Targeting chromatin: Transcriptional gene activation (saRNA)

It is well-recognized that siRNA and miRNA have therapeutic potential through their ability to post-transcriptionally downregulate gene expression and translation. Common targets for disease modulation with these small RNAs are mutated or aberrantly overexpressed genes. An emerging technology exploits the endogenous mechanism of transcriptional gene activation to upregulate the expression of genes altered in disease. Called small-activating RNAs (saRNAs), these short duplex RNA oligonucleotides are structurally similar to siRNA and share a dependence on Argonaute-2 (Ago2) for activity but are distinct in their mechanism. In this chapter, we will discuss the discovery and mechanism of action of RNA activation and explore the therapeutic applications that have been demonstrated preclinically and in clinical trials.