Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Weingärtner, Adrien; Bethge, Lucas; Weiss, Lisa; Sternberger, Maria; Lindholm, Marie Wikström

doi:10.1016/j.omtn.2020.05.026

Cited by 23 publications

(19 citation statements)

References 36 publications

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“…Several miRNA-targeted therapeutic delivery strategies have reached clinical development 61 , including lipid-based nanoparticle formulations 62 . Hepatocyte-specific deliveries include miRNA-conjugation to cholesterol 63 , 64 , and N-acetyl-glucosamine (GalNac) which binds with high affinity to the asialoglycoprotein receptor expressed in hepatocytes 61 , 65 . Recent studies have also developed folate-linked miRNAs targeting folate receptor overexpressing cancer cells 66 .…”

Section: Discussionmentioning

confidence: 99%

Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma

Mani¹,

Yan²,

Cui³

et al. 2020

Theranostics

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Rationale: RNA helicase DDX5 is downregulated during hepatitis B virus (HBV) replication, and poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC, and identify biologics to prevent DDX5 downregulation. Methods: Molecular approaches including immunoblotting, qRT-PCR, luciferase transfections, hepatosphere assays, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and RNA-seq were used with cellular models of HBV replication, HBV infection, and HBV-related liver tumors, as well as bioinformatic analyses of liver cancer cells from two independent cohorts. Results: We demonstrate that HBV infection induces expression of the proto-oncogenic miR17~92 and miR106b~25 clusters which target the downregulation of DDX5. Increased expression of these miRNAs is also detected in HBV-driven HCCs exhibiting reduced DDX5 mRNA. Stable DDX5 knockdown (DDX5 KD ) in HBV replicating hepatocytes increased viral replication, and resulted in hepatosphere formation, drug resistance, Wnt activation, and pluripotency gene expression. ATAC-seq of DDX5 KD compared to DDX5 wild-type (WT) cells identified accessible chromatin regions enriched in regulation of Wnt signaling genes. RNA-seq analysis comparing WT versus DDX5 KD cells identified enhanced expression of multiple genes involved in Wnt pathway. Additionally, expression of Disheveled , DVL1 , a key regulator of Wnt pathway activation, was significantly higher in liver cancer cells with low DDX5 expression, from two independent cohorts. Importantly, inhibitors (antagomirs) to miR17~92 and miR106b~25 restored DDX5 levels, reduced DVL1 expression, and suppressed both Wnt activation and viral replication. Conclusion : DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels by miR17~92 / miR106b~25 antagomirs in HBV-infected patients can be explored as both antitumor and antiviral strategy.

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Section: Discussionmentioning

confidence: 99%

Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma

Mani¹,

Yan²,

Cui³

et al. 2020

Theranostics

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“…Several miRNA-based therapeutic delivery strategies have reached clinical development [109] , including lipid-based nanoparticle formulations [110] . Hepatocyte-specific deliveries utilize miRNA-conjugation to cholesterol [111,112] and N-acetyl-glucosamine (GalNac), which exhibits high affinity for the asialoglycoprotein receptor expressed in hepatocytes [109,113] . Recent studies have also developed folate-linked miRNAs targeting folate receptoroverexpressing cancer cells [114] .…”

Section: Noncoding Rnas In Hbv-related Hccmentioning

confidence: 99%

Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma

Andrisani¹

2021

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Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.

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“…[ 46 ] Enhanced long‐term activity and organ specificity were found in siRNA conjugated with trivalent N‐acetylgalactosamine (GalNAc) therapeutics, allowing a continuous activity of RNAi for months in vitro and in vivo. [ 47 , 48 ]…”

Section: Classification Of Rna Therapeuticsmentioning

confidence: 99%

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

et al. 2021

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In recent years, the main quest of science has been the pioneering of the groundbreaking biomedical strategies needed for achieving a personalized medicine. Ribonucleic acids (RNAs) are outstanding bioactive macromolecules identified as pivotal actors in regulating a wide range of biochemical pathways. The ability to intimately control the cell fate and tissue activities makes RNA‐based drugs the most fascinating family of bioactive agents. However, achieving a widespread application of RNA therapeutics in humans is still a challenging feat, due to both the instability of naked RNA and the presence of biological barriers aimed at hindering the entrance of RNA into cells. Recently, material scientists’ enormous efforts have led to the development of various classes of nanostructured carriers customized to overcome these limitations. This work systematically reviews the current advances in developing the next generation of drugs based on nanotechnology‐assisted RNA delivery. The features of the most used RNA molecules are presented, together with the development strategies and properties of nanostructured vehicles. Also provided is an in‐depth overview of various therapeutic applications of the presented systems, including coronavirus disease vaccines and the newest trends in the field. Lastly, emerging challenges and future perspectives for nanotechnology‐mediated RNA therapies are discussed.

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Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders

Cited by 23 publications

References 36 publications

Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma

Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma

Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

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