Regulatable systems: applications in gene therapy and replicating viruses

Agha-Mohammadi, Siamak; Lotze, Michael T.

doi:10.1172/jci10027

Cited by 71 publications

(45 citation statements)

References 39 publications

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“…35 Tight control is especially needed when potentially toxic transgenes are delivered. The ideal regulatory system is turned on by application of an exogenously added small molecule ligand, should have no basal activity in the absence of the ligand ('off'-state), promote high expression levels in the 'on'-state and allow multiple switching between the 'on' and the 'off'-state.…”

Section: Discussionmentioning

confidence: 99%

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

et al. 2005

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Interferons control viral replication and the growth of some malignant tumors. Since systemic application may cause severe adverse effects, tissue-specific expression is an attractive alternative. Liver-directed interferon gene therapy offers promising applications such as chronic viral hepatitis B or C or hepatocellular carcinoma and thus needs testing in vivo in suitable animal models. We therefore used the Tet-On system to regulate gene expression in adenoviral vectors, and studied the effect of liver-specific and regulated interferon g expression in a mouse model of chronic hepatitis B virus (HBV) infection. In a first generation adenoviral vector, genes encoding for firefly luciferase and interferons a, b or g, respectively, were coexpressed under control of the bidirectional tetracycline-regulated promoter P tet bi. Liverspecific promoters driving expression of the reverse tetracycline controlled transactivator ensured local expression in the livers of HBV transgenic mice. Following gene transfer, we demonstrated low background, tight regulation and a 1000-fold induction of gene expression by doxycycline. Both genes within the bidirectional transcription unit were expressed simultaneously, and in a liver-specific fashion in cell culture and in living mice. Doxycycline-dependent interferon g expression effectively controlled HBV replication in mice, but did not eliminate HBV transcripts. This system will help to study the effects of local cytokine expression in mouse disease models in detail. Gene Therapy (2005) 12, 668-677.

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Section: Discussionmentioning

confidence: 99%

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

et al. 2005

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“…1 Genes encoding for a secreted reporter or therapeutic proteins are often injected in the muscle as an easy accessible tissue and safer organ. We, therefore, chose this tissue to explore the degree of SEAP inducibility achievable by the HD vectors carrying the Tet regulation system.…”

Section: Dox-dependent Seap Expression In C57/b6 Micementioning

confidence: 99%

“…Different control systems have been developed based on orally available small molecules acting at transcription or post-transcriptional levels and capable of activating transcription factors delivered in the context of viral or non-viral vectors (reviewed in Ref. 1). Among them, the Tet system appears to be the most flexible, as it allows control not only of transcription induction, but also repression of the basal transcription utilizing the same orally bioavailable antibiotic doxycycline (Dox).…”

Section: Introductionmentioning

confidence: 99%

Tight control of gene expression by a helper-dependent adenovirus vector carrying the rtTA2s-M2 tetracycline transactivator and repressor system

Salucci¹,

Scarito²,

Aurisicchio³

et al. 2002

Gene Ther

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Control of gene expression for gene therapy application requires the design of a sophisticated system embodying multiple properties. The ideal system should present the following features: (1) low or undetectable gene expression in the absence of inducer; (2) strong expression upon induction; and (3) fast kinetics of induction in the presence of inducers and rapid reversal of induction after its withdrawal. To evaluate these parameters, the features of the latest generation tetracycline-sensitive reverse-transactivator (rtTA2 s -M2) alone or in combination with Tet-repressor (tTS-Kid)

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“…[35][36][37][38][39][40] Four major systems have been developed, including regulation by the antibiotic tetracycline, the insect steroid ecdysone or its analogs, the antiprogestin mifepristone (RU486), and chemical "dimerizers" such as the immunosuppressant rapamycin and its analogs. [41][42][43] They all involve the drugdependent recruitment of a transcriptional activation domain to a basal promoter driving the gene of interest but differ in the mechanism of recruitment.…”

mentioning

confidence: 99%

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

et al. 2004

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Regulatable systems: applications in gene therapy and replicating viruses

Cited by 71 publications

References 39 publications

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

Liver-specific expression of interferon γ following adenoviral gene transfer controls hepatitis B virus replication in mice

Tight control of gene expression by a helper-dependent adenovirus vector carrying the rtTA2s-M2 tetracycline transactivator and repressor system

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

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