01/30/2025
The Macro Potential of MicroRNAs
MicroRNAs (miRNAs) are a class of short noncoding RNAs that modulate gene expression across a broad range of developmental and diseaseprocesses. Following their discovery in C. elegans in 1993, miRNAs were initially dismissed as a nematode-specific anomaly. Not until the early 2000s did researchers, empowered by advances in genomics, realize that miRNAs are present in virtually all eukaryotic organisms, where they represent a powerful and essential mechanism for the post-transcriptional regulation of gene expression. miRNAs are single-stranded, typically between 21 and 25 nucleotides in length, and synthesized thorough a well-defined multi-stage process. In brief, loci are first transcribed into primary miRNAs (pri-miRNAs), which adopt a characteristic hairpin structure and are cleaved by the nuclear enzyme Drosha. The resultant precursor miRNAs (pre-miRNAs) are exported to the cytoplasm, where they are subjected to further cleavage by the enzyme Dicer. Finally, mature miRNAs are loaded into a specialized ribonucleotide complex called RISC (RNA-Induced Silencing Complex). Binding of RISC to appropriate targets is directed by complementary interactions between the loaded miRNA guide and its cognate sequence, typically found within the 3’ UTR of a target mRNA. Engagement with RISC is generally repressive, inhibiting translation of the bound transcript and, in some cases, inducing target degradation. However, researchers have reported a number of cases in which miRNAs directly upregulate target expression, suggesting a broader repertoire of regulatory functions.
The human genome is projected to contain as many as 2,300 miRNAs, many of which exhibit tissue-specific expression patterns or are expressed at specific developmental stages. As a class, miRNAs regulate at least 30% of protein-coding genes in humans, with some estimates suggesting that this number may actually be as high as 60%. While they exert a diverse array of functions, miRNAs frequently play key roles in developmental and signaling pathways, not only modulating the expression of a direct target but also effecting a broader range of downstream consequences. This regulatory centrality makes miRNAs attractive targets for clinical intervention. While they can be modulated with antisense oligonucleotides (ASOs) or miRNA “sponges,” oligonucleotide-based approaches face significant clinical barriers due to delivery challenges, immune stimulation, and off-target effects. In contrast, small-molecule drugs are well-suited for therapeutic application thanks to their established physicochemical properties, pharmacodynamics, and safety profiles. Because of their distinctive structural elements and well-defined processing pipeline, pri- and pre-mRNAs are particularly tractable as small-molecule targets; ligands binding at or near Drosha and Dicer cleavage sites are well-positioned to inhibit transcript processing and reduce levels of mature miRNA.
Several research groups have shared preclinical results that support the therapeutic utility of miRNA-targeted small-molecule drugs. In 2016, the Disney Lab (Scripps Research Institute) reported their discovery of Targaprimir-96, a small molecule that interacts directly with pre-miR-96 in breast cancer cells to potently inhibit miR-96 biogenesis and trigger apoptosis. This group has also reported another small-molecule drug (TGP-515) that binds pri-miR-515 and sensitizes HER2- breast cancer cells to Herceptin treatment. In 2018, a French team successfully reduced levels of miR-372, known to promote proliferation of gastric adenocarcinoma cells, by using a small-molecule polyamine (PA-3) that specifically blocks pre-miR-372 processing. Using a similar approach, the same group identified a potent inhibitor of the oncogenic and pro-inflammatory miRNA miR-21 that interacts with the associated pre-miRNA to block its processing. In late 2023, researchers from the University of Washington described a series of pre-miR21-binding small molecules with promising effects on gastric and pancreatic cancer cell lines, further supporting the pharmacological potential of miRNA-targeted therapies.
miRNAs are known to be dysregulated across a broad spectrum of diseases, including many cancers, and their role as master regulators makes them attractive therapeutic targets. While no miRNA-targeting small molecules have entered clinical trials to date, small-molecule drugs targeting other RNA species have been approved by the FDA, validating the viability of this strategy. In the broader pre-clinical space, miRNA targeting remains an active area of research and innovation. Indeed, the awarding of the 2024 Nobel Prize in Physiology or Medicine to Victor Ambros and Gary Ruvkun for “the discovery of microRNA and its role in post-transcriptional gene regulation” provides clear confirmation that miRNAs have transcended from a mere C. elegans quirk to an incredibly powerful clinical target.
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