肝硬化
CEBPA公司
生物
癌症研究
肝癌
肝病
癌症
肝细胞癌
内科学
医学
基因
突变
遗传学
生物化学
作者
Vikash Reebye,Kai‐Wen Huang,Vivian Lin,Sheba Jarvis,Pedro Cutilas,Stephanie Dorman,Simona Ciriello,Pinelopi Andrikakou,Jon Voutila,Pål Sætrom,Paul J. Mintz,Isabella Reccia,John J. Rossi,Hans E. Huber,Robert Habib,Nikos Kostomitsopoulos,David C. Blakey,Nagy Habib
出处
期刊:Oncogene
[Springer Nature]
日期:2018-03-07
卷期号:37 (24): 3216-3228
被引量:60
标识
DOI:10.1038/s41388-018-0126-2
摘要
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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