Therapeutic editing of hepatocyte genome in vivo

Lujambio, Amaia

doi:10.1016/j.jhep.2017.05.012

Cited by 22 publications

(16 citation statements)

References 108 publications

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“…Targeted mutagenesis has attracted considerable interest in recent years. This was achieved through the use of sequence-specific RNA-guided nucleases (RGNs) and proteins as a means to cure HBV infection by permanently disabling cccDNA [ 26 , 27 ]. The RGN family includes zinc finger nucleases (ZFNs) [ 28 ], transcription activator-like effector nucleases (TALENs) [ 29 , 30 ], and clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated (Cas) systems [ 31 , 32 ], all showing antiviral efficacy.…”

Section: Direct Acting Antiviralsmentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

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The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

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Section: Direct Acting Antiviralsmentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

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“…Genome-editing technologies, including ZFN, TALEN, and Cas9 systems, have significantly broadened the ability to edit the genomic DNA in vitro, and even in vivo [29,32,177,178]. Delivery of in vitro-transcribed mRNA-mediated delivery of nucleases has various applications and future prospects of genome editing in research and clinical trials [179].…”

Section: Recent Progressmentioning

confidence: 99%

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

Kamimura

Yokoo

Abé

et al. 2019

Cancers

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The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies.

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“…While the HBV therapeutic landscape is vast, few approaches are being developed to disable cccDNA directly. Targeted mutagenesis by sequence-specific RNA-guided nucleases (RGNs) and proteins has thus generated considerable interest, as the technology potentially provides the means to cure HBV infection by permanently disabling cccDNA [ 33 , 34 ].…”

Section: Gene-based Therapies To Target Covalently Closed Circularmentioning

confidence: 99%

Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

Bloom

Maepa

Ely

et al. 2018

Genes

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Chronic infection with the hepatitis B virus (HBV) is a global health concern and accounts for approximately 1 million deaths annually. Amongst other limitations of current anti-HBV treatment, failure to eliminate the viral covalently closed circular DNA (cccDNA) and emergence of resistance remain the most worrisome. Viral rebound from latent episomal cccDNA reservoirs occurs following cessation of therapy, patient non-compliance, or the development of escape mutants. Simultaneous viral co-infections, such as by HIV-1, further complicate therapeutic interventions. These challenges have prompted development of novel targeted hepatitis B therapies. Given the ease with which highly specific and potent nucleic acid therapeutics can be rationally designed, gene therapy has generated interest for antiviral application. Gene therapy strategies developed for HBV include gene silencing by harnessing RNA interference, transcriptional inhibition through epigenetic modification of target DNA, genome editing by designer nucleases, and immune modulation with cytokines. DNA-binding domains and effectors based on the zinc finger (ZF), transcription activator-like effector (TALE), and clustered regularly interspaced short palindromic repeat (CRISPR) systems are remarkably well suited to targeting episomal cccDNA. This review discusses recent developments and challenges facing the field of anti-HBV gene therapy, its potential curative significance and the progress towards clinical application.

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Therapeutic editing of hepatocyte genome in vivo

Cited by 22 publications

References 108 publications

New Approaches to the Treatment of Chronic Hepatitis B

New Approaches to the Treatment of Chronic Hepatitis B

Gene Therapy for Liver Cancers: Current Status from Basic to Clinics

Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

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