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Small-Molecule Degradation of the MicroRNA-21 Precursor Rescues Pathogenic Pathways in Cellular Models of Fibrosis
Tenghui Wang1,2, Xueyi Yang1,2, Yeongju Lee1,2
1Department of Chemistry, and Center for RNA Genomic Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology130 Scripps Way, Jupiter, Florida33458, United States.
Abstract:
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 derepressed miR-21's downstream targets, programmed cell death 4 (PDCD4) and peroxisome proliferator-activated receptor alpha (PPARα), 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 β (TGF-β)-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.
Insights
A novel molecule, TGP-21-RiboTAC, effectively degrades microRNA-21 (miR-21) precursors. This targeted RNA degradation approach shows promise in treating diseases like autosomal dominant polycystic kidney disease and pulmonary fibrosis by inhibiting fibrosis.
Area of Science:
- Molecular Biology
- RNA Therapeutics
- Disease Pathology
Background:
- MicroRNAs (miRNAs) regulate gene expression; miR-21 overexpression is linked to diseases like ADPKD and pulmonary fibrosis.
- Autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis are debilitating conditions with limited therapeutic options.
Purpose of the Study:
- To investigate the efficacy of the heterobifunctional molecule TGP-21-RiboTAC in degrading miR-21 precursors.
- To evaluate the therapeutic potential of TGP-21-RiboTAC in preclinical models of ADPKD and pulmonary fibrosis.
Main Methods:
- TGP-21-RiboTAC was tested in polycystic kidney cell lines and a lung fibroblast cell line (MRC-5).
- Degradation of pre-miR-21 and mature miR-21 levels were assessed.
- Downstream targets of miR-21, including PDCD4, PPARα, and SMAD7, were analyzed.
- Effects on cyst growth, metabolic alterations, and cell invasion were evaluated.
Main Results:
- TGP-21-RiboTAC successfully degraded pre-miR-21 in kidney cells, leading to derepression of PDCD4 and PPARα, key drivers of ADPKD.
- The molecule inhibited cyst growth and corrected metabolic abnormalities in ADPKD models.
- In lung fibroblasts, TGP-21-RiboTAC reduced miR-21 levels, rescued TGF-β-induced SMAD7 repression, and inhibited cell invasion.
Conclusions:
- Targeted RNA degradation using molecules like TGP-21-RiboTAC is a viable therapeutic strategy.
- This approach shows potential for retarding the development of organ fibrosis in diseases such as ADPKD and pulmonary fibrosis.
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