Disease Pathways and Mechanisms of Potential Drug Targets

Ghany, Marc G.; Block, Timothy M.

doi:10.1002/cld.735

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…The most direct anti-cccDNA strategy is its specific degradation, after editing, using effector enzymes that activate transcription, or through a system of palindromic repeats, which aim to interrupt the HBV cccDNA. 123,124 These editing systems promote the DNA double-strand break (DSB) at a specific target site and repair the cleavage sites by altering the DNA sequence, leading to a reduction in intrahepatic cccDNA in vivo. 125 Despite the effectiveness of this approach, mistargeting leading to nonspecific cleavage in the host genome or integrated HBV genome can occur.…”

Section: Therapeutic Approaches That Act On Cccdnamentioning

confidence: 99%

Elimination of the hepatitis B virus: A goal, a challenge

Pondé,

Amorim

2024

Medicinal Research Reviews

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The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines—blocking transmission and antiviral therapy—inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother‐to‐child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.

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Section: Therapeutic Approaches That Act On Cccdnamentioning

confidence: 99%

Elimination of the hepatitis B virus: A goal, a challenge

Pondé,

Amorim

2024

Medicinal Research Reviews

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“…Several compounds which are currently under development, called core protein and capsid assembly modulators (CAMs), bind to the hydrophobic pockets of the capsids and inhibit nucleocapsid assembly, pregenomic RNA encapsidation, or both. As a result, synthesis of rcDNA from pgRNA is inhibited [30,31].…”

Section: Core Protein and Capsid Assembly Modulatorsmentioning

confidence: 99%

Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B

Watanabe

Tanaka

2021

Microorganisms

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The hepatitis B core-related antigen (HBcrAg) is an unprecedented novel HBV biomarker that plays an essential role in reflecting covalently closed circular DNA (cccDNA) in chronic hepatitis B (CHB) because its levels correlate with intrahepatic cccDNA and serum HBV DNA. In this review, we describe the clinical application of serum HBcrAg in CHB patients, with a particular focus on new therapies targeting intrahepatic HBV replication. (1) HBcrAg can be detected in clinical cases where serum HBV DNA is undetectable during anti-HBV therapy. (2) A highly sensitive HBcrAg assay (iTACT-HBcrAg) may be useful for monitoring HBV reactivation, as an alternative to HBV DNA. (3) Decreased HBcrAg levels have been significantly associated with promising outcomes in CHB patients, reducing the risk of progression or recurrence of hepatocellular carcinoma. Additionally, we focus on and discuss several drugs in development that target HBV replication, and monitoring HBcrAg may be useful for determining the therapeutic efficacies of such novel drugs. In conclusion, HBcrAg, especially when measured by the recently developed iTACT-HBcrAg assay, may be the most appropriate surrogate marker, over other HBV biomarkers, to predict disease progression and treatment response in CHB patients.

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“…1). The major editing systems, including the zinc finger nuclease (ZFN) [25], transcription activator-like effector nucleases (TALENs) [26] and the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system [27], have been used to disrupt HBV cccDNA. All these editing systems create a DNA double-strand break in a specific target site and repair the cleavage sites by altering DNA sequence.…”

Section: Direct Cccdna Degradationmentioning

confidence: 99%

Targeting Viral cccDNA for Cure of Chronic Hepatitis B

Ligat

Goto

Verrier

2020

Curr Hepatology Rep

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Purpose of Review Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a major cause of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. HBV replication is characterized by the synthesis of covalently closed circular (ccc) DNA which is not targeted by antiviral nucleos(t)ide analogues (NUCs) the key modality of standard of care. While HBV replication is successfully suppressed in treated patients, they remain at risk for developing HCC. While functional cure, characterized by loss of HBsAg, is the first goal of novel antiviral therapies, curative treatments eliminating cccDNA remain the ultimate goal. This review summarizes recent advances in the discovery and development of novel therapeutic strategies and their impact on cccDNA biology. Recent Findings Within the last decade, substantial progress has been made in the understanding of cccDNA biology including the discovery of host dependency factors, epigenetic regulation of cccDNA transcription and immune-mediated degradation. Several approaches targeting cccDNA either in a direct or indirect manner are currently at the stage of discovery, preclinical or early clinical development. Examples include genome-editing approaches, strategies targeting host dependency factors or epigenetic gene regulation, nucleocapsid modulators and immune-mediated degradation. Summary While direct-targeting cccDNA strategies are still largely at the preclinical stage of development, capsid assembly modulators and immune-based approaches have reached the clinical phase. Clinical trials are ongoing to assess their efficacy and safety in patients including their impact on viral cccDNA. Combination therapies provide additional opportunities to overcome current limitations of individual approaches.

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Disease Pathways and Mechanisms of Potential Drug Targets

Cited by 5 publications

References 42 publications

Elimination of the hepatitis B virus: A goal, a challenge

Elimination of the hepatitis B virus: A goal, a challenge

Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B

Targeting Viral cccDNA for Cure of Chronic Hepatitis B

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