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.

• Authors: Marius Maximilian Woitok, Miguel Eugenio Zoubek, Dennis Doleschel, Matthias Bartneck, Mohamed Ramadan Mohamed, Fabian Kießling, Wiltrud Lederle, Christian Trautwein, Francisco Javier Cubero
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 5 Pg. 343 (05 11 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32393755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Lipids
• NEMO protein, mouse
• RNA, Small Interfering
• Mitogen-Activated Protein Kinase 9

Topics

• Animals
• Apoptosis
• Cell Line
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Disease Models, Animal
• Gene Transfer Techniques
• Hepatocytes (enzymology, pathology)
• Intracellular Signaling Peptides and Proteins (genetics)
• Lipids (chemistry)
• Liver (enzymology, pathology)
• Liver Cirrhosis (enzymology, genetics, pathology, therapy)
• Liver Neoplasms (enzymology, genetics, pathology, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 9 (deficiency, genetics, metabolism)
• Nanoparticles
• RNA, Small Interfering (chemistry, genetics, metabolism)
• RNAi Therapeutics