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

Abstract:

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.

Citation: Cell Death Dis 11(5),343

Date Published: 1st May 2020

Registered Mode: by DOI

Authors: Marius Maximilian Woitok, Miguel Eugenio Zoubek, Dennis Doleschel, Matthias Bartneck, Mohamed Ramadan Mohamed, Fabian Kießling, Wiltrud Lederle, Christian Trautwein, Francisco Javier Cubero

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Woitok, M. M., Zoubek, M. E., Doleschel, D., Bartneck, M., Mohamed, M. R., Kießling, F., … Cubero, F. J. (2020). Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease. Cell Death & Disease, 11(5). http://doi.org/10.1038/s41419-020-2571-4
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Created: 26th Jul 2020 at 18:48

Last updated: 26th Jul 2020 at 18:55

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