Improved specificity and safety of anti-hepatitis B virus TALENs using obligate heterodimeric fokI nuclease domains
Abstract: 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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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Viruses. - 13, 7 (2021) , 1344, ISSN: 1999-4915
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
-
Universität
- (wann)
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2021
- Urheber
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Smith, Tiffany
Singh, Prashika
Chmielewski, Kay O.
Bloom, Kristie
Cathomen, Anton
Arbuthnot, Patrick
Ely, Abdullah
- DOI
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10.3390/v13071344
- URN
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urn:nbn:de:bsz:25-freidok-2197507
- Rechteinformation
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Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:29 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Smith, Tiffany
- Singh, Prashika
- Chmielewski, Kay O.
- Bloom, Kristie
- Cathomen, Anton
- Arbuthnot, Patrick
- Ely, Abdullah
- Universität
Entstanden
- 2021
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