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

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Title: Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer
Author(s): Reebye, V
Huang, K-W
Lin, V
Jarvis, S
Cutilas, P
Dorman, S
Ciriello, S
Andrikakou, P
Voutila, J
Saetrom, P
Mintz, PJ
Reccia, I
Rossi, JJ
Huber, H
Habib, R
Kostomitsopoulos, N
Blakey, DC
Habib, NA
Item Type: Journal Article
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.
Publication Date: 7-Mar-2018
Date of Acceptance: 12-Dec-2017
DOI: 10.1038/s41388-018-0126-2
ISSN: 0950-9232
Publisher: Nature Publishing Group
Start Page: 3216
End Page: 3228
Journal / Book Title: Oncogene
Volume: 37
Sponsor/Funder: Mina Therapeutics Ltd
Funder's Grant Number: P58698
Copyright Statement: © Macmillan Publishers Limited, part of Springer Nature 2018
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Conference Place: England
Appears in Collections:Division of Surgery
Faculty of Medicine

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