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

Reebye, Vikash; Huang, Kai‐Wen; Lin, Vivian; Jarvis, Sheba; Cutilas, Pedro; Dorman, Stephanie; Ciriello, Simona; Andrikakou, Pinelopi; Voutila, Jon; Sætrom, Pål; Mintz, Paul J.; Reccia, Isabella; Rossi, John J.; Huber, Hans E.; Habib, Robert; Kostomitsopoulos, Nikos; Blakey, David C.; Habib, Nagy

doi:10.1038/s41388-018-0126-2

Cited by 74 publications

(56 citation statements)

References 18 publications

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“…Searching for molecular mechanisms, we found that stabilization of key regulators of liver biology (C/EBPα, HNF4α, CUGBP1, Rb, and p53) under conditions of an HFD contributes to inhibition of steatosis. In agreement with this, several reports from Habib's group showed that the elevation of C/EBPα by a short‐activating RNA causes inhibition of liver cancer, metastasis, cirrhosis, fibrosis, and hepatosteatosis . In agreement with these observations, HFD‐treated GLKO mice and C/EBPα‐S193A mice have reduced C/EBPα and increased proliferation and spontaneously develop fibrosis and HCC, a situation observed in CUGBP1‐S302A mice.…”

Section: Discussionsupporting

confidence: 76%

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) involves development of hepatic steatosis, fibrosis, and steatohepatitis. Because hepatic steatosis appears first in NAFLD animal models, the current therapy development focuses on inhibition of hepatic steatosis, suggesting that further steps of NAFLD will be also inhibited. In this report, we show that the first event of NAFLD is liver proliferation, which drives fibrosis in NAFLD. We have deleted a strong driver of liver proliferation, gankyrin (Gank), and examined development of NAFLD in this animal model under conditions of a high‐fat diet (HFD). We found that proliferating livers of wild‐type mice develop fibrosis; however, livers of Gank liver‐specific knockout (GLKO) mice with reduced proliferation show no fibrosis. Interestingly, an HFD causes the development of strong macrovesicular steatosis in GLKO mice and is surprisingly associated with improvements in animal health. We observed that key regulators of liver biology CCAAT/enhancer binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), p53, and CUG repeat binding protein 1 (CUGBP1) are elevated due to the deletion of Gank and that these proteins support liver functions leading to healthy conditions in GLKO mice under an HFD. To examine the role of one of these proteins in the protection of liver from fibrosis, we used CUGBP1‐S302A knockin mice, which have a reduction of CUGBP1 due to increased degradation of this mutant by Gank. These studies show that reduction of CUGBP1 inhibits steatosis and facilitates liver proliferation, leading to fibrosis and the development of liver tumors. Conclusion: Liver proliferation drives fibrosis, while steatosis might play a protective role. Therapy for NAFLD should include inhibition of proliferation rather than inhibition of steatosis.

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Section: Discussionsupporting

confidence: 76%

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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“…We calculated human-equivalent doses of 3 mg/kg MTL-CEBPA on the basis of individual animal weights. 22 In these conditions, the MTL-CEBPA administration via i.v. injection demonstrated the specific activation of its target C/EBPα mRNA and its downstream gene p21 ( Figures 4 B and 4C).…”

Section: Resultsmentioning

confidence: 99%

“… 17 , 20 , 21 Upregulation of C/EBPα activity has the potential to improve liver function and limit hepatocellular carcinoma (HCC) growth. 22 , 23 , 24 These findings demonstrated a critical role of C/EBPα expression in the regulation of cell motility, maturation, and tumorigenesis. 13 The role of C/EBPα expression in inflammation is not well characterized 25 although other CCAAT/EBPs such as C/EBPα have a clear role and are associated with activation of the NF-κB transcription factor.…”

Section: Introductionmentioning

confidence: 82%

“…In a liver inflammation and/or failure rat model, the MTL-CEBPA was demonstrated to improve survival and prevent liver failure with normalization of liver enzyme. 22 Moreover, in a diethylnitrosamine (DEN)-induced cirrhotic HCC rat model, C/EBPα saRNA delivered by a transferrin receptor (TfR) aptamer improved liver function and downregulated cytokines, including IFN-α, IL-6, IL-1β, and TGF-β1 (K.W.H., R.H., and N.H., unpublished data). Consistently, these data demonstrate the beneficial effect of the use of MTL-CEBPA in an actual disease scenario.…”

Section: Discussionmentioning

confidence: 98%

“…MTL-CEBPA (liposome-formulated C/EBPα saRNA nanoparticles), and the control liposome-formulated Luc-siRNA nanoparticles were provided by MiNA Therapeutics, London, UK. 22 …”

Section: Methodsmentioning

confidence: 99%

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

Zhou

Xia

et al. 2019

Molecular Therapy

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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.

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Small Activating RNA Modulation of the G Protein‐Coupled Receptor for Cancer Treatment

et al. 2022

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G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.

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

Cited by 74 publications

References 18 publications

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

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

Small Activating RNA Modulation of the G Protein‐Coupled Receptor for Cancer Treatment

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