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

Autor: Reebye V; Department of Surgery, Imperial College London, London, UK. v.reebye@ic.ac.uk., Huang KW; Department of Surgery and Hepatitis Research and Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan., Lin V; Department of Surgery and Hepatitis Research and Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan., Jarvis S; Department of Surgery and Cancer, Imperial College London, London, UK., Cutilas P; Cell Signalling and Proteomics Group, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK., Dorman S; Department of Surgery, Imperial College London, London, UK., Ciriello S; MiNA Therapeutics Ltd, London, UK., Andrikakou P; Department of Surgery, Imperial College London, London, UK., Voutila J; MiNA Therapeutics Ltd, London, UK., Saetrom P; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway., Mintz PJ; Department of Surgery, Imperial College London, London, UK., Reccia I; Department of Surgery, Imperial College London, London, UK., Rossi JJ; Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Huber H; BioTD Strategies, LLC, Lansdale, PA, USA., Habib R; MiNA Therapeutics Ltd, London, UK., Kostomitsopoulos N; Biomedical Research Foundation of the Academy of Athens, Centre of Clinical, Experimental Surgery and Translational Research, Athens, Greece., Blakey DC; MiNA Therapeutics Ltd, London, UK., Habib NA; Department of Surgery, Imperial College London, London, UK.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2018 Jun; Vol. 37 (24), pp. 3216-3228. Date of Electronic Publication: 2018 Mar 07.
DOI: 10.1038/s41388-018-0126-2
Abstrakt: 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.
Databáze: MEDLINE
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