Novel therapeutic approaches with small activating RNA

Oligonucleotide therapeutics is a major platform for drug discovery with great potential for diseases where endogenous gene expression is downregulated. In 2016, MTL-CEBPA was the first RNA activating oligonucleotide drug targeting CEBPA to enter clinical development for patients with advanced hepatocellular carcinoma (HCC). The aim of this PhD project is to develop new therapeutic small activating RNAs (saRNAs) for genes which are suppressed in the pathology of inflammation, Non-alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH). saRNAs for three different targets namely Sirtuin 1 (SIRT1), Hepatocyte Nuclear Factor 1-Alpha (HNF1A) and Fibroblast Growth Factor 21 (FGF21) are investigated. SIRT1 is a protein with anti-apoptotic, anti-ageing and anti-inflammatory properties. SIRT1-PR57 saRNA is identified as the most promising candidate to upregulate SIRT1 mRNA and protein levels. The therapeutic potential of SIRT1-PR57 saRNA is experimentally explored in cell models of lipid metabolic disorders as well as inflammatory diseases and is the central theme of this thesis. Other targets touched upon but not fully explored include HNF1A and FGF21. HNF1A is a liver enriched transcription factor involved in Maturity Onset Diabetes of the Young (MODY), pancreatic ductal adenocarcinoma (PDAC) and HCC. HNF1A-PR1 saRNA is shown to successfully upregulate the mRNA levels of the HNF1A(A) isoform, while protein levels still require further validation. Investigation in relation to FGF21, a metabolic hormone regulating lipid metabolism, demonstrated that the FGF21 transcript is not present in hepatocytes. FGF21 saRNA candidates might yield more promising results in other liver cell lines with the potential to reverse the pathology of NAFLD and NASH. Finally, SIRT1 saRNA could have therapeutic effect as an anti-inflammatory regulatory component within macrophages.Open Acces