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1
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Mnyandu NZ, Limani SW, Ely A, Wadee R, Arbuthnot P, Maepa MB. Long-term inhibition of Hepatitis B virus gene expression by a primary microrna expressing ancestral adeno-associated viral vector. Virol J 2025; 22:41. [PMID: 39962472 PMCID: PMC11834259 DOI: 10.1186/s12985-025-02662-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/12/2025] [Indexed: 02/20/2025] Open
Abstract
Current treatments for chronic infection with the hepatitis B virus (HBV) rarely cure carriers from the disease. Previously reported use of serotype 8 adeno-associated viral (AAV8) vectors to deliver expression cassettes encoding anti-HBV artificial primary microRNAs (apri-miRs) has shown promise in preclinical studies. A recently designed synthetic ancestral AAV (Anc80L65) with high liver transduction efficiency is a promising new addition to the anti-HBV vector toolbox. This study engineered Anc80L65 to express HBx-targeting apri-miRs. Single dose administration of the vectors to cultured cells and HBV transgenic mice effected reductions of secreted HBV surface antigen (HBsAg). Circulating HBV particles and HBV core antigen (HBcAg) were also significantly diminished in mice receiving the anti-HBV apri-miR-expressing ancestral AAVs. Downregulation of HBV biomarkers occurred over a period of 12 months. Absence of inflammatory responses or liver toxicity indicated that the vectors had a good safety profile. These data suggest that a single dose of apri-miR-expressing Anc80L65 is safe and capable of mediating durable suppression of HBV gene expression. Targeting HBx, which is required for transcriptional activity of covalently closed circular DNA of HBV, makes this Anc80L65-derived vector a promising candidate for functional cure from chronic HBV infection.
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Affiliation(s)
- Njabulo Ziphezinhle Mnyandu
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Private Bag X3, Johannesburg, Wits 2050, South Africa
| | - Shonisani Wendy Limani
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Private Bag X3, Johannesburg, Wits 2050, South Africa
| | - Abdullah Ely
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Private Bag X3, Johannesburg, Wits 2050, South Africa
| | - Reubina Wadee
- Department of Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Services, Johannesburg, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Private Bag X3, Johannesburg, Wits 2050, South Africa
| | - Mohube Betty Maepa
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Infectious Diseases and Oncology Research Institute (IDORI), Faculty of Health Sciences, University of the Witwatersrand, Private Bag X3, Johannesburg, Wits 2050, South Africa.
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Hua Y, Li X, Yin B, Lu S, Qian B, Zhou Y, Li Z, Meng Z, Ma Y. Genome-wide analysis of alternative splicing differences in hepatic ischemia reperfusion injury. Sci Rep 2024; 14:31349. [PMID: 39732885 PMCID: PMC11682299 DOI: 10.1038/s41598-024-82846-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Alternative splicing (AS) contributes to transcript and protein diversity, affecting their structure and function. However, the specific transcriptional regulatory mechanisms underlying AS in the context of hepatic ischemia reperfusion (IR) injury in mice have not been extensively characterized. In this study, we investigated differentially alternatively spliced (DAS) genes and differentially expressed transcripts (DETs) in a mouse model of hepatic IR injury using the high throughput RNA sequencing (RNA-seq) analysis and replicate multivariate analysis of transcript splicing (rMATS) analysis. We further conducted Gene ontology (GO) term enrichment, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the protein-protein interaction (PPI) network. A total of 898 DAS genes (p ≤ 0.05) were screened out in the hepatic IR group compared to the sham group, while functional enrichment analysis revealed that DETs and DAS genes were significantly associated with the ATP-dependent chromain, splicesome and metabolic pathways. The expression level of the DAS genes: Gabpb2, Smg1, Tnrc6c, Mettl17, Smpd4, Kcnt2, D16Ertd472e, Rab3gap2, Echdc2 and Ssx2ip were verified by RT-PCR and qRT-PCR. Our findings provide a comprehensive genome-wide view of AS events in hepatic IR injury in mice, enhancing our understanding of AS dynamics and the molecular mechanisms governing alternative pre-mRNA splicing.
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Affiliation(s)
- Yongliang Hua
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
- Department of Pediatric Surgery, Key Laboratory of Hepatosplenic Surgery, the Sixth Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Xinglong Li
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Bing Yin
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Shounan Lu
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Baolin Qian
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Yongzhi Zhou
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Zhongyu Li
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Zhanzhi Meng
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China
| | - Yong Ma
- Department of Minimally Invasive Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, the First Affiliated Hospital of Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China.
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Beretta M, Vesin B, Wei Y, Planchais C, Rosenbaum P, Ait-Goughoulte M, Pelletier N, Hardy D, Mouquet H, Bourgine M. Enhanced hepatitis B virus-specific immunity by combining neutralizing antibody therapy and DNA vaccination in a murine model of chronic hepatitis B virus infection. Hepatology 2024:01515467-990000000-01102. [PMID: 39652775 DOI: 10.1097/hep.0000000000001179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 11/06/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND AND AIMS Successful treatment of chronic HBV infection remains a great challenge due to the difficulty in inducing efficient immune responses. Here, we investigated the therapeutic potential of DNA vaccination combined with a potent HBV broadly neutralizing antibody targeting the small surface viral antigen. APPROACH AND RESULTS C57BL/6 mice were transduced with adeno-associated virus-HBV and were treated twice a week with HBV broadly neutralizing antibodies for 5 weeks. A DNA-based vaccine encoding the HBV core, envelope, and polymerase proteins was administered once to mice 3 weeks after initiating antibody therapy. The antiviral effects and antigen-specific immune responses were evaluated before and for 8 weeks after therapeutic vaccination. Vaccine administration with or without antibody treatment induced the development of functional HBV-specific CD8+ T cells and envelope-specific resident memory T cells in the liver. The combination of antibody treatment and DNA vaccination enhanced the recruitment of B and CD8+ T lymphocytes into the liver of HBV-carrier mice 2 weeks after vaccination. However, although still detectable 2 months after vaccination, HBV-specific CD8+ T cells showed an exhausted phenotype, suggesting that they are dysfunctional. In contrast, more effective control of antigenemia was observed following combination therapy, which was associated with the presence of HBs-specific memory B cells. CONCLUSIONS Although the combination therapy did not result in a functional cure, our findings indicate it produced additive effects on the development of HBV-specific T cells in the liver immediately following treatment, offering a better insight into the mechanisms underlying hepatic tolerance.
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Affiliation(s)
- Maxime Beretta
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
| | - Benjamin Vesin
- Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, Paris, France
| | - Yu Wei
- Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, Paris, France
| | - Cyril Planchais
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
| | - Pierre Rosenbaum
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
| | - Malika Ait-Goughoulte
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Nadège Pelletier
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - David Hardy
- Histopathology Platform, Institut Pasteur, Université Paris Cité, Paris, France
| | - Hugo Mouquet
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
| | - Maryline Bourgine
- Institut Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, Paris, France
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Zeng W, Zheng L, Li Y, Yang J, Mao T, Zhang J, Liu Y, Ning J, Zhang T, Huang H, Chen X, Lu F. Engineered extracellular vesicles for delivering functional Cas9/gRNA to eliminate hepatitis B virus cccDNA and integration. Emerg Microbes Infect 2024; 13:2284286. [PMID: 37982370 PMCID: PMC10763861 DOI: 10.1080/22221751.2023.2284286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 11/13/2023] [Indexed: 11/21/2023]
Abstract
The persistence of HBV covalently closed circular DNA (cccDNA) and HBV integration into the host genome in infected hepatocytes pose significant challenges to the cure of chronic HBV infection. Although CRISPR/Cas9-mediated genome editing shows promise for targeted clearance of viral genomes, a safe and efficient delivery method is currently lacking. Here, we developed a novel approach by combining light-induced heterodimerization and protein acylation to enhance the loading efficiency of Cas9 protein into extracellular vesicles (EVs). Moreover, vesicular stomatitis virus-glycoprotein (VSV-G) was incorporated onto the EVs membrane, significantly facilitating the endosomal escape of Cas9 protein and increasing its gene editing activity in recipient cells. Our results demonstrated that engineered EVs containing Cas9/gRNA and VSV-G can effectively reduce viral antigens and cccDNA levels in the HBV-replicating and infected cell models. Notably, we also confirmed the antiviral activity and high safety of the engineered EVs in the HBV-replicating mouse model generated by hydrodynamic injection and the HBV transgenic mouse model. In conclusion, engineered EVs could successfully mediate functional CRISPR/Cas9 delivery both in vitro and in vivo, leading to the clearance of episomal cccDNA and integrated viral DNA fragments, and providing a novel therapeutic approach for curing chronic HBV infection.
