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 endstage 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.

CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy

“…This risk can be mitigated by the addition of tissue-or cell-specific miR binding sites to the mRNA sequence, which results in tissue-specific suppression of mRNA translation (47,48). The main off-target site of LNP-based platforms is the liver, more specifically hepatocytes and Kupffer cells (49,50), and suppression of mRNAs in these cell types can be achieved by inserting miR122 and miR142 binding sites, respectively. Using these tissue-specific mRNA suppression approaches is crucial for further clinical development of gene editing technologies.…”

Rationally Designed Galactose Dendrimer for Hepatocyte-Specific Targeting and Intracellular Drug Delivery for the Treatment of Liver Disorders

“…There have been reports where therapeutic molecules including small drug molecules, protein scaffolds, or antibodies are conjugated to galactose, GalNAc, lactose, or glucose monomers, or a small cluster of carbohydrates to target liver hepatocytes. ,, Monovalent binding of carbohydrates with proteins is often weak, in the millimolar range, and is not strong enough to retain the molecule when facing rapid systemic blood flow. Multivalent binding has therefore been explored, and the binding affinity of trivalent and tetravalent carbohydrate constructs to ASGP-R have been proven to be 100- to 1000-fold stronger compared to monovalent ligands due to the glyco-cluster effect. , Despite abundant reports of liver-targeting nanoparticles, − translation of hepatocyte-targeting nanotherapeutics to the clinic is rarely successful. In addition to the challenge of achieving hepatocyte-specific localization, other hurdles in the clinical translation and commercialization of hepatocyte-targeting nanoparticles relate to their cytotoxicity, scale-up, structural defects, complex synthetic design and reproducibility, product purity, in vivo stability, and short half-life. , …”

Emerging Therapies for Hepatocellular Carcinoma (HCC)

“…This LDLR-mediated delivery mechanism has led to FDA approval of hepatocyte-targeted delivery of siRNA for an inherited disease [ 37 ]. Using a similar principle, LNP was generated to deliver siRNA for Jun N-terminal kinase-2 (Jnk2), which ameliorated hepatitis, fibrosis and the initiation of HCC in a spontaneous mouse model [ 38 ]. Defective Hippo/YAP signaling results in tissue overgrowth and development of HCC.…”