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Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease

Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment...

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Autores principales: Woitok, Marius Maximilian, Zoubek, Miguel Eugenio, Doleschel, Dennis, Bartneck, Matthias, Mohamed, Mohamed Ramadan, Kießling, Fabian, Lederle, Wiltrud, Trautwein, Christian, Cubero, Francisco Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214425/
https://www.ncbi.nlm.nih.gov/pubmed/32393755
http://dx.doi.org/10.1038/s41419-020-2571-4
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author Woitok, Marius Maximilian
Zoubek, Miguel Eugenio
Doleschel, Dennis
Bartneck, Matthias
Mohamed, Mohamed Ramadan
Kießling, Fabian
Lederle, Wiltrud
Trautwein, Christian
Cubero, Francisco Javier
author_facet Woitok, Marius Maximilian
Zoubek, Miguel Eugenio
Doleschel, Dennis
Bartneck, Matthias
Mohamed, Mohamed Ramadan
Kießling, Fabian
Lederle, Wiltrud
Trautwein, Christian
Cubero, Francisco Javier
author_sort Woitok, Marius Maximilian
collection PubMed
description Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.
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spelling pubmed-72144252020-05-14 Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease Woitok, Marius Maximilian Zoubek, Miguel Eugenio Doleschel, Dennis Bartneck, Matthias Mohamed, Mohamed Ramadan Kießling, Fabian Lederle, Wiltrud Trautwein, Christian Cubero, Francisco Javier Cell Death Dis Article Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD. Nature Publishing Group UK 2020-05-11 /pmc/articles/PMC7214425/ /pubmed/32393755 http://dx.doi.org/10.1038/s41419-020-2571-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Woitok, Marius Maximilian
Zoubek, Miguel Eugenio
Doleschel, Dennis
Bartneck, Matthias
Mohamed, Mohamed Ramadan
Kießling, Fabian
Lederle, Wiltrud
Trautwein, Christian
Cubero, Francisco Javier
Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title_full Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title_fullStr Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title_full_unstemmed Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title_short Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
title_sort lipid-encapsulated sirna for hepatocyte-directed treatment of advanced liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214425/
https://www.ncbi.nlm.nih.gov/pubmed/32393755
http://dx.doi.org/10.1038/s41419-020-2571-4
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