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Affiliation(s)
- Wanjia Zeng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Liwei Zheng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Yukun Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Jing Yang
- School of Medicine, Shihezi University, Shihezi, People’s Republic of China
| | - Tianhao Mao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Jing Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Yanna Liu
- Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Jing Ning
- Department of Gastroenterology, Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, Beijing, People’s Republic of China
| | - Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Hongxin Huang
- Department of Pathogen Biology and Biosecurity, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
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Nguyen L, Nguyen TT, Kim JY, Jeong JH. Advanced siRNA delivery in combating hepatitis B virus: mechanistic insights and recent updates. J Nanobiotechnology 2024; 22:745. [PMID: 39616384 PMCID: PMC11608496 DOI: 10.1186/s12951-024-03004-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/09/2024] [Indexed: 12/06/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major health problem, causing thousands of deaths each year worldwide. Although current medications can often inhibit viral replication and reduce the risk of liver carcinoma, several obstacles still hinder their effectiveness. These include viral resistance, prolonged treatment duration, and low efficacy in clearing viral antigens. To address these challenges in current HBV treatment, numerous approaches have been developed with remarkable success. Among these strategies, small-interfering RNA (siRNA) stands out as one of the most promising therapies for hepatitis B. However, naked siRNAs are vulnerable to enzymatic digestion, easily eliminated by renal filtration, and unable to cross the cell membrane due to their large, anionic structure. Therefore, effective delivery systems are required to protect siRNAs and maintain their functionality. In this review, we have discussed the promises of siRNA therapy in treating HBV, milestones in their delivery systems, and products that have entered clinical trials. Finally, we have outlined the future perspectives of siRNA-based therapy for HBV treatment.
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Affiliation(s)
- Linh Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea
| | - Tiep Tien Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Ju-Yeon Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
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6
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Angelice GP, Roque PH, Valente G, Galvão K, Villar LM, Mello VM, Mello FCA, Lago BV. Evaluation of Interfering RNA Efficacy in Treating Hepatitis B: Is It Promising? Viruses 2024; 16:1710. [PMID: 39599825 PMCID: PMC11598949 DOI: 10.3390/v16111710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Despite an existing safe and effective vaccine for hepatitis B virus (HBV), it is still a major public health concern. Nowadays, several drugs are used to treat chronic hepatitis B; however, full healing remains controversial. The viral covalently closed circular DNA (cccDNA) formed by HBV forms a major challenge in its treatment, as does the ability of HBV to integrate itself into the host genome, which enables infection reactivation. Interfering RNA (RNAi) is a gene-silencing post-transcriptional mechanism which forms as a promising alternative to treat chronic hepatitis B. The aim of the present review is to assess the evolution of hepatitis B treatment approaches based on using RNA interference. METHODS Data published between 2016 and 2023 in scientific databases (PubMed, PMC, LILACS, and Bireme) were assessed. RESULTS In total, 76,949 articles were initially identified and quality-checked, and 226 eligible reports were analyzed in depth. The main genomic targets, delivery systems, and major HBV therapy innovations are discussed in this review. This review reinforces the therapeutic potential of RNAi and identifies the need for conducting further studies to fill the remaining gaps between bench and clinical practice.
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Zai W, Yang M, Jiang K, Guan J, Wang H, Hu K, Huang C, Chen J, Fu W, Zhan C, Yuan Z. Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection. Signal Transduct Target Ther 2024; 9:150. [PMID: 38902241 PMCID: PMC11189933 DOI: 10.1038/s41392-024-01871-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 06/22/2024] Open
Abstract
This study aimed to develop a pan-genotypic and multifunctional small interfering RNA (siRNA) against hepatitis B virus (HBV) with an efficient delivery system for treating chronic hepatitis B (CHB), and explore combined RNA interference (RNAi) and immune modulatory modalities for better viral control. Twenty synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and evaluated. The lipid nanoparticle (LNP) formulation was optimized by adopting HO-PEG2000-DMG lipid and modifying the molar ratio of traditional polyethylene glycol (PEG) lipid in LNP prescriptions. The efficacy and safety of this formulation in delivering siHBV (tLNP/siHBV) along with the mouse IL-2 (mIL-2) mRNA (tLNP/siHBVIL2) were evaluated in the rAAV-HBV1.3 mouse model. A siRNA combination (terms "siHBV") with a genotypic coverage of 98.55% was selected, chemically modified, and encapsulated within an optimized LNP (tLNP) of high efficacy and security to fabricate a therapeutic formulation for CHB. The results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA (up to 3log10 reduction; vs PBS) in dose- and time-dependent manners at single-dose or multi-dose frequencies, with satisfactory safety profiles. Further studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus, via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4+ and CD8+ T cell responses by expressed mIL-2 protein. By adopting tLNP as nucleic acid nanocarriers, the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV, thus offering a promising translational therapeutic strategy for treating CHB.
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Affiliation(s)
- Wenjing Zai
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Min Yang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China
- Shanghai Engineering Research Center for Synthetic Immunology, Fudan University, Shanghai, P. R. China
| | - Kuan Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China
- Eye Institute and Department of Ophthamology, Eye and ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Juan Guan
- Pharmacy Department of Huashan Hospital, Fudan University, Shanghai, P. R. China
| | - Huijing Wang
- Institute of Pediatric Translational Medicine, Shanghai Institute for Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kongying Hu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Chao Huang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Wei Fu
- Institute of Pediatric Translational Medicine, Shanghai Institute for Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Changyou Zhan
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China.
- Shanghai Engineering Research Center for Synthetic Immunology, Fudan University, Shanghai, P. R. China.
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, P. R. China.
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Motamedi H, Ari MM, Alvandi A, Abiri R. Principle, application and challenges of development siRNA-based therapeutics against bacterial and viral infections: a comprehensive review. Front Microbiol 2024; 15:1393646. [PMID: 38939184 PMCID: PMC11208694 DOI: 10.3389/fmicb.2024.1393646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/28/2024] [Indexed: 06/29/2024] Open
Abstract
While significant progress has been made in understanding and applying gene silencing mechanisms and the treatment of human diseases, there have been still several obstacles in therapeutic use. For the first time, ONPATTRO, as the first small interfering RNA (siRNA) based drug was invented in 2018 for treatment of hTTR with polyneuropathy. Additionally, four other siRNA based drugs naming Givosiran, Inclisiran, Lumasiran, and Vutrisiran have been approved by the US Food and Drug Administration and the European Medicines Agency for clinical use by hitherto. In this review, we have discussed the key and promising advances in the development of siRNA-based drugs in preclinical and clinical stages, the impact of these molecules in bacterial and viral infection diseases, delivery system issues, the impact of administration methods, limitations of siRNA application and how to overcome them and a glimpse into future developments.
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Affiliation(s)
- Hamid Motamedi
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzie Mahdizade Ari
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Microbial Biotechnology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhoushang Alvandi
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ramin Abiri
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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9
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Kasianchuk N, Dobrowolska K, Harkava S, Bretcan A, Zarębska-Michaluk D, Jaroszewicz J, Flisiak R, Rzymski P. Gene-Editing and RNA Interference in Treating Hepatitis B: A Review. Viruses 2023; 15:2395. [PMID: 38140636 PMCID: PMC10747710 DOI: 10.3390/v15122395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on interferons and/or nucleos(t)ide analogs, suppress the virus replication but do not eliminate the pathogen and suffer from several constraints. This paper reviews the progress on biotechnological approaches in functional and definitive HBV treatments, including gene-editing tools, i.e., zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9, as well as therapeutics based on RNA interference. The advantages and challenges of these approaches are also discussed. Although the safety and efficacy of gene-editing tools in HBV therapies are yet to be demonstrated, they show promise for the revitalization of a much-needed advance in the field and offer viral eradication. Particular hopes are related to CRISPR/Cas9; however, therapeutics employing this system are yet to enter the clinical testing phases. In contrast, a number of candidates based on RNA interference, intending to confer a functional cure, have already been introduced to human studies. However, larger and longer trials are required to assess their efficacy and safety. Considering that prevention is always superior to treatment, it is essential to pursue global efforts in HBV vaccination.
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Affiliation(s)
- Nadiia Kasianchuk
- Faculty of Biology, Adam Mickiewicz University in Poznań, 61-614 Poznań, Poland
| | | | - Sofiia Harkava
- Junior Academy of Sciences of Ukraine, Regional Branch in Dnipro, 49000 Dnipro, Ukraine;
| | - Andreea Bretcan
- National College “Ienăchiță Văcărescu”, 130016 Târgoviște, Romania;
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, 25-317 Kielce, Poland;
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, 15-540 Białystok, Poland;
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, 60-806 Poznań, Poland
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10
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Ghaemi Z, Nafiu O, Tajkhorshid E, Gruebele M, Hu J. A computational spatial whole-Cell model for hepatitis B viral infection and drug interactions. Sci Rep 2023; 13:21392. [PMID: 38049515 PMCID: PMC10695947 DOI: 10.1038/s41598-023-45998-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 10/26/2023] [Indexed: 12/06/2023] Open
Abstract
Despite a vaccine, hepatitis B virus (HBV) remains a world-wide source of infections and deaths. We develop a whole-cell computational platform combining spatial and kinetic models describing the infection cycle of HBV in a hepatocyte host. We simulate key parts of the infection cycle with this whole-cell platform for 10 min of biological time, to predict infection progression, map out virus-host and virus-drug interactions. We find that starting from an established infection, decreasing the copy number of the viral envelope proteins shifts the dominant infection pathway from capsid secretion to re-importing the capsids into the nucleus, resulting in more nuclear-localized viral covalently closed circular DNA (cccDNA) and boosting transcription. This scenario can mimic the consequence of drugs designed to manipulate viral gene expression. Mutating capsid proteins facilitates capsid destabilization and disassembly at nuclear pore complexes, resulting in an increase in cccDNA copy number. However, excessive destabilization leads to premature cytoplasmic disassembly and does not increase the cccDNA counts. Finally, our simulations can predict the best drug dosage and its administration timing to reduce the cccDNA counts. Our adaptable computational platform can be parameterized to study other viruses and identify the most central viral pathways that can be targeted by drugs.
