Improved Specificity and Safety of Anti-Hepatitis B Virus TALENs Using Obligate Heterodimeric FokI Nuclease Domains
| Autor: | Kristie Bloom, Tiffany S. Smith, Prashika Singh, Patrick Arbuthnot, Abdullah Ely, Kay O. Chmielewski, Toni Cathomen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Hepatitis B virus
obligate heterodimeric TALENs Context (language use) medicine.disease_cause Virus Replication Microbiology Antiviral Agents Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Hepatitis B Chronic Virology Transcription Activator-Like Effector Nucleases medicine Animals Outbred Strains HBV Gene silencing Animals Humans Deoxyribonucleases Type II Site-Specific 030304 developmental biology 0303 health sciences Nuclease Transcription activator-like effector nuclease biology Nucleoside analogue DNA Viruses cccDNA Genetic Therapy Hep G2 Cells Sharkey Endonucleases Hepatitis B QR1-502 FokI Disease Models Animal Infectious Diseases HEK293 Cells DNA Viral biology.protein Female DNA Circular 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Viruses Volume 13 Issue 7 Viruses, Vol 13, Iss 1344, p 1344 (2021) |
| ISSN: | 1999-4915 |
| DOI: | 10.3390/v13071344 |
| Popis: | Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no therapeutic benefit to chronic sufferers and has had a limited impact on infection rates. Although immunomodulators and nucleotide and nucleoside analogs have been licensed for treatment of chronic HBV, cure rates remain low. Transcription activator-like effector nucleases (TALENs) designed to bind and cleave viral DNA offer a novel therapeutic approach. Importantly, TALENs can target covalently closed circular DNA (cccDNA) directly with the potential of permanently disabling this important viral replicative intermediate. Potential off-target cleavage by engineered nucleases leading to toxicity presents a limitation of this technology. To address this, in the context of HBV gene therapy, existing TALENs targeting the viral core and surface open reading frames were modified with second- and third-generation FokI nuclease domains. As obligate heterodimers these TALENs prevent target cleavage as a result of FokI homodimerization. Second-generation obligate heterodimeric TALENs were as effective at silencing viral gene expression as first-generation counterparts and demonstrated an improved specificity in a mouse model of HBV replication. |
| Databáze: | OpenAIRE |
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