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dc.contributor.authorYang, Taihua
dc.contributor.authorPoenisch, Marion
dc.contributor.authorKhanal, Rajendra
dc.contributor.authorHu, Qingluan
dc.contributor.authorDai, Zhen
dc.contributor.authorLi, Ruomeng
dc.contributor.authorSong, Guangqi
dc.contributor.authorYuan, Qinggong
dc.contributor.authorYao, Qunyan
dc.contributor.authorShen, Xizhong
dc.contributor.authorTaubert, Richard
dc.contributor.authorEngel, Bastian
dc.contributor.authorJaeckel, Elmar
dc.contributor.authorVogel, Arndt
dc.contributor.authorFalk, Christine S
dc.contributor.authorSchambach, Axel
dc.contributor.authorGerovska, Daniela
dc.contributor.authorAraúzo-Bravo, Marcos J
dc.contributor.authorVondran, Florian W R
dc.contributor.authorCantz, Tobias
dc.contributor.authorHorscroft, Nigel
dc.contributor.authorBalakrishnan, Asha
dc.contributor.authorChevessier, Frédéric
dc.contributor.authorOtt, Michael
dc.contributor.authorSharma, Amar Deep
dc.date.accessioned2021-10-12T13:07:50Z
dc.date.available2021-10-12T13:07:50Z
dc.date.issued2021-08-25
dc.identifier.citationJ Hepatol. 2021 Aug 25:S0168-8278(21)02006-7. doi: 10.1016/j.jhep.2021.08.011. Epub ahead of print.en_US
dc.identifier.pmid34453962
dc.identifier.doi10.1016/j.jhep.2021.08.011
dc.identifier.urihttp://hdl.handle.net/10033/623071
dc.description.abstractBackground & aims: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis. Methods: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation. Results: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Conclusion: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver. Lay summary: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectTranscription factorsen_US
dc.subjectmRNA therapeuticsen_US
dc.subjectprotein replacement and cirrhosisen_US
dc.titleTherapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.en_US
dc.typeArticleen_US
dc.identifier.eissn1600-0641
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
dc.identifier.journalJournal of hepatologyen_US
refterms.dateFOA2021-10-12T13:07:50Z
dc.source.journaltitleJournal of hepatology
dc.source.countryNetherlands


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