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Affiliation(s)
- Zhaleh Ghaemi
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
- National Science Foundation Science and Technology Center for Quantitative Cell Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
| | - Oluwadara Nafiu
- Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Emad Tajkhorshid
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- National Science Foundation Science and Technology Center for Quantitative Cell Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Martin Gruebele
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- National Science Foundation Science and Technology Center for Quantitative Cell Biology, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
- Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Jianming Hu
- Department of Microbiology and Immunology, Pennsylvania State University, Hershey, PA, 17033, USA
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11
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Bauer AN, Majumdar N, Williams F, Rajput S, Pokhrel LR, Cook PP, Akula SM. MicroRNAs: Small but Key Players in Viral Infections and Immune Responses to Viral Pathogens. BIOLOGY 2023; 12:1334. [PMID: 37887044 PMCID: PMC10604607 DOI: 10.3390/biology12101334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/21/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023]
Abstract
Since the discovery of microRNAs (miRNAs) in C. elegans in 1993, the field of miRNA research has grown steeply. These single-stranded non-coding RNA molecules canonically work at the post-transcriptional phase to regulate protein expression. miRNAs are known to regulate viral infection and the ensuing host immune response. Evolving research suggests miRNAs are assets in the discovery and investigation of therapeutics and diagnostics. In this review, we succinctly summarize the latest findings in (i) mechanisms underpinning miRNA regulation of viral infection, (ii) miRNA regulation of host immune response to viral pathogens, (iii) miRNA-based diagnostics and therapeutics targeting viral pathogens and challenges, and (iv) miRNA patents and the market landscape. Our findings show the differential expression of miRNA may serve as a prognostic biomarker for viral infections in regard to predicting the severity or adverse health effects associated with viral diseases. While there is huge market potential for miRNA technology, the novel approach of using miRNA mimics to enhance antiviral activity or antagonists to inhibit pro-viral miRNAs has been an ongoing research endeavor. Significant hurdles remain in terms of miRNA delivery, stability, efficacy, safety/tolerability, and specificity. Addressing these challenges may pave a path for harnessing the full potential of miRNAs in modern medicine.
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Affiliation(s)
- Anais N. Bauer
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (A.N.B.); (N.M.); (F.W.)
| | - Niska Majumdar
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (A.N.B.); (N.M.); (F.W.)
| | - Frank Williams
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (A.N.B.); (N.M.); (F.W.)
| | - Smit Rajput
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
| | - Lok R. Pokhrel
- Department of Public Health, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
| | - Paul P. Cook
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
| | - Shaw M. Akula
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (A.N.B.); (N.M.); (F.W.)
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
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12
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Abdul Majeed N, Zehnder B, Koh C, Heller T, Urban S. Hepatitis delta: Epidemiology to recent advances in therapeutic agents. Hepatology 2023; 78:1306-1321. [PMID: 36738087 DOI: 10.1097/hep.0000000000000331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/19/2022] [Indexed: 02/05/2023]
Abstract
Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.
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Affiliation(s)
- Nehna Abdul Majeed
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Benno Zehnder
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF) - Heidelberg Partner Site, Heidelberg, Germany
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13
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Pei J, Tian Y, Ye W, Han J, Dang Y, Cheng T, Wang W, Zhao Y, Ye W, Huangfu S, Li Y, Zhang F, Lei Y, Qian A. A novel recombinant ORF7-siRNA delivered by flexible nano-liposomes inhibits varicella zoster virus infection. Cell Biosci 2023; 13:167. [PMID: 37700336 PMCID: PMC10496174 DOI: 10.1186/s13578-023-01108-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 08/18/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Varicella zoster virus (VZV), which is a human restricted alpha-herpesvirus, causes varicella (chickenpox) and zoster (shingles). The subsequent post-herpetic neuralgia (PHN) due to VZV infection is excruciating for most patients. Thus, developing specific therapeutics against VZV infection is imperative. RNA interference (RNAi) represents an effective approach for alternative antiviral therapy. This study aimed to develop a novel anti-VZV therapeutics based on RNAi. RESULTS In this study, we screened and found the open reading frame 7 (ORF7) of the VZV genome was an ideal antiviral target based on RNAi. Therefore, a novel siRNA targeting ORF7 (si-ORF7) was designed to explore the potential of RNAi antiviral treatment strategy toward VZV. We used a bio-engineering approach to manufacture recombinant siRNA agents with high yield in E. coli. Then, the efficacy of recombinant ORF7-siRNA (r/si-ORF7) in inhibiting VZV infection both in cellular level and 3D human epidermal skin model was evaluated. The r/si-ORF7 was proved to inhibit the VZV replication and reduce the virus copy numbers significantly in vitro. Furthermore, flexible nano-liposomes were established to deliver r/si-ORF7 to 3D human epidermal skin model and found r/si-ORF7 also could inhibit the VZV infection, thus maintaining normal skin morphology. CONCLUSIONS Taken together, our results highlighted that transdermal administration of antiviral r/si-ORF7 was a promising therapeutic strategy for functional cure of VZV infection.
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Affiliation(s)
- Jiawei Pei
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Ye Tian
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Wei Ye
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiangfan Han
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yamei Dang
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tong Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, China
| | - Wei Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, China
| | - Yipu Zhao
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Weiliang Ye
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shuyuan Huangfu
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yu Li
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
| | - Fanglin Zhang
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Yingfeng Lei
- Department of Microbiology, School of Preclinical Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Airong Qian
- key Lab for Space Biosciences and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
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14
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Chatterjee K, Lakdawala S, Quadir SS, Puri D, Mishra DK, Joshi G, Sharma S, Choudhary D. siRNA-Based Novel Therapeutic Strategies to Improve Effectiveness of Antivirals: An Insight. AAPS PharmSciTech 2023; 24:170. [PMID: 37566146 DOI: 10.1208/s12249-023-02629-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
Since the ground-breaking discovery of RNA interference (RNAi), scientists have made significant progress in the field of small interfering RNA (siRNA) treatments. Due to severe barriers to the therapeutic application of siRNA, nanoparticle technologies for siRNA delivery have been designed. For pathological circumstances such as viral infection, toxic RNA abnormalities, malignancies, and hereditary diseases, siRNAs are potential therapeutic agents. However, systemic administration of siRNAs in vivo remains a substantial issue due to a lack of "drug-likeness" (siRNA are relatively larger than drugs and have low hydrophobicity), physiological obstacles, and possible toxicities. This write-up covers important accomplishment in the field of clinical trials and patents specially based of siRNAs using targeting viruses. Furthermore, it offers deep insight of nanoparticle applied for siRNA delivery and strategies to improve the effectiveness of antivirals.
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Affiliation(s)
- Krittika Chatterjee
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India
| | - Sagheerah Lakdawala
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India
| | - Sheikh Shahnawaz Quadir
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India
| | - Dinesh Puri
- School of Pharmacy, Graphic Era Hill University, Dehradun, Uttarakhand, 248001, India
| | - Dinesh Kumar Mishra
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Koni, Bilaspur (C.G.), 495009, India
| | - Garima Joshi
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India
| | - Sanjay Sharma
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India.
| | - Deepak Choudhary
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India.
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15
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Silva AJD, de Sousa MMG, de Macêdo LS, de França Neto PL, de Moura IA, Espinoza BCF, Invenção MDCV, de Pinho SS, da Gama MATM, de Freitas AC. RNA Vaccines: Yeast as a Novel Antigen Vehicle. Vaccines (Basel) 2023; 11:1334. [PMID: 37631902 PMCID: PMC10459952 DOI: 10.3390/vaccines11081334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/28/2023] Open
Abstract
In the last decades, technological advances for RNA manipulation enabled and expanded its application in vaccine development. This approach comprises synthetic single-stranded mRNA molecules that direct the translation of the antigen responsible for activating the desired immune response. The success of RNA vaccines depends on the delivery vehicle. Among the systems, yeasts emerge as a new approach, already employed to deliver protein antigens, with efficacy demonstrated through preclinical and clinical trials. β-glucans and mannans in their walls are responsible for the adjuvant property of this system. Yeast β-glucan capsules, microparticles, and nanoparticles can modulate immune responses and have a high capacity to carry nucleic acids, with bioavailability upon oral immunization and targeting to receptors present in antigen-presenting cells (APCs). In addition, yeasts are suitable vehicles for the protection and specific delivery of therapeutic vaccines based on RNAi. Compared to protein antigens, the use of yeast for DNA or RNA vaccine delivery is less established and has fewer studies, most of them in the preclinical phase. Here, we present an overview of the attributes of yeast or its derivatives for the delivery of RNA-based vaccines, discussing the current challenges and prospects of this promising strategy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Antonio Carlos de Freitas
- Laboratory of Molecular Studies and Experimental Therapy—LEMTE, Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Brazil; (A.J.D.S.)
