The prognosis for hepatocellular carcinoma (HCC) remains poor and has not 
improved in over two decades. Most patients with advanced HCC who are not 
eligible for surgery have limited treatment options due to poor liver function 
or large, unresectable tumors. Although sorafenib is the standard-of-care 
treatment for these patients, only a small number respond. For the remaining, 
the outlook remains bleak. A better approach to target "undruggable" molecular 
pathways that reverse HCC is therefore urgently needed. Small activating RNAs 
(saRNAs) may provide a novel strategy to activate expression of genes that 
become dysregulated in chronic disease. The transcription factor 
CCAAT/enhancer-binding protein alpha (C/EBPα), a critical regulator of 
hepatocyte function, is suppressed in many advanced liver diseases. By using an 
saRNA to activate C/EBPα, we can exploit the cell's own transcription machinery 
to enhance gene expression without relying on exogenous vectors that have been 
the backbone of gene therapy. saRNAs do not integrate into the host genome and 
can be modified to avoid immune stimulation. In preclinical models of liver 
disease, treatment with C/EBPα saRNA has shown reduction in tumor volume and 
improvement in serum markers of essential liver function such as albumin, 
bilirubin, aspartate aminotransferase (AST), and alanine transaminase (ALT). 
This saRNA that activates C/EBPα for advanced HCC is the first saRNA therapy to 
have entered a human clinical trial. The hope is that this new tool will help 
break the dismal 20-year trend and provide a more positive prognosis for 
patients with severe liver disease.