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

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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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This work was funded by MiNA Therapeutics.

Author contributions:

V.R, K-W H, H.H, R.H., and D.B: designed the experiments. V.R, S.J, P.A, S.D, S.C., and J.V. performed the in vitro studies and analyzed the data. K-WH, V.L., and N.K. performed the DEN studies. V.R, S.J, S.D, P.A, P.J.M. assisted with in vitro work. P.S. designed the saRNA sequence. V.R, N.H, R.H, D.B: contributed to construction and writing of the manuscript. I.R, J.J.R assisted in manuscript editing. R.H, D.B, N.H managed execution of this study.

Author information


  1. Department of Surgery, Imperial College London, London, UK

    • Vikash Reebye
    • , Stephanie Dorman
    • , Pinelopi Andrikakou
    • , Paul J. Mintz
    • , Isabella Reccia
    •  & Nagy A. Habib
  2. Department of Surgery and Hepatitis Research and Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan

    • Kai-Wen Huang
    •  & Vivian Lin
  3. Department of Surgery and Cancer, Imperial College London, London, UK

    • Sheba Jarvis
  4. Cell Signalling and Proteomics Group, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

    • Pedro Cutilas
  5. MiNA Therapeutics Ltd, London, UK

    • Simona Ciriello
    • , Jon Voutila
    • , Robert Habib
    •  & David C. Blakey
  6. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    • Pal Saetrom
  7. Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway

    • Pal Saetrom
  8. Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA

    • John J. Rossi
  9. BioTD Strategies, LLC, Lansdale, PA, USA

    • Hans Huber
  10. Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece

    • Nikos Kostomitsopoulos


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Conflict of interest

J.V., S.C., D.B., and R.H. are current or former employees of MiNA Therapeutics Limited. V.R., P.J.M., K.W.-H., P.S., J.J.R., and N.H. own stock in MiNA (Holdings) Limited. All remaining authors have no conflicts to declare.

Corresponding authors

Correspondence to Vikash Reebye or Nagy A. Habib.

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