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

Wang, Lin; Hernández-Alcoceba, Rubén; Shankar, Vijay; Zabala, Maider; Kochanek, Stefan; Sangro, Bruno; Kramer, M. Gabriela; Prieto, Jesús; Qian, Cheng

doi:10.1053/j.gastro.2003.10.075

Cited by 77 publications

(86 citation statements)

References 50 publications

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“…In any case, evidence for healthy liver parenchyma gene transfer has therapeutic implications for the use of gutless adenoviruses to treat primary or metastatic liver cancer as well as for the correction of liver metabolic diseases. 18 These findings demonstrate for the first time the real possibility of serial gene expression imaging in nonhuman primates using viral vectors in a useful manner for gene therapy development. 19 Images can even be compiled in three-dimensional rotating reconstructions (Supplementary online material).…”

Section: Quantitative Pet Transgene Imaging In Primatesmentioning

confidence: 72%

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

et al. 2008

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and 4 CIBER en enfermedades hepáticas y digestivas, SpainNon-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors.

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Section: Quantitative Pet Transgene Imaging In Primatesmentioning

confidence: 72%

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

et al. 2008

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“…35 Higher and more sustained levels of circulating IL-15 upon gene transfer could be achieved by exogenously regulatable promoters targeting transcription to the liver and using liver-tropic viral vectors such as those based on 'gut-less' adenoviruses or adeno-associated viruses. 36 Alternatively, a way to optimize the pharmacokinetics of IL-15 is to complex it with an IgFc chimeric protein that encompasses IL-15Ra, in such a way that renal elimination is retarded and trans-presentation is favored. 30,37 Overall, hydrodynamic gene transfer was by far a better method to get sustained levels of the cytokine in serum, when compared to the systemic administration of the protein.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

et al. 2008

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“…We used the HC-Ad/RUmIL-12 virus, which encodes the murine interleukin-12 (IL-12) under the control of a mifepristoneinducible system. 18 This is a stringent test, as IL-12 exerts potent immunostimulatory functions 19 that could reduce the persistence of the vector. HC-Ad/RUmIL-12 was administered intravenously to C57BL/6 mice, and IL-12 expression was induced by intraperitoneal injection of mifepristone at the indicated times.…”

Section: Hc-ad Vectors Amplified With the Aid Of Adtetcre Sustain Lonmentioning

confidence: 99%

Self-inactivating helper virus for the production of high-capacity adenoviral vectors

et al. 2011

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Standard methods for producing high-capacity adenoviral vectors (HC-Ads) are based on co-infection with a helper adenovirus (HV). To avoid HV encapsidation, its packaging signal (C) is flanked by recognition sequences for recombinases expressed in the producing cells. However, accumulation of HV and low yield of HC-Ad are frequently observed, due in part to insufficient recombinase expression. We describe here a novel HV (AdTetCre) in which C is flanked by loxP sites that can be excised by a chimeric MerCreMer recombinase encoded in the same viral genome. Efficient modulation of cleavage was obtained by simultaneous control of MerCreMer expression using a tet-on inducible system, and translocation to the nucleus by 4-hydroxytamoxifen (TAM). Encapsidation of AdTetCre was strongly inhibited by TAM plus doxycicline. Using AdTetCre and 293Cre4 cells for the production of HC-Ads, we found that cellular and virus-encoded recombinases cooperate to minimize HV contamination. The method was highly reproducible and allowed the routine production of different HC-Ads in a medium-scale laboratory setting in adherent cells, with titers 410 10 infectious units and o0.1% HV contamination. The residual HVs lacked C and were highly attenuated. We conclude that self-inactivating HVs based on virally encoded recombinases are promising tools for the production of

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

Cited by 77 publications

References 50 publications

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

Self-inactivating helper virus for the production of high-capacity adenoviral vectors

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