AbstractmicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported a systemically delivered miR-29 mimic MRG-201 that reduced fibrosis in animal models, but at doses prohibiting clinical translation. Here, we generated MRG-229, a next-gen miR-29 mimic with improved chemical stability, conjugated with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide). In TGF-b-treated human lung fibroblasts and precision cut lung slices, MRG-229 decreased COL1A1 and ACTA2 gene expression and reduced collagen production. In bleomycin-treated mice, intravenous or subcutaneous delivery of MRG-229 downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, and at clinically relevant doses, MRG-229 was well tolerated, with no adverse findings observed. In human peripheral blood decreased mir-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. Collectively, our results provide support for the development of MRG-229 as a potential therapy in humans with IPF.One Sentence SummaryOne Sentence Summary: A stabilized, next-generation miR-29 mimic has been developed that demonstrates efficacy at commercially viable doses with a robust safety margin in non-human primates.
S67 Figure 1S67 on August 4, 2020 by guest. Protected by copyright. Hypothesis Idiopathic pulmonary fibrosis (IPF) remains an incurable fibrotic lung disease. A mesenchymal stem cell (MSC)-mediated S70 Abstract S68 Figure 1 on August 4, 2020 by guest. Protected by copyright.
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