and growth factors including IL-17A, IL-22, GM-CSF, IL-23A, VEGF-A and IL-1β. IL-17A has been reported to be significantly elevated in the bronchoalveolar lavage (BAL) fluid of IPF patients. We therefore propose targeting the IL-17A mRNA with a specific TSB and assess its efficacy in the established bleomycin- induced lung fibrosis (IPF) model. In partnership with Matinas Biopharma, attempts will be made to encapsulate the IL-17A TSB in multilayered lipid nanocrystals, which are optimized for oral delivery. We will validate the efficacy of these TSB-LNC in Th17 cells in vitro, and for their biological activity in reduction of LPS-induced IL- 17A in mice. The efficacy of LNC-encapsulated and naked (PBS) IL-17A TSB oligos will be tested, both by intraperitoneal and oral (via gavage) delivery, in the bleomycin-induced murine IPF model. Primary assessment parameters will be lung fibrosis, histopathological and biochemically, as well as BAL fluid and serum IL-17A levels. A reduction in disease severity, as determined by >50% reduction in quantifiable fibrosis, is expected as an achievable milestone and a definable criterion for success. Experimental evidence from this project will confirm whether the IL-17 mRNA-directed oligos beneficially modify the disease, providing a novel therapeutic in the treatment of IPF.