Reebye V.KAI-WEN HUANGLin V.Jarvis S.Cutilas P.Dorman S.Ciriello S.Andrikakou P.Voutila J.Saetrom P.Mintz P.J.Reccia I.Rossi J.J.Huber H.Habib R.Kostomitsopoulos N.Blakey D.C.Habib N.A.2020-06-192020-06-1920180950-9232https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042877246&doi=10.1038%2fs41388-018-0126-2&partnerID=40&md5=451f7a7468050b9faf86e63ba566fe5ahttps://scholars.lib.ntu.edu.tw/handle/123456789/503605Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis, and significantly reduces tumor burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride-induced rat model of fibrosis following 2 weeks of MTL-CEBPA therapy. At 14 weeks, animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic-deficient diet-induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL-CEBPA treatment led to a significant reduction in tumor burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases. ? 2018 The Author(s).[SDGs]SDG3CCAAT enhancer binding protein alpha small activating RNA; liposome; RNA; unclassified drug; CCAAT enhancer binding protein; CEBPA protein, human; diethylnitrosamine; small untranslated RNA; adolescent; adult; animal cell; animal experiment; animal model; animal tissue; Article; carbon tetrachloride-induced liver fibrosis; controlled study; fatty liver; gene activation; Hep-G2 cell line; human; human cell; in vitro study; in vivo study; K-9 cell line; liposomal gene delivery system; liver cell; liver cell carcinoma; liver cirrhosis; liver function; male; mouse; nonhuman; oligonucleotide therapy; preclinical study; priority journal; rat; real time polymerase chain reaction; survival rate; tumor volume; Western blotting; Wistar rat; animal; C57BL mouse; chemically induced; end stage liver disease; experimental liver cirrhosis; experimental liver neoplasm; gene expression regulation; gene therapy; genetics; middle aged; nonalcoholic fatty liver; procedures; Sprague Dawley rat; transcription initiation; transgenic mouse; Animals; CCAAT-Enhancer-Binding Proteins; Diethylnitrosamine; End Stage Liver Disease; Gene Expression Regulation, Neoplastic; Genetic Therapy; Hep G2 Cells; Humans; Liver Cirrhosis, Experimental; Liver Neoplasms, Experimental; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Non-alcoholic Fatty Liver Disease; Rats, Sprague-Dawley; Rats, Wistar; RNA, Small Untranslated; Transcriptional Activationjournal article10.1038/s41388-018-0126-2295113462-s2.0-85042877246