From concept to clinic: the therapeutic journey of small activating RNAs

Small activating RNAs (saRNAs) represent a novel class of oligonucleotide therapeutics capable of selectively upregulating gene expression by harnessing an evolutionarily conserved RNA-mediated transcriptional activation mechanism termed RNA activation (RNAa). Building on two decades of foundational work, initially conceptualized as a molecular tool to induce gene expression, saRNAs have successfully translated into clinical development, offering a unique therapeutic strategy for diseases where targeted gene activation could be beneficial. This article provides a comprehensive overview of the 20-year therapeutic journey of saRNAs, from early discovery and preclinical validation to their current status in clinical trials. We discuss key preclinical and clinical programs, including those targeting tumor suppressor genes as well as those targeting neuromuscular and sickle cell diseases. Finally, we outline future directions for saRNAs, emphasizing their potential to reshape the oligotherapeutic landscape and expand therapeutic options for broader indications.

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