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16
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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17
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Kurakula H, Vaishnavi S, Sharif MY, Ellipilli S. Emergence of Small Interfering RNA-Based Gene Drugs for Various Diseases. ACS OMEGA 2023; 8:20234-20250. [PMID: 37323391 PMCID: PMC10268023 DOI: 10.1021/acsomega.3c01703] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/17/2023]
Abstract
Small molecule, peptide, and protein-based drugs have been developed over decades to treat various diseases. The importance of gene therapy as an alternative to traditional drugs has increased after the discovery of gene-based drugs such as Gendicine for cancer and Neovasculgen for peripheral artery disease. Since then, the pharma sector is focusing on developing gene-based drugs for various diseases. After the discovery of the RNA interference (RNAi) mechanism, the development of siRNA-based gene therapy has been accelerated immensely. siRNA-based treatment for hereditary transthyretin-mediated amyloidosis (hATTR) using Onpattro and acute hepatic porphyria (AHP) by Givlaari and three more FDA-approved siRNA drugs has set up a milestone and further improved the confidence for the development of gene therapeutics for a spectrum of diseases. siRNA-based gene drugs have more advantages over other gene therapies and are under study to treat different types of diseases such as viral infections, cardiovascular diseases, cancer, and many more. However, there are a few bottlenecks to realizing the full potential of siRNA-based gene therapy. They include chemical instability, nontargeted biodistribution, undesirable innate immune responses, and off-target effects. This review provides a comprehensive view of siRNA-based gene drugs: challenges associated with siRNA delivery, their potential, and future prospects.
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Affiliation(s)
- Harshini Kurakula
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Swetha Vaishnavi
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Mohammed Yaseen Sharif
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
| | - Satheesh Ellipilli
- Department
of Chemistry, School of Engineering and Sciences, SRM University-AP, Amaravati, Andhra Pradesh 522240, India
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18
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Tian L, Tang S, Wang N, Deng H, Zhang Q, Shi T. Hepatic and portal vein Doppler ultrasounds in assessing liver inflammation and fibrosis in chronic HBV infection with a normal ALT level. Front Med (Lausanne) 2023; 10:1178944. [PMID: 37305137 PMCID: PMC10248231 DOI: 10.3389/fmed.2023.1178944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/08/2023] [Indexed: 06/13/2023] Open
Abstract
Aims To discuss the clinical value of hepatic and portal vein Doppler ultrasounds in assessing liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection, and a normal alanine transaminase (ALT) level. Methods 94 patients with chronic HBV infections who had undergone ultrasound-guided liver biopsies were enrolled and grouped by the liver tissue pathological results. Analyzed the differences and correlation between parameters of the hepatic and portal vein Doppler ultrasounds are discussed across different degrees of liver inflammation and fibrosis. Results There were 27 patients with no significant liver damage and 67 patients with significant liver damage, there were significant differences in the parameters of the hepatic and portal vein Doppler ultrasounds between them (p < 0.05). As liver inflammation was aggravated, the inner diameter of the portal vein increased, and the blood flow velocities of the portal and superior mesenteric veins decreased (p < 0.05). When liver fibrosis became more severe, the inner diameter of the portal vein increased, while the blood flow velocities of the portal, superior mesenteric, and splenic veins decreased, and the Doppler waveforms of hepatic veins became unidirectional or flat (p < 0.05). The receiver operating characteristic (ROC) curve showed the assessment efficacy of hepatic and portal vein Doppler ultrasounds was superior to abdominal Doppler ultrasound alone in assessing liver fibrosis, and the combination of the two examination techniques outperformed any technique used alone. Conclusion The hepatic and portal vein Doppler ultrasounds have important clinical value for assessing liver fibrosis in patients with chronic HBV infection, to aid improve the diagnosis of liver fibrosis.
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Affiliation(s)
- Li Tian
- Department of Infectious Disease, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuyao Tang
- Department of Infectious Disease, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Wang
- Department of Infectious Disease, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huan Deng
- Department of Infectious Disease, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qunxia Zhang
- Department of Ultrasound Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tongdong Shi
- Department of Infectious Disease, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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19
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Kakuda TN, Halabi A, Klein G, Sanga M, Guinard-Azadian C, Kowalik M, Nedoschinsky K, Nangosyah J, Ediage EN, Hillewaert V, Verboven P, Goris I, Snoeys J, Palmer M, Biermer M. Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment. J Clin Pharmacol 2023; 63:732-741. [PMID: 36786053 DOI: 10.1002/jcph.2214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/06/2023] [Indexed: 02/15/2023]
Abstract
JNJ-73763989 is comprised of 2 short interfering RNAs (siRNAs), JNJ-73763976 and JNJ-73763924, that target hepatitis B virus (HBV) mRNAs for degradation, thereby inhibiting HBV replication. JNJ-56136379 is a capsid assembly modulator that inhibits HBV replication by inducing the formation of empty capsids (CAM-E). In 2 phase 1, open-label, non-randomized, single-center studies, the single-dose pharmacokinetics, safety, and tolerability of JNJ-73763989 or JNJ-56136379 were assessed in participants with moderate hepatic impairment (Child-Pugh Class B) versus participants with normal liver function. Participants in both studies received a single subcutaneous dose of JNJ-73763989 200 mg or oral JNJ-56136379 250 mg, followed by an evaluation of plasma pharmacokinetic parameters and safety assessments. Plasma exposure to JNJ-73763976, JNJ-73763924, and JNJ-56136379 was 1.3- to 1.4-, 1.8- to 2.2-, and 1.1- to 1.3-fold higher in participants with moderate hepatic impairment versus participants with normal liver function; however, these increases were not considered clinically relevant. Both drugs were well tolerated and safe, with 7 (21.9%) participants experiencing 1 or more treatment-emergent adverse events, 3 of which were related to JNJ-56136379. Overall, the plasma exposures of JNJ-73763989 and JNJ-56136379 were higher in participants with moderate hepatic impairment, but both were well tolerated. Further studies are needed to evaluate the effect of hepatic impairment under multiple-dose administration.
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Affiliation(s)
- Thomas N Kakuda
- Janssen Research & Development, LLC, Brisbane, California, USA
| | - Atef Halabi
- Clinical Research Services Kiel GmbH, Kiel, Germany
| | | | - Madhu Sanga
- Janssen Research & Development, LLC, Brisbane, California, USA
| | | | - Monika Kowalik
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | | | | | | | | | | | - Ivo Goris
- Janssen Pharmaceutica NV, Beerse, Belgium
| | - Jan Snoeys
- Janssen Pharmaceutica NV, Beerse, Belgium
| | - Martyn Palmer
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
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20
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Yosyingyong P, Viriyapong R. Global dynamics of multiple delays within-host model for a hepatitis B virus infection of hepatocytes with immune response and drug therapy. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:7349-7386. [PMID: 37161155 DOI: 10.3934/mbe.2023319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
In this paper, a mathematical model describing the hepatitis B virus (HBV) infection of hepatocytes with the intracellular HBV-DNA containing capsids, cytotoxic T-lymphocyte (CTL), antibodies including drug therapy (blocking new infection and inhibiting viral production) with two-time delays is studied. It incorporates the delay in the productively infected hepatocytes and the delay in an antigenic stimulation generating CTL. We verify the positivity and boundedness of solutions and determine the basic reproduction number. The local and global stability of three equilibrium points (infection-free, immune-free, and immune-activated) are investigated. Finally, the numerical simulations are established to show the role of these therapies in reducing viral replication and HBV infection. Our results show that the treatment by blocking new infection gives more significant results than the treatment by inhibiting viral production for infected hepatocytes. Further, both delays affect the number of infections and duration i.e. the longer the delay, the more severe the HBV infection.
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Affiliation(s)
- Pensiri Yosyingyong
- Department of Mathematics, Faculty of Science, Naresuan University, Phitsanulok, 65000, Thailand
| | - Ratchada Viriyapong
- Department of Mathematics, Faculty of Science, Naresuan University, Phitsanulok, 65000, Thailand
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21
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Jing X, Arya V, Reynolds KS, Rogers H. Clinical Pharmacology of RNA Interference-Based Therapeutics: A Summary Based on Food and Drug Administration-Approved Small Interfering RNAs. Drug Metab Dispos 2023; 51:193-198. [PMID: 36332914 PMCID: PMC9900864 DOI: 10.1124/dmd.122.001107] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/11/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differs from small molecules and protein therapeutics in various ways, including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas. With these unique attributes as well as growing therapeutic potential, oligonucleotide therapeutics have generated significant interest from a clinical pharmacology perspective. The Food and Drug Administration (FDA) previously published results of a survey that summarized clinical pharmacology studies supporting oligonucleotide therapies approved and in development between 2012 and 2018. Since the first approval of a small interfering RNA (siRNA) therapeutic in 2018, this class of modalities has gained momentum in various therapeutic areas. Hence, a comprehensive examination of the clinical pharmacology of FDA-approved siRNA therapeutics would benefit the path forward for many stakeholders. Thus, in this current review, we thoroughly examine and summarize clinical pharmacology data of the FDA-approved siRNA therapeutics approved from 2018 (year of first approval) to 2022, aimed at facilitating future drug development and regulatory decision making. SIGNIFICANCE STATEMENT: This review systematically summarizes the clinical pharmacology information of Food and Drug Administration (FDA)-approved small interfering RNAs (siRNA) therapeutics. SiRNAs are revolutionizing the drug development field. Unique clinical pharmacology characteristics represent a differentiating factor for this class of therapeutics. The FDArecently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics. As clinical development of this class of therapeutics is fast growing, this review will inform discovery and clinical-stage evaluation of upcoming siRNA-associated drug candidates.
