2. Academic Validation
  3. Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

  • Mol Ther. 2019 May 8;27(5):999-1016. doi: 10.1016/j.ymthe.2019.02.018.
Jiehua Zhou 1,  Haitang Li 1,  Xin Xia 1,  Alberto Herrera 2,  Nicolette Pollock 2,  Vikash Reebye 3,  Mikael H Sodergren 3,  Stephanie Dorman 3,  Bruce H Littman 4,  Declan Doogan 5,  Kai-Wen Huang 6,  Robert Habib 5,  David Blakey 5,  Nagy A Habib 7,  John J Rossi 8
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
  • 2 Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
  • 3 Department of Surgery and Cancer, Imperial College London, London SW7 5NH, UK.
  • 4 Translational Medicine Associates, LLC, Savannah, GA 31302, USA.
  • 5 MiNA Therapeutics, Ltd., London W12 0BZ, UK.
  • 6 Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, College of Medicine, Taipei 10617, Taiwan.
  • 7 Department of Surgery and Cancer, Imperial College London, London SW7 5NH, UK; MiNA Therapeutics, Ltd., London W12 0BZ, UK. Electronic address: [email protected].
  • 8 Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. Electronic address: [email protected].
PMID: 30852139 DOI: 10.1016/j.ymthe.2019.02.018
Abstract

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.

Keywords

MTL-CEBPA; anti-inflammation; humanized mice; monocytes; saRNA; small activating RNA.

Figures
Products