CRISPR-Cas9 Targeting of Hepatitis B Virus Covalently Closed Circular DNA Generates Transcriptionally Active Episomal Variants

Martínez, María del Carmen Jiménez; Combe, Emmanuel; Inchauspé, Aurore; Mangeot, Philippe; Delberghe, Elodie; Chapus, Fleur; Neveu, Grégory; Alam, Antoine; Carter, Kara; Testoni, Barbara; Zoulim, Fabien

doi:10.1128/mbio.02888-21

Cited by 20 publications

(30 citation statements)

References 48 publications

(52 reference statements)

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“…The dependence of viral persistence on functional cccDNA makes this HBV replication intermediate an ideal target for achieving a sterilising cure from HBV infection. cccDNA targeting using TALENs or CRISPR/Cas9-based therapies has shown promise [ 55 , 56 , 57 , 58 ]. These gene editors mediate sequence-specific deleterious mutations within the HBV DNA [ 22 ].…”

Section: Adenoviruses As Vectors Of Gene Therapy Against Hbvmentioning

confidence: 99%

Adenoviral Vectors: Potential as Anti-HBV Vaccines and Therapeutics

Farhad

Neves

Arbuthnot

et al. 2022

Genes

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Adenoviral vaccines have been at the front line in the fight against pandemics caused by viral infections such as Ebola and the coronavirus disease 2019. This has revived an interest in developing these vectors as vaccines and therapies against other viruses of health importance such as hepatitis B virus (HBV). Current hepatitis B therapies are not curative; hence, chronic hepatitis B remains the major risk factor for development of liver disease and death in HBV-infected individuals. The ability to induce a robust immune response and high liver transduction efficiency makes adenoviral vectors attractive tools for anti-HBV vaccine and therapy development, respectively. This review describes recent developments in designing adenoviral-vector-based therapeutics and vaccines against HBV infection.

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Section: Adenoviruses As Vectors Of Gene Therapy Against Hbvmentioning

confidence: 99%

Adenoviral Vectors: Potential as Anti-HBV Vaccines and Therapeutics

Farhad

Neves

Arbuthnot

et al. 2022

Genes

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“…Therefore, gene therapy that targets cccDNA holds a potential therapeutic avenue to attain complete clinical curing of CHB infection ( Maepa et al., 2015 ; Bloom et al., 2018 ). Multiple studies have investigated the application of CRISPR/Cas9 for targeting and cleavage of many essential loci of HBV such as cccDNA, surface antigen, and X gene in cell cultures or animal models ( Seeger and Sohn, 2014a ; Kennedy et al., 2015 ; Ramanan et al., 2015a ; Zhen et al., 2015 ; Yan et al., 2021 ; Martinez et al., 2022 ). Seeger and Shon demonstrated the first use of the CRISPR/Cas9 strategy to disrupt the HBV cccDNA.…”

Section: Applications Of Crispr/cas Technology In Targeting Viral And...mentioning

confidence: 99%

“…The presence of the cccDNA and incorporation of the viral DNA into the host genome accelerates the progression of CHB and the development of hepatocellular carcinomas ( Martinez et al., 2022 ). The CRISPR/Cas9 system successfully abolishes cccDNA, yet the integrated HBV DNA particles remain potent pro-oncogenic mediators.…”

Section: Applications Of Crispr/cas Technology In Targeting Viral And...mentioning

confidence: 99%

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19

Hawsawi

Shams

Theyab

et al. 2022

Front. Cell. Infect. Microbiol.

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Gene therapy delivers a promising hope to cure many diseases and defects. The discovery of gene-editing technology fueled the world with valuable tools that have been employed in various domains of science, medicine, and biotechnology. Multiple means of gene editing have been established, including CRISPR/Cas, ZFNs, and TALENs. These strategies are believed to help understand the biological mechanisms of disease progression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been designated the causative virus for coronavirus disease 2019 (COVID-19) that emerged at the end of 2019. This viral infection is a highly pathogenic and transmissible disease that caused a public health pandemic. As gene editing tools have shown great success in multiple scientific and medical areas, they could eventually contribute to discovering novel therapeutic and diagnostic strategies to battle the COVID-19 pandemic disease. This review aims to briefly highlight the history and some of the recent advancements of gene editing technologies. After that, we will describe various biological features of the CRISPR-Cas9 system and its diverse implications in treating different infectious diseases, both viral and non-viral. Finally, we will present current and future advancements in combating COVID-19 with a potential contribution of the CRISPR system as an antiviral modality in this battle.