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Affiliation(s)
- Xing Jing
- Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
| | - Vikram Arya
- Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
| | - Kellie Schoolar Reynolds
- Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
| | - Hobart Rogers
- Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
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22
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Qi R, Cao J, Wu Y, Lei X, He J, Zhang L, Fu R, Chen F, Wang Y, Zhang T, Xia N, Yuan Q. Combination therapy of therapeutic antibody and vaccine or entecavir in HBV carrier mice. Front Microbiol 2023; 14:1173061. [PMID: 37213494 PMCID: PMC10196021 DOI: 10.3389/fmicb.2023.1173061] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/11/2023] [Indexed: 05/23/2023] Open
Abstract
Chronic infection with the hepatitis B virus (HBV) is a leading causes of liver cirrhosis and hepatocellular carcinoma. However, managing HBV treatments is challenging due to the lack of effective monotherapy. Here, we present two combination approaches, both of which aim to target and enhance the clearance of HBsAg and HBV-DNA. The first approach involves the use of antibodies to continuously suppress HBsAg, followed by the administration of a therapeutic vaccine in a sequential manner. This approach results in better therapeutic outcomes compared to the use of these treatments individually. The second approach involves combining antibodies with ETV, which effectively overcomes the limitations of ETV in suppressing HBsAg. Thus, the combination of therapeutic antibodies, therapeutic vaccines, and other existing drugs is a promising strategy for the development of novel strategies to treat hepatitis B.
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Affiliation(s)
- Ruoyao Qi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Jiali Cao
- Department of Clinical Laboratory, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Yangtao Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Xing Lei
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Jinhang He
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Liang Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Rao Fu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Feng Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Yingbin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
- *Correspondence: Yingbin Wang,
| | - Tianying Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
- Tianying Zhang,
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian, China
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences & School of Public Health, Xiamen University, Xiamen, Fujian, China
- Quan Yuan,
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Shivatare SS, Shivatare VS, Wong CH. Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments. Chem Rev 2022; 122:15603-15671. [PMID: 36174107 PMCID: PMC9674437 DOI: 10.1021/acs.chemrev.1c01032] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glycoconjugates are major constituents of mammalian cells that are formed via covalent conjugation of carbohydrates to other biomolecules like proteins and lipids and often expressed on the cell surfaces. Among the three major classes of glycoconjugates, proteoglycans and glycoproteins contain glycans linked to the protein backbone via amino acid residues such as Asn for N-linked glycans and Ser/Thr for O-linked glycans. In glycolipids, glycans are linked to a lipid component such as glycerol, polyisoprenyl pyrophosphate, fatty acid ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined and biosynthetically understood, especially those associated with human diseases, and are accessible to new drug, diagnostic, and therapeutic developments. This review describes the status and new advances in the biological study and therapeutic applications of natural and synthetic glycoconjugates, including proteoglycans, glycoproteins, and glycolipids. The scope, limitations, and novel methodologies in the synthesis and clinical development of glycoconjugates including vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., and their future prospectus are discussed.
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Affiliation(s)
- Sachin S Shivatare
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Vidya S Shivatare
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Chi-Huey Wong
- Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
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24
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Ning L, Liu M, Gou Y, Yang Y, He B, Huang J. Development and application of ribonucleic acid therapy strategies against COVID-19. Int J Biol Sci 2022; 18:5070-5085. [PMID: 35982905 PMCID: PMC9379410 DOI: 10.7150/ijbs.72706] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/16/2022] [Indexed: 11/17/2022] Open
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), remaining a global health crisis since its outbreak until now. Advanced biotechnology and research findings have revealed many suitable viral and host targets for a wide range of therapeutic strategies. The emerging ribonucleic acid therapy can modulate gene expression by post-transcriptional gene silencing (PTGS) based on Watson-Crick base pairing. RNA therapies, including antisense oligonucleotides (ASO), ribozymes, RNA interference (RNAi), aptamers, etc., were used to treat SARS-CoV whose genome is similar to SARV-CoV-2, and the past experience also applies for the treatment of COVID-19. Several studies against SARS-CoV-2 based on RNA therapeutic strategy have been reported, and a dozen of relevant preclinical or clinical trials are in process globally. RNA therapy has been a very active and important part of COVID-19 treatment. In this review, we focus on the progress of ribonucleic acid therapeutic strategies development and application, discuss corresponding problems and challenges, and suggest new strategies and solutions.
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Affiliation(s)
- Lin Ning
- School of Healthcare Technology, Chengdu Neusoft University, Sichuan, China.,School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Mujiexin Liu
- Ineye Hospital of Chengdu University of TCM, Sichuan, China
| | - Yushu Gou
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Yue Yang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
| | - Bifang He
- Medical College, Guizhou University, Guizhou, China
| | - Jian Huang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Sichuan, China
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25
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Skrlec I, Talapko J. Hepatitis B and circadian rhythm of the liver. World J Gastroenterol 2022; 28:3282-3296. [PMID: 36158265 PMCID: PMC9346465 DOI: 10.3748/wjg.v28.i27.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm in humans is determined by the central clock located in the hypothalamus's suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus's life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.
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Affiliation(s)
- Ivana Skrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Jasminka Talapko
- Department of Anatomy Histology, Embryology, Pathology Anatomy and Pathology Histology, Faculty of Dental Medicine and Health, Osijek 31000, Croatia
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26
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Codelivery of HBx-siRNA and Plasmid Encoding IL-12 for Inhibition of Hepatitis B Virus and Reactivation of Antiviral Immunity. Pharmaceutics 2022; 14:pharmaceutics14071439. [PMID: 35890334 PMCID: PMC9318813 DOI: 10.3390/pharmaceutics14071439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/24/2022] [Accepted: 07/04/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the virus. Herein, we demonstrate that the HBV-related antigen can be effectively inhibited and antiviral immunity can be successfully reactivated through codelivery of the small interfering RNA (siRNA) targeting HBV X protein (HBx) and the plasmid encoding interleukin 12 (pIL-12) to hepatocytes and immune cells. After being treated by the siRNA/pIL-12 codelivery system, HBx mRNA and hepatitis B surface antigen (HBsAg) are dramatically reduced in HepG2.215 cells. More importantly, the downregulated CD47 and programmed death ligand 1 (PD-L1) and the upregulated interferon-β promoter stimulator-1 (IPS-1), retinoic acid-inducible gene-1 (RIG-1), CD80, and human leukocyte antigen-1 (HLA-1) in treated HepG2.215 cells indicate that the immunosuppression is reversed by the codelivery system. Furthermore, the codelivery system results in inhibition of extracellular regulated protein kinases (ERK) and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways, as well as downregulation of B-cell lymphoma-2 (Bcl-2) and upregulation of p53, implying its potential in preventing the progression of HBV-induced HCC. In addition, J774A.1 macrophages treated by the codelivery system were successfully differentiated into the M1 phenotype and expressed enhanced cytokines with anti-hepatitis B effects such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Therefore, we believe that codelivery of siRNA and pIL-12 can effectively inhibit hepatitis B virus, reverse virus-induced immunosuppression, reactivate antiviral immunity, and hinder the progression of HBV-induced hepatocellular carcinoma. This investigation provides a promising approach for the synergistic treatment of HBV infection.
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27
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Mao Y, Wang X, Hu W, Li A, Li Y, Huang H, Yan R, Zhang Y, Li J, Li H, Wang S. Long-term and efficient inhibition of hepatitis B virus replication by AAV8-delivered artificial microRNAs. Antiviral Res 2022; 204:105366. [PMID: 35732226 DOI: 10.1016/j.antiviral.2022.105366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 05/28/2022] [Accepted: 06/15/2022] [Indexed: 11/02/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a global health problem and current treatments are insufficient due to immune tolerance to hepatitis B surface antigen (HBsAg). RNA interference (RNAi) is a more promising approach for antiviral therapy. Here, 17 single artificial microRNAs (amiRNAs) targeting the highly conserved regions of HBV genome were screened to inhibit HBV replication. In addition, we compared three tandem amiRNAs, each containing 3 different amiRNAs, out of which amiRNA135 was selected to be studied in detail. In vitro data showed that amiRNA135 significantly inhibited the replication of different HBV genotypes (including resistant and mutant). In vivo study was carried out by adeno-associated virus 8-mediated gene delivery, we found that the anti-HBV effects of AAV8-amiRNA135 were time and dose-dependent. Serum HBsAg and HBeAg in high dose groups were significantly reduced at 7 days after a single intravenous vector injection, and maintained at low levels throughout a 15-month experiment. Immunohistochemical staining and HBV core particle DNA analysis confirmed that HBV replication in the liver was strongly inhibited by AAV8-amiRNA135. Taken together, our data suggest that AAV8-mediated trimeric amiRNA expression is a promising therapeutic approach for chronic HBV infection.
