Imperial College London
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ProfessorNagyHabib

Faculty of Medicine, Department of Surgery & Cancer

Professor of Hepatobiliary Surgery
 
 
 
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Contact

 

+44 (0)20 3313 8574nagy.habib

 
 
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Assistant

 

Mrs Benita White +44 (0)7960 986 387

 
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Location

 

BN1/18 B BlockHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Voutila:2017:10.1016/j.ymthe.2017.07.018,
author = {Voutila, J and Reebye, V and Roberts, TC and Protopapa, P and Andrikakou, P and Blakey, DC and Habib, R and Huber, H and Saetrom, P and Rossi, JJ and Habib, NA},
doi = {10.1016/j.ymthe.2017.07.018},
journal = {Molecular Therapy},
pages = {2705--2714},
title = {Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.},
url = {http://dx.doi.org/10.1016/j.ymthe.2017.07.018},
volume = {25},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic.
AU  - Voutila,J
AU  - Reebye,V
AU  - Roberts,TC
AU  - Protopapa,P
AU  - Andrikakou,P
AU  - Blakey,DC
AU  - Habib,R
AU  - Huber,H
AU  - Saetrom,P
AU  - Rossi,JJ
AU  - Habib,NA
DO  - 10.1016/j.ymthe.2017.07.018
EP  - 2714
PY  - 2017///
SN  - 1525-0016
SP  - 2705
TI  - Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.
T2  - Molecular Therapy
UR  - http://dx.doi.org/10.1016/j.ymthe.2017.07.018
UR  - http://hdl.handle.net/10044/1/53047
VL  - 25
ER  -
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