Background: Oligonucleotide drug development has revolutionised the drug discovery
field. Within this field, ‘small’ or ‘short’ activating RNAs (saRNA) are a more recently discovered
category of short double-stranded RNA with clinical potential. saRNAs promote transcription from
target loci, a phenomenon widely observed in mammals known as RNA activation (RNAa).
Objective: The ability to target a particular gene is dependent on the sequence of the saRNA. Hence,
the potential clinical application of saRNAs is to increase target gene expression in a sequence-specific
manner. saRNA-based therapeutics present opportunities for expanding the “druggable genome” with
particular areas of interest including transcription factor activation and cases of haploinsufficiency.
Results and Conclusion: In this mini-review, we describe the pre-clinical development of the first
saRNA drug to enter the clinic. This saRNA, referred to as MTL-CEBPA, induces increased expression
of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα), a tumour suppressor
and critical regulator of hepatocyte function. MTL-CEBPA is presently in Phase I clinical trials for hepatocellular
carcinoma (HCC). The clinical development of MTL-CEBPA will demonstrate “proof of
concept” that saRNAs can provide the basis for drugs which enhance target gene expression and consequently
improve treatment outcome in patients.