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möglich sobald bei der ZB eingereicht worden ist.
Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA.
EMBO Mol. Med. 8, 1082-1098 (2016)
Hepatitis B virus (HBV) is a promising target for therapies based on RNA interference (RNAi) since it replicates via RNA transcripts that are vulnerable to RNAi silencing. Clinical translation of RNAi technology, however, requires improvements in potency, specificity and safety. To this end, we systematically compared different strategies to express anti-HBV short hairpin RNA (shRNA) in a pre-clinical immunocompetent hepatitis B mouse model. Using recombinant Adeno-associated virus (AAV) 8 vectors for delivery, we either (i) embedded the shRNA in an artificial mi(cro)RNA under a liver-specific promoter; (ii) co-expressed Argonaute-2, a rate-limiting cellular factor whose saturation with excess RNAi triggers can be toxic; or (iii) co-delivered a decoy ("TuD") directed against the shRNA sense strand to curb off-target gene regulation. Remarkably, all three strategies minimised adverse side effects as compared to a conventional shRNA vector that caused weight loss, liver damage and dysregulation of > 100 hepatic genes. Importantly, the novel AAV8 vector co-expressing anti-HBV shRNA and TuD outperformed all other strategies regarding efficiency and persistence of HBV knock-down, thus showing substantial promise for clinical translation.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
9.547
1.822
19
20
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Adeno‐associated Virus ; Rna Interference ; Hepatitis B Virus ; Short Hairpin Rna ; Tough Decoy; Adenoassociated Viral Vectors; Complementary Aav Vectors; Mammalian-cells; In-vivo; Hemophilia-b; Hepatocellular-carcinoma; Artificial Micrornas; Argonaute Proteins; Interfering Rnas; Gene-expression
Sprache
Veröffentlichungsjahr
2016
HGF-Berichtsjahr
2016
ISSN (print) / ISBN
1757-4676
e-ISSN
1757-4684
Zeitschrift
EMBO Molecular Medicine
Quellenangaben
Band: 8,
Heft: 9,
Seiten: 1082-1098
Verlag
Wiley
Verlagsort
Chichester
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30203 - Molecular Targets and Therapies
30205 - Bioengineering and Digital Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30205 - Bioengineering and Digital Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er)
Immune Response and Infection
Enabling and Novel Technologies
Enabling and Novel Technologies
PSP-Element(e)
G-502700-003
G-503800-001
G-551600-001
G-503800-001
G-551600-001
PubMed ID
27473329
WOS ID
WOS:000383634100008
Scopus ID
84984822471
Scopus ID
84979732940
Erfassungsdatum
2016-08-01