Rethinking RNA Modifications: Therapeutic Strategies for Targeting Dysregulated RNA.

The vast array of cellular ribonucleic acid (RNA) modifications hold a crucial role in regulating RNA stability, folding, localization, and the accuracy of translation. Numerous diseases have been associated with mutations found in genes of RNA-modifying enzymes that can lead to truncated or misfolded proteins incapable of modifying their RNA substrates, causing downstream defects. In contrast, dysregulated levels of RNA-modifying enzymes and the resulting changes in RNA modifications on their substrates are increasingly linked to the activation of oncogenic pathways. This phenomenon has been especially studied through the lens of methyltransferases such as METTL1 and METTL3. The field has developed several small molecule inhibitors of RNA-modifying enzymes to mitigate their related diseases, including targeting the upregulation of METTL3 in cancer. However, increasing evidence suggests that RNA-modifying enzymes play essential roles in numerous cellular processes, including the immune response, neural health, and regeneration, among others. This could lead to off-target effects when treating proteins with small molecules, particularly when these enzymes are upregulated. We propose that developing treatments to specifically target the RNA substrates mis-regulated due to abnormal levels of RNA-modifying enzymes responsible for malignant hallmarks may offer an alternative strategy for treating diseases. We review current RNA-targeted therapies and the diseases they target, including advancements in oligonucleotide modalities and small molecules. We also identify gaps in knowledge that need to be addressed to enhance drug development in the epitranscriptome field to use these therapies to target mis-regulated RNA stemming from altered RNA-modifying enzyme levels.