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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)

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.

Original languageEnglish
Article number343
Number of pages14
JournalCell Death & Disease
Volume11
Issue number5
DOIs
Publication statusPublished - 11 May 2020

Keywords

  • CATIONIC LIPIDS
  • NANOPARTICLES
  • INFLAMMATION
  • DELIVERY
  • DELETION

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