Small Molecule Degradation of the microRNA-21 Precursor Rescues Pathogenic Pathways in Cellular Models of Fibrosis
Wang, T.; Yang, X.; Li, Y.; Song, J. H.; Disney, J. L.; Garcia, J. G. N.; Disney, M. D.
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MicroRNAs (miRNAs) are short RNA molecules that bind to target mRNAs, resulting in translational repression and gene silencing. Overexpression of microRNA-21 (miR-21) is associated with various human diseases, including autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis. In this study, a previously described heterobifunctional molecule, TGP-21-RiboTAC, that degrades the miR-21 precursor (pre-miR-21) in triple negative breast cancer cells was investigated in polycystic kidney cell lines and a lung fibroblast cell line. In the former, TGP-21-RiboTAC degraded pre-miR-21 and de-repressed of miR-21s downstream target, Programmed Cell Death 4 (PDCD4) and Peroxisome Proliferator-Activated Receptor alpha (PPAR), known drivers of ADPKD. The heterobifunctional molecule also inhibited cyst growth and rescued the metabolic alterations that occur in ADPKD. In the lung fibroblast cell line, MRC-5, TGP-21-RiboTAC also reduced pre- and mature miR-21 levels, rescued Transforming Growth Factor {beta} (TGF-{beta})-induced repression of SMAD Family Member 7 (SMAD7) and inhibited cell invasion. Collectively, these studies demonstrate the potential of targeted RNA degradation as therapeutic agents that retard the development of organ fibrosis.
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