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Affiliation(s)
- Yingying Mao
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Xuejun Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
| | - Wei Hu
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Andrew Li
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, USA
| | - Ying Li
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Hai Huang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Renhe Yan
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yanling Zhang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jinlong Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Hongwei Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
| | - Shengqi Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
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Gane E, Yuen MF, Kakuda TN, Ogawa T, Takahashi Y, Goeyvaerts N, Lonjon-Domanec I, Vaughan T, Schluep T, Hamilton J, Njumbe Ediage E, Hillewaert V, Snoeys J, Lenz O, Talloen W, Biermer M. JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B. Antivir Ther 2022; 27:13596535221093856. [PMID: 35695169 DOI: 10.1177/13596535221093856] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). METHODS Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). RESULTS Thirty non-Japanese (n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants (n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. CONCLUSION JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
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Affiliation(s)
- Ed Gane
- New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand
| | - Man-Fung Yuen
- Department of Medicine, 25809The University of Hong Kong, Hong Kong, China
| | | | | | | | | | | | | | | | | | | | | | - Jan Snoeys
- 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | - Oliver Lenz
- 50148Janssen Pharmaceutica NV, Beerse, Belgium
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Design of siRNA molecules for silencing of membrane glycoprotein, nucleocapsid phosphoprotein, and surface glycoprotein genes of SARS-CoV2. J Genet Eng Biotechnol 2022; 20:65. [PMID: 35482116 PMCID: PMC9047631 DOI: 10.1186/s43141-022-00346-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 04/18/2022] [Indexed: 12/24/2022]
Abstract
The global COVID-19 pandemic caused by SARS-CoV2 infected millions of people and resulted in more than 4 million deaths worldwide. Apart from vaccines and drugs, RNA silencing is a novel approach for treating COVID-19. In the present study, siRNAs were designed for the conserved regions targeting three structural genes, M, N, and S, from forty whole-genome sequences of SARS-CoV2 using four different software, RNAxs, siDirect, i-Score Designer, and OligoWalk. Only siRNAs which were predicted in common by all the four servers were considered for further shortlisting. A multistep filtering approach has been adopted in the present study for the final selection of siRNAs by the usage of different online tools, viz., siRNA scales, MaxExpect, DuplexFold, and SMEpred. All these web-based tools consider several important parameters for designing functional siRNAs, e.g., target-site accessibility, duplex stability, position-specific nucleotide preference, inhibitory score, thermodynamic parameters, GC content, and efficacy in cleaving the target. In addition, a few parameters like GC content and dG value of the entire siRNA were also considered for shortlisting of the siRNAs. Antisense strands were subjected to check for any off-target similarities using BLAST. Molecular docking was carried out to study the interactions of guide strands with AGO2 protein. A total of six functional siRNAs (two for each gene) have been finally selected for targeting M, N, and S genes of SARS-CoV2. The siRNAs have not shown any off-target effects, interacted with the domain(s) of AGO2 protein, and were efficacious in cleaving the target mRNA. However, the siRNAs designed in the present study need to be tested in vitro and in vivo in the future.
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Verma HK, Prasad K, Kumar P, Lvks B. Viral hepatitis: A global burden needs future directions for the management. World J Gastroenterol 2022; 28:1718-1721. [PMID: 35581964 PMCID: PMC9048788 DOI: 10.3748/wjg.v28.i16.1718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/09/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is an acute or chronic liver disease due to the infection from Hepatitis A, B, C, D and E viruses. It can cause severe liver damage such as cirrhosis, liver failure and liver cancer. To avoid such fatal complications, hepatitis patients must be diagnosed, pathologized and treated as soon as possible. Furthermore, these hepatitis viruses infect through different routes, resulting in distinct disease pathologies, severity and even the need for specific treatment strategies to combat the infection.
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Affiliation(s)
- Henu Kumar Verma
- Department of Immunopathology, Institute of Lungs Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum, Munich 80331, Bayren, Germany
| | - Kiran Prasad
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
| | - Pramod Kumar
- Department of Drug Delivery, Institute of Lung Biology and Disease, Helmholtz Research Center, Munich 80331, Bayren, Germany
| | - Bhaskar Lvks
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
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31
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Lei L, Cheng A, Wang M, Jia R. The Influence of Host miRNA Binding to RNA Within RNA Viruses on Virus Multiplication. Front Cell Infect Microbiol 2022; 12:802149. [PMID: 35531344 PMCID: PMC9069554 DOI: 10.3389/fcimb.2022.802149] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
microRNAs (miRNAs), non-coding RNAs about 22 nt long, regulate the post-transcription expression of genes to influence many cellular processes. The expression of host miRNAs is affected by virus invasion, which also affects virus replication. Increasing evidence has demonstrated that miRNA influences RNA virus multiplication by binding directly to the RNA virus genome. Here, the knowledge relating to miRNAs’ relationships between host miRNAs and RNA viruses are discussed.
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Affiliation(s)
- Lin Lei
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
- *Correspondence: Renyong Jia,
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Leoni S, Casabianca A, Biagioni B, Serio I. Viral hepatitis: Innovations and expectations. World J Gastroenterol 2022; 28:517-531. [PMID: 35316960 PMCID: PMC8905017 DOI: 10.3748/wjg.v28.i5.517] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is a significant health problem worldwide, associated with morbidity and mortality. Hepatitis B, C, D, and occasionally E viruses (HBV, HCV, HDV, and HEV) can evolve in chronic infections, whereas hepatitis A virus (HAV) frequently produces acute self-limiting hepatitis. In the last years, different studies have been performed to introduce new antiviral therapies. The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications. This review analyzes currently available therapies, in particular for viruses associated with chronic liver disease. The focus is especially on HBV and HCV therapies, investigating new drugs already introduced in clinical practice and clinical trials. We also describe new entry inhibitors, developed for the treatment of chronic HDV and HBV and currently available treatments for HEV. The last drugs introduced have shown important efficacy in HCV, with achievable target HCV elimination by 2030. Concurrently, renewed interest in curative HBV therapies has been registered; current nucleotide/ nucleoside analogs positively impact liver-related complications, ensuring high safety and tolerability. Novel approaches to HBV cure are based on new antivirals, targeting different steps of the HBV life cycle and immune modulators. The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents, as bulevirtide, the first drug conditionally approved in Europe for HDV associated compensated liver disease. Further studies are required to identify a new therapeutic approach in hepatitis E, especially in immunosuppressed patients.
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Affiliation(s)
- Simona Leoni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Alberto Casabianca
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Benedetta Biagioni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
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Leowattana W, Leowattana T. Chronic hepatitis B: New potential therapeutic drugs target. World J Virol 2022; 11:57-72. [PMID: 35117971 PMCID: PMC8788212 DOI: 10.5501/wjv.v11.i1.57] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/13/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) infection remains the most causative agent of liver-related morbidity and mortality worldwide. It impacts nearly 300 million people. The current treatment for chronic infection with the hepatitis B virus (HBV) is complex and lacks a durable treatment response, especially hepatitis B surface antigen (HBsAg) loss, necessitating indefinite treatment in most CHB patients due to the persistence of HBV covalently closed circular DNA (cccDNA). New drugs that target distinct steps of the HBV life cycle have been investigated, which comprise inhibiting the entry of HBV into hepatocytes, disrupting or silencing HBV cccDNA, modulating nucleocapsid assembly, interfering HBV transcription, and inhibiting HBsAg release. The achievement of a functional cure or sustained HBsAg loss in CHB patients represents the following approach towards HBV eradication. This review will explore the up-to-date advances in the development of new direct-acting anti-HBV drugs. Hopefully, with the combination of the current antiviral drugs and the newly developed direct-acting antiviral drugs targeting the different steps of the HBV life cycle, the ultimate eradication of CHB infection will soon be achieved.
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Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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Zhang X, Wang Y, Yang G. Research progress in hepatitis B virus covalently closed circular DNA. Cancer Biol Med 2021; 19:j.issn.2095-3941.2021.0454. [PMID: 34931766 PMCID: PMC9088183 DOI: 10.20892/j.issn.2095-3941.2021.0454] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/16/2021] [Indexed: 11/28/2022] Open
Abstract
Hepatitis B virus (HBV) infections are a global public health issue. HBV covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs, is a key factor in the HBV replication cycle. Notably, many host factors involved in HBV cccDNA epigenetic modulation promote the development of hepatocellular carcinoma (HCC). The HBV cccDNA minichromosome is a clinical obstacle that cannot be efficiently eliminated. In this review, we provide an update on the advances in research on HBV cccDNA and further discuss factors affecting the modulation of HBV cccDNA. Hepatitis B virus X protein (HBx) contributes to HBV cccDNA transcription and the development of hepatocarcinogenesis through modulating host epigenetic regulatory factors, thus linking the cccDNA to hepatocarcinogenesis. The measurable serological biomarkers of continued transcription of cccDNA, the effects of anti-HBV drugs on cccDNA, and potential therapeutic strategies targeting cccDNA are discussed in detail. Thus, this review describes new insights into HBV cccDNA mechanisms and therapeutic strategies for cleaning cccDNA, which will benefit patients with liver diseases.
