Artigo Acesso aberto Revisado por pares

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

2020; Springer Nature; Volume: 11; Issue: 5 Linguagem: Inglês

10.1038/s41419-020-2571-4

ISSN

2041-4889

Autores

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

Tópico(s)

MicroRNA in disease regulation

Resumo

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.

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