Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice
Journal
Molecular Therapy
Journal Volume
27
Journal Issue
5
Pages
999-1016
Date Issued
2019
Author(s)
Zhou J.
Li H.
Xia X.
Herrera A.
Pollock N.
Reebye V.
Sodergren M.H.
Dorman S.
Littman B.H.
Doogan D.
Habib R.
Blakey D.
Habib N.A.
Rossi J.J.
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. MTL-CEBPA is a small activating RNA that targets the upregulation of transcription factor C/EBPα, currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. Zhou et al. demonstrate that MTL-CEBPA increases the expression of C/EBPα and displays anti-inflammatory effects in a tissue culture system and a humanized mouse model. ? 2019 The Author(s)
Subjects
anti-inflammation; humanized mice; monocytes; MTL-CEBPA; saRNA; small activating RNA
SDGs
Other Subjects
bacterium lipopolysaccharide; CCAAT enhancer binding protein alpha; CCAAT enhancer binding protein beta; chemokine receptor CXCR4; colony stimulating factor receptor; double stranded RNA; endotoxin; gamma interferon; interleukin 10; interleukin 1beta; interleukin 6; messenger RNA; programmed death 1 ligand 1; small activating RNA; tumor necrosis factor; unclassified drug; antiinflammatory agent; CCAAT enhancer binding protein; CEBPA protein, human; IL10 protein, human; IL1B protein, human; interleukin 10; interleukin 1beta; lipopolysaccharide; messenger RNA; RNA; tumor necrosis factor; animal experiment; animal model; antiinflammatory activity; Article; blood analysis; cell stimulation; controlled study; cytokine production; human; human cell; in vitro study; in vivo study; inflammation; inhibition kinetics; monocyte; mouse; nonhuman; THP-1 cell line; animal; drug effect; gene expression regulation; genetics; inflammation; metabolism; pathology; Animals; Anti-Inflammatory Agents; CCAAT-Enhancer-Binding Proteins; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Mice; Monocytes; RNA; RNA, Messenger; Tumor Necrosis Factor-alpha
Publisher
Cell Press
Type
journal article