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Affiliation(s)
- Xiaodong Zhang
- Department of Gastrointestinal Cancer Biology, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yufei Wang
- Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guang Yang
- Department of Gastrointestinal Cancer Biology, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
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Khan IW, Dad Ullah MU, Choudhry M, Ali MJ, Ali MA, Lam SLK, Shah PA, Kaur SP, Lau DTY. Novel Therapies of Hepatitis B and D. Microorganisms 2021; 9:2607. [PMID: 34946209 PMCID: PMC8707465 DOI: 10.3390/microorganisms9122607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue and is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) requires the hepatitis B surface antigen (HBsAg) to replicate. The eradication of HBV, therefore, can also cure HDV. The current therapies for chronic hepatitis B and D are suboptimal and cannot definitely cure the viruses. In order to achieve functional or complete cure of these infections, novel therapeutic agents that target the various sites of the viral replicative cycle are necessary. Furthermore, novel immunomodulatory agents are also essential to achieve viral clearance. Many of these new promising compounds such as entry inhibitors, covalently closed circular DNA (cccDNA) inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators and nucleic acid polymers are in various stages of clinical developments. In this review article, we provided a comprehensive overview of the structure and lifecycle of HBV, the limitations of the current therapies and a summary of the novel therapeutic agents for both HDV and HBV infection.
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Affiliation(s)
- Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mati Ullah Dad Ullah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mina Choudhry
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Muhammad Ashar Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Sam L. K. Lam
- Liver Center, Department of Medicine, Department of Pharmacy, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Pir Ahmad Shah
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA;
| | - Satinder Pal Kaur
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
| | - Daryl T. Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; (I.W.K.); (M.U.D.U.); (M.C.); (M.J.A.); (M.A.A.); (S.P.K.)
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Medhat A, Arzumanyan A, Feitelson MA. Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma. Oncotarget 2021; 12:2421-2433. [PMID: 34853663 PMCID: PMC8629409 DOI: 10.18632/oncotarget.28077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
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Affiliation(s)
- Arvin Medhat
- Department of Molecular Cell Biology, Azad University, North Unit, Tehran, Iran
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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Liu Z, Jin Q, Zhang Y, Gong G, Wu G, Yao L, Wen X, Gao Z, Huang Y, Yang D, Chen E, Mao Q, Lin S, Shang J, Gong H, Zhong L, Yin H, Wang F, Hu P, Xiao L, Li C, Wu Q, Sun C, Niu J, Hou J. Randomised clinical trial: 48 weeks of treatment with tenofovir amibufenamide versus tenofovir disoproxil fumarate for patients with chronic hepatitis B. Aliment Pharmacol Ther 2021; 54:1134-1149. [PMID: 34587302 PMCID: PMC9292801 DOI: 10.1111/apt.16611] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 06/10/2021] [Accepted: 09/07/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Tenofovir amibufenamide (TMF) can provide more efficient delivery than tenofovir disoproxil fumarate (TDF). AIM To compare the efficacy and safety of TMF and TDF for 48 weeks in patients with chronic hepatitis B (CHB). METHODS We performed a randomised, double-blind, non-inferiority study at 49 sites in China. Patients with CHB were assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo. The primary efficacy endpoint was the proportion of patients with hepatitis B virus (HBV) DNA less than 20 IU/mL at week 48. We also assessed safety, particularly bone, renal and metabolic abnormalities. RESULTS We randomised 1002 eligible patients. The baseline characteristics were well balanced between groups. After a median 48 weeks of treatment, the non-inferiority criterion was met in all analysis sets. In the HBeAg-positive population, 50.2% of patients receiving TMF and 53.7% receiving TDF achieved HBV DNA less than 20 IU/mL. In the HBeAg-negative population, 88.9% and 87.8%, respectively, achieved HBV DNA less than 20 IU/mL in the TMF and TDF groups. Patients receiving TMF had significantly less decrease in bone mineral density at both hip (P < 0.001) and spine (P < 0.001), and a smaller increase in serum creatinine at week 48 (P < 0.05). Other safety results were similar between groups. CONCLUSION TMF was non-inferior to TDF in terms of anti-HBV efficacy and showed better bone and renal safety. (NCT03903796).
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Affiliation(s)
- T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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Philips CA, Ahamed R, Abduljaleel JK, Rajesh S, Augustine P. Critical Updates on Chronic Hepatitis B Virus Infection in 2021. Cureus 2021; 13:e19152. [PMID: 34733599 PMCID: PMC8557099 DOI: 10.7759/cureus.19152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.
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Affiliation(s)
- Cyriac A Philips
- Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, IND
| | - Rizwan Ahamed
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Jinsha K Abduljaleel
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Sasidharan Rajesh
- Diagnostic and Interventional Radiology, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Philip Augustine
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
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Abstract
Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
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Bartoli A, Gabrielli F, Tassi A, Cursaro C, Pinelli A, Andreone P. Treatments for HBV: A Glimpse into the Future. Viruses 2021; 13:1767. [PMID: 34578347 PMCID: PMC8473442 DOI: 10.3390/v13091767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/17/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.
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Affiliation(s)
- Alessandra Bartoli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Filippo Gabrielli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Andrea Tassi
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
| | - Ambra Pinelli
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy; (A.B.); (F.G.); (A.T.); (C.C.); (A.P.)
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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Yang S, Zeng W, Zhang J, Lu F, Chang J, Guo JT. Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary? Emerg Microbes Infect 2021; 10:1545-1554. [PMID: 34227927 PMCID: PMC8354158 DOI: 10.1080/22221751.2021.1952851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The prolonged viral antigen stimulation is the driving force for the development of immune tolerance to chronic hepatitis B virus (HBV) infection. The sustained reduction of viral proteins may allow for the recovery and efficient activation of HBV-specific T and B cells by immune-stimulating agents, checkpoint blockades and/or therapeutic vaccinations. Recently, several therapeutic approaches have been shown to significantly reduce intrahepatic viral proteins and/or circulating HBV surface antigen (HBsAg) with variable impacts on the host antiviral immune responses in animal models or human clinical trials. It remains to be further investigated whether reduction of viral protein expression or induction of intrahepatic viral protein degradation is more efficacious to break the immune tolerance to chronic HBV infection. It is also of great interest to know if the accelerated clearance of circulating HBsAg by antibodies has a long-term immunological impact on HBV infection and disease progression. Although it is clear that removal of antigen stimulation alone is not sufficient to induce the functional recovery of exhausted T and B cells, accumulating evidence suggests that the reduction of viral antigen load appears to facilitate the therapeutic activation of functional antiviral immunity in chronic HBV carriers. Based on a systematic review of the findings in animal models and clinical studies, the research directions toward discovery and development of more efficacious therapeutic approaches to reinvigorate HBV-specific adaptive immune function and achieve the durable control of chronic HBV infection, i.e. a functional cure, in the vast majority of treated patients are discussed.
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Affiliation(s)
- Sisi Yang
- Baruch S. Blumberg Institute, Doylestown, PA, USA.,Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wanjia Zeng
- Peking University Health Science Center, Beijing, People's Republic of China
| | - Jiming Zhang
- Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Fengmin Lu
- Peking University Health Science Center, Beijing, People's Republic of China
| | | | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, USA
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Ligat G, Verrier ER, Nassal M, Baumert TF. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol 2021; 49:41-51. [PMID: 34029994 PMCID: PMC7613419 DOI: 10.1016/j.coviro.2021.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Chronic infection with HBV is a major cause of advanced liver disease and hepatocellular carcinoma. Nucleos(t)ide analogues effectively control HBV replication but viral cure is rare. Hence treatment has often to be administered for an indefinite duration, increasing the risk for selection of drug resistant virus variants. PEG-interferon-α-based therapies can sometimes cure infection but suffer from a low response rate and severe side-effects. CHB is characterized by the persistence of a nuclear covalently closed circular DNA (cccDNA), which is not targeted by approved drugs. Targeting host factors which contribute to the viral life cycle provides new opportunities for the development of innovative therapeutic strategies aiming at HBV cure. An improved understanding of the host immune system has resulted in new potentially curative candidate approaches. Here, we review the recent advances in understanding HBV-host interactions and highlight how this knowledge contributes to exploiting host-targeting strategies for a viral cure.
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Affiliation(s)
- Gaëtan Ligat
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Eloi R Verrier
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Michael Nassal
- University Hospital Freiburg, Dept. of Internal Medicine 2/Molecular Biology, D79106 Freiburg, Germany.
| | - Thomas F Baumert
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.
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44
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Tsai E. Review of Current and Potential Treatments for Chronic Hepatitis B Virus Infection. Gastroenterol Hepatol (N Y) 2021; 17:367-376. [PMID: 34602899 PMCID: PMC8475260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health burden. Millions of people are at risk for complications of chronic HBV infection, despite the widespread availability of an effective prophylactic vaccine. The current available treatments for HBV infection-interferon and nucleos(t)ide analogues-are effective at suppressing viral replication and decreasing the risk of cirrhosis. However, these treatments have a number of limitations, creating the need for alternative therapeutic agents. Recent advances in drug therapy have heralded a new horizon of novel therapeutic approaches for chronic HBV infection, with several promising antiviral and immunomodulatory agents currently in preclinical or clinical testing. This article reviews the current landscape of HBV treatments and highlights the most recent therapeutic strategies designed to directly target HBV or to improve immune response during chronic infection.
