Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma.

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.