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

  • Oncogene. 2018 Jun;37(24):3216-3228. doi: 10.1038/s41388-018-0126-2.
Vikash Reebye  1 ,  Kai-Wen Huang  2 ,  Vivian Lin  2 ,  Sheba Jarvis  3 ,  Pedro Cutilas  4 ,  Stephanie Dorman  5 ,  Simona Ciriello  6 ,  Pinelopi Andrikakou  5 ,  Jon Voutila  6 ,  Pal Saetrom  7  8 ,  Paul J Mintz  5 ,  Isabella Reccia  5 ,  John J Rossi  9 ,  Hans Huber  10 ,  Robert Habib  6 ,  Nikos Kostomitsopoulos  11 ,  David C Blakey  6 ,  Nagy A Habib  5
Affiliations
  • 1. Department of Surgery, Imperial College London, London, UK. [email protected].
  • 2. Department of Surgery and Hepatitis Research and Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
  • 3. Department of Surgery and Cancer, Imperial College London, London, UK.
  • 4. Cell Signalling and Proteomics Group, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 5. Department of Surgery, Imperial College London, London, UK.
  • 6. MiNA Therapeutics Ltd, London, UK.
  • 7. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 8. Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway.
  • 9. Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 10. BioTD Strategies, LLC, Lansdale, PA, USA.
  • 11. Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece.
PMID: 29511346 DOI: 10.1038/s41388-018-0126-2
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.

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