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Affiliation(s)
- Eugenia Tsai
- Texas Liver Institute and UT Health San Antonio, San Antonio, Texas
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Zhang W, Aryan M, Qian S, Cabrera R, Liu X. A Focused Review on Recent Advances in the Diagnosis and Treatment of Viral Hepatitis. Gastroenterology Res 2021; 14:139-156. [PMID: 34267829 PMCID: PMC8256899 DOI: 10.14740/gr1405] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/11/2021] [Indexed: 12/14/2022] Open
Abstract
The global burden of viral hepatitis remains substantial despite advances in antiviral therapy and effective vaccines. There are five hepatitis viruses (hepatitis A, B, C, D, and E). Mortality related to hepatitis B virus and hepatitis C virus infections is among the top four global infectious diseases, together with human immunodeficiency virus infection, malaria, and tuberculosis. Of those deaths, approximately 47% are attributable to hepatitis B virus, 48% to hepatitis C virus and the remainder to hepatitis A virus and hepatitis E virus. Ending hepatitis epidemics as a major public health threat is feasible with the tools and approaches currently available. Effective vaccines are available for preventing viral hepatitis A, B and E infections. New oral, well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Effective treatment is also available for people with chronic hepatitis B virus infection; although for most people such treatment needs to be long-term, and recent advanced aim at a "functional cure" of hepatitis B. In this review article, we discuss the most recent advances of the diagnosis and treatment of viral hepatitis.
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Affiliation(s)
- Wei Zhang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA
| | - Mahmoud Aryan
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Steve Qian
- Department of Internal Medicine, University of Florida, Gainesville, FL, USA
| | - Roniel Cabrera
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Florida, Gainesville, FL, USA
| | - Xiuli Liu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
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Maepa MB, Bloom K, Ely A, Arbuthnot P. Hepatitis B virus: promising drug targets and therapeutic implications. Expert Opin Ther Targets 2021; 25:451-466. [PMID: 33843412 DOI: 10.1080/14728222.2021.1915990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Current therapy for infection with hepatitis B virus (HBV) rarely clears the virus, and viremia commonly resurges following treatment withdrawal. To prevent serious complications of the infection, research has been aimed at identifying new viral and host targets that can be exploited to inactivate HBV replication.Areas covered: This paper reviews the use of these new molecular targets to advance anti-HBV therapy. Emphasis is on appraising data from pre-clinical and early clinical studies described in journal articles published during the past 10 years and available from PubMed.Expert opinion: The wide range of viral and host factors that can be targeted to disable HBV is impressive and improved insight into HBV molecular biology continues to provide the basis for new drug design. In addition to candidate therapies that have direct or indirect actions on HBV covalently closed circular DNA (cccDNA), compounds that inhibit HBsAg secretion, viral entry, destabilize viral RNA and effect enhanced immune responses to HBV show promise. Preclinical and clinical evaluation of drug candidates, as well as investigating use of treatment combinations, are encouraging. The field is poised at an interesting stage and indications are that reliably achieving functional cure from HBV infection is a tangible goal.
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Affiliation(s)
- Mohube Betty Maepa
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Kristie Bloom
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Abdullah Ely
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
| | - Patrick Arbuthnot
- School of Pathology, Faculty of Health Sciences, Wits/SAMRC Antiviral Gene Therapy Research Unit, University of the Witwatersrand, Johannesburg, South Africa
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Garcia-Garcia S, Cortese MF, Rodríguez-Algarra F, Tabernero D, Rando-Segura A, Quer J, Buti M, Rodríguez-Frías F. Next-generation sequencing for the diagnosis of hepatitis B: current status and future prospects. Expert Rev Mol Diagn 2021; 21:381-396. [PMID: 33880971 DOI: 10.1080/14737159.2021.1913055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis B virus (HBV) causes a complex and persistent infection with a major impact on patients health. Viral-genome sequencing can provide valuable information for characterizing virus genotype, infection dynamics and drug and vaccine resistance. AREAS COVERED This article reviews the current literature to describe the next-generation sequencing progress that facilitated a more comprehensive study of HBV quasispecies in diagnosis and clinical monitoring. EXPERT OPINION HBV variability plays a key role in liver disease progression and treatment efficacy. Second-generation sequencing improved the sensitivity for detecting and quantifying mutations, mixed genotypes and viral recombination. Third-generation sequencing enables the analysis of the entire HBV genome, although the high error rate limits its use in clinical practice.
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Affiliation(s)
- Selene Garcia-Garcia
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco Rodríguez-Algarra
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David Tabernero
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
| | - Ariadna Rando-Segura
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Josep Quer
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Maria Buti
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
| | - Francisco Rodríguez-Frías
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma De Barcelona, Barcelona Spain
- Clinical Biochemistry Research Group, Vall d'Hebron Institut Recerca (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas, Instituto De Salud Carlos III, Madrid Spain
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Lan T, Wei Z, He Y, Wan S, Liu L, Cheng B, Li R, Chen H, Liu G, Meng Z. Immunostimulatory siRNA with a uridine bulge leads to potent inhibition of HBV and activation of innate immunity. Virol J 2021; 18:37. [PMID: 33602251 PMCID: PMC7890953 DOI: 10.1186/s12985-021-01509-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/08/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is difficult to cure. HBV-specific immune tolerance plays a key role in HBV persistence, and enhancing cellular and humoral immunity will improve the control of HBV infection. The purpose of the study was to explore the anti-HBV and immunostimulatory effects of msiRNAs that introduce unpaired uridine bulges in the passenger strand. METHODS msiRNAs targeting the HBV S and X genes were designed and named msiHBs and msiHBx, respectively. HepG2 cells were cotransfected with siRNA or msiRNA and the HBV replication-competent plasmid pHY106-wta or pHY106-X15. HepG2.215 cells were transfected with siRNA or msiRNA. The levels of HBsAg, HBeAg, and the cytokines TNF-α, IFN-α, IFN-β, IL-1α, and IL-6 in the culture supernatant was detected by ELISA. The levels of intracellular HBV RNA, nuclear HBV replication intermediates, and HBV DNA in the supernatant were measured by quantitative RT-PCR and PCR. The levels of HBV replication intermediates were detected by Southern blotting. Peripheral blood mononuclear cells were transfected with siRNA or msiRNA, and the levels of secreted cytokines IFN-α and IFN-β were detected by ELISA. The bioactivity of type I interferons in the supernatants was detected by the virus protection assay. RESULTS msiHBx treatment led to a significant decrease in HBsAg (to a negative level) and HBV DNA (95.5%) in the supernatant and intrahepatocellular HBV replication intermediates (89.8%) in HepG2 cells with transient HBV replication and in HepG2.2.15 cells. There was no significant difference between msiHBx and siHBx in terms of the reduction in HBV proteins and HBV replication (P > 0.05). Compared with siHBx, msiHBx treatment of HepG2 cells transfected with the HBV replication-competent plasmid led to a significant increase in the levels of the antiviral cytokines TNF-α (3.3-fold), IFN-α (1.4-fold), and IFN-β (2.5-fold) (P < 0.01), without upregulation of the proinflammatory cytokines IL-1α and IL-6. The virus protection assay results showed msiHBx-mediated type I interferons effectively protected L929 cells against ECMV infection. CONCLUSIONS msiHBx could effectively inhibit HBV expression and replication and induce an antiviral innate immune response without proinflammatory activation. The dual RNAi and immunostimulatory activity of msiRNAs may play an important role in the control of HBV infection.
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Affiliation(s)
- Tingyu Lan
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhiqiang Wei
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Yulin He
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Song Wan
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Li Liu
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Bin Cheng
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Ruimin Li
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Hongxia Chen
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Guohua Liu
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Zhongji Meng
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, 442000, Hubei Province, China.
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
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In Vitro Infection with Hepatitis B Virus Using Differentiated Human Serum Culture of Huh7.5-NTCP Cells without Requiring Dimethyl Sulfoxide. Viruses 2021; 13:v13010097. [PMID: 33445753 PMCID: PMC7828204 DOI: 10.3390/v13010097] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/08/2021] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
An estimated two billion people worldwide have been infected with hepatitis B virus (HBV). Despite the high infectivity of HBV in vivo, a lack of easily infectable in vitro culture systems hinders studies of HBV. Overexpression of the sodium taurocholate co-transporting polypeptide (NTCP) bile acid transporter in hepatoma cells improved infection efficiency. We report here a hepatoma cell culture system that does not require dimethyl sulfoxide (DMSO) for HBV infection. We overexpressed NTCP in Huh7.5 cells and allowed these cells to differentiate in a medium supplemented with human serum (HS) instead of fetal bovine serum (FBS). We show that human serum culture enhanced HBV infection in Huh7.5-NTCP cells, e.g., in HS cultures, HBV pgRNA levels were increased by as much as 200-fold in comparison with FBS cultures and 19-fold in comparison with FBS+DMSO cultures. Human serum culture increased levels of hepatocyte differentiation markers, such as albumin secretion, in Huh7.5-NTCP cells to similar levels found in primary human hepatocytes. N-glycosylation of NTCP induced by culture in human serum may contribute to viral entry. Our study demonstrates an in vitro HBV infection of Huh7.5-NTCP cells without the use of potentially toxic DMSO.
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Kadelka S, Dahari H, Ciupe SM. Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection. Sci Rep 2021; 11:200. [PMID: 33420293 PMCID: PMC7794570 DOI: 10.1038/s41598-020-80594-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/21/2020] [Indexed: 01/29/2023] Open
Abstract
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.
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Affiliation(s)
- Sarah Kadelka
- Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA
| | - Harel Dahari
- Program for Experimental and Theoretical Modeling, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Stanca M Ciupe
- Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA.
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