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“…Another recent study showed that the RNP delivery of CRISPR/Cas9 in HBV-infected HepG2-NTCP cells induced DSBs in cccDNA, which affected HBV replication. Moreover, Cas9-induced effects were sustained even after RNP degradation/loss of detection, suggesting stable changes due to transcriptional interference (Martinez et al, 2022). However, the efficacy of LNP-based CRISPR/Cas RNP delivery targeting the HBV genome remains to be investigated using a bona fide in vivo HBV infection model.…”

Section: Non-viral Vectors For Clustered Regularly Interspaced Short ...mentioning

confidence: 99%

“…With the advent of the CRISPR/Cas technology, several studies have reported varying degrees of inhibition of HBV replication and/or cccDNA formation using the CRISPR/Cas9 system with different delivery tools (Figure 2; Lin et al, 2014;Seeger and Sohn, 2014;Dong et al, 2015;Lin et al, 2015;Liu et al, 2015Liu et al, , 2018Ramanan et al, 2015;Wang et al, 2015;Zhen et al, 2015;Li H. et al, 2016;Seeger and Sohn, 2016;Zhu et al, 2016;Li et al, 2017Li et al, , 2018Kostyusheva et al, 2019;Kayesh et al, 2020;Suzuki et al, 2021;Yan et al, 2021;Martinez et al, 2022;Wang D. et al, 2022). Notably, it is difficult to efficiently quantify cccDNA (Wang Z. et al, 2022), and accurate quantification of intrahepatic cccDNA is important for assessing the efficiency of anti-HBV therapy.…”

Section: Introductionmentioning

confidence: 99%

In vivo Delivery Tools for Clustered Regularly Interspaced Short Palindromic Repeat/Associated Protein 9-Mediated Inhibition of Hepatitis B Virus Infection: An Update

Kayesh

Hashem²,

Kohara³

et al. 2022

Front. Microbiol.

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Chronic hepatitis B virus (HBV) infection remains a major global health problem despite the availability of an effective prophylactic HBV vaccine. Current antiviral therapies are unable to fully cure chronic hepatitis B (CHB) because of the persistent nature of covalently closed circular DNA (cccDNA), a replicative template for HBV, which necessitates the development of alternative therapeutic approaches. The CRISPR/Cas system, a newly emerging genome editing tool, holds great promise for genome editing and gene therapy. Several in vitro and/or in vivo studies have demonstrated the effectiveness of HBV-specific clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (CRISPR/Cas9) systems in cleaving HBV DNA and cccDNA. Although recent advances in CRISPR/Cas technology enhance its prospects for clinical application against HBV infection, in vivo delivery of the CRISPR/Cas9 system at targets sites remains a major challenge that needs to be resolved before its clinical application in gene therapy for CHB. In the present review, we discuss CRISPR/Cas9 delivery tools for targeting HBV infection, with a focus on the development of adeno-associated virus vectors and lipid nanoparticle (LNP)-based CRISPR/Cas ribonucleoprotein (RNP) delivery to treat CHB. In addition, we discuss the importance of delivery tools in the enhancement of the antiviral efficacy of CRISPR/Cas9 against HBV infection.

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CRISPR-Cas9 Targeting of Hepatitis B Virus Covalently Closed Circular DNA Generates Transcriptionally Active Episomal Variants

Abstract: Hepatitis B virus infection can develop into chronic infection, cirrhosis, and hepatocellular carcinoma. Treatment of chronic hepatitis B requires novel approaches to directly target the viral minichromosome, which is responsible for the persistence of the disease.

Cited by 20 publications

References 48 publications

Adenoviral Vectors: Potential as Anti-HBV Vaccines and Therapeutics

Adenoviral Vectors: Potential as Anti-HBV Vaccines and Therapeutics

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19

In vivo Delivery Tools for Clustered Regularly Interspaced Short Palindromic Repeat/Associated Protein 9-Mediated Inhibition of Hepatitis B Virus Infection: An Update

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