Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer.

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.

• Authors: Vikash Reebye, Kai-Wen Huang, Vivian Lin, Sheba Jarvis, Pedro Cutilas, Stephanie Dorman, Simona Ciriello, Pinelopi Andrikakou, Jon Voutila, Pal Saetrom, Paul J Mintz, Isabella Reccia, John J Rossi, Hans Huber, Robert Habib, Nikos Kostomitsopoulos, David C Blakey, Nagy A Habib
• Journal: Oncogene (Oncogene) Vol. 37 Issue 24 Pg. 3216-3228 (06 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29511346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• RNA, Small Untranslated
• Diethylnitrosamine

Topics

• Animals
• CCAAT-Enhancer-Binding Proteins (genetics)
• Diethylnitrosamine (toxicity)
• End Stage Liver Disease (chemically induced, genetics, therapy)
• Gene Expression Regulation, Neoplastic
• Genetic Therapy (methods)
• Hep G2 Cells
• Humans
• Liver Cirrhosis, Experimental (genetics, therapy)
• Liver Neoplasms, Experimental (chemically induced, genetics, therapy)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Non-alcoholic Fatty Liver Disease (etiology, genetics, therapy)
• RNA, Small Untranslated (administration & dosage, pharmacology)
• Rats, Sprague-Dawley
• Rats, Wistar
• Transcriptional Activation