Gene activation of CEBPA using saRNA: Preclinical studies of the first in human saRNA drug candidate for liver cancer
Journal
Oncogene
Journal Volume
37
Journal Issue
24
Pages
3216-3228
Date Issued
2018
Author(s)
Reebye V.
Lin 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.
Abstract
Liver 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
Other Subjects
CCAAT 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 Activation
Publisher
Nature Publishing Group
Type
journal article