Ryan L. Setten, Helen L. Lightfoot, Nagy A. Habib and John J. Rossi* Pages 611 - 621 ( 11 )
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.
MiNA therapeutics, MTL-CEBPA, CEBPα, saRNA, hepatocellular carcinoma, liver, RNA therapeutics.
Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, MiNA Therapeutics Limited, Translation & Innovation Hub, 80 Wood Lane, London, W12 0BZ, Department of Surgery and Cancer, Imperial College London, London, Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA