MicroRNA mimicry blocks pulmonary fibrosis

• Published in: EMBO molecular medicine 2014-10, Vol.6 (10), p.1347-1356
• Main Authors: Montgomery, Rusty L, Yu, Guoying, Latimer, Paul A, Stack, Christianna, Robinson, Kathryn, Dalby, Christina M, Kaminski, Naftali, van Rooij, Eva
• Format: Article
• Language: English
• Subjects: Animals; Bleomycin; Blotting, Northern; Cell Line; Cell Line, Tumor; Collagen; Cytokines; Disease; EMBO28; EMBO35; Experiments; Extracellular matrix; Fibroblasts; Fibrosis; Gene expression; Gene Expression Profiling; Gene Expression Regulation - physiology; Gene regulation; Health aspects; Humans; Intravenous administration; Lung diseases; Lungs; Male; Medical research; Medicine, Experimental; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; mimic; Mimicry; miRNA; miR‐29; Molecular Mimicry - genetics; Molecular Mimicry - physiology; NIH 3T3 Cells; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - physiopathology; Recovery of function; Reverse Transcriptase Polymerase Chain Reaction; Spleen; therapeutics
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201303604

Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR‐29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast‐enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR‐29 levels in vivo for several days. Moreover, therapeutic delivery of these miR‐29 mimics during bleomycin‐induced pulmonary fibrosis restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR‐29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. Synopsis Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function thereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. MicroRNA mimics can be used to increase levels of miRNAs in vivo in a time and dose‐dependent manner. miR‐29 mimic does not affect target gene expression under basal conditions. miR‐29 mimic can block and reverse aspects of bleomycin‐induced pulmonary fibrosis. Graphical Abstract Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.