Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state

Brown, Brian D.; Gentner, Bernhard; Cantore, Alessio; Colleoni, Silvia; Amendola, Mario; Zingale, Anna; Baccarini, Alessia; Lazzari, Giovanna; Galli, Cesare; Naldini, Luigi

doi:10.1038/nbt1372

Cited by 506 publications

(504 citation statements)

References 59 publications

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“…Due to their regulatory nature, microRNAs are often tissue specific and with that knowledge miR-122 can be used as a hepatocyte-specific promoter [73]. As one might expect, the expression of a hepatic upregulated microRNA, miR-122a, can also be exploited in the reverse fashion, namely by inserting a microRNA target site in the 3ʹ UTR region of the gene therapy transgene, effectively preventing transgene expression in hepatocytes but retaining expression in the sinusoidal endothelial cells [74]. The same group used another microRNA target site, 142-3pT, to effectively prevent expression in transduced APCs, thereby avoiding immune responses caused by antigen presentation of the expressed transgene [75].…”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

View full text Add to dashboard Cite

show abstract

“…It is plausible that the simultaneous targeting of the three components will have a more profound impact on melanoma progression than targeting of miR-182 alone. Therefore, various combinations of anti-miR oligonucleotides or decoys (artificial miRNA binding sites) (Brown et al, 2007) against the three cluster components should be tested.…”

Section: Targeting Liver Metastasis With Anti-mir-182mentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

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Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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“…One of these elements was the CTE of Mason-Pfizer monkey virus, which was initially introduced to the antisense message 14 to support the export of (unspliced) RNA from the nucleus. Of note, new generations of LV bidirectional vectors 42 lacked the CTE, as it was found to reduce the expression of a number of transgenes (Luigi Naldini, CONSERT Annual Meeting, 2008).…”

Section: Coexpression Efficiency Is Enhanced In Cte-deprived Gv and Lmentioning

confidence: 99%

Mechanisms controlling titer and expression of bidirectional lentiviral and gammaretroviral vectors

et al. 2009

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Bidirectional lentiviral vectors mediate expression of two or more cDNAs from a single internal promoter. In this study, we examined mechanisms that control titer and expression properties of this vector system. To address whether the bidirectional design depends on lentiviral (LV) backbone components, especially the Rev/Rev responsive element (RRE) system, we constructed similar expression cassettes for LV and gammaretroviral (GV) vectors. Bidirectional expression levels could be adjusted by the use of different internal promoters. Furthermore, removal of the constitutive RNA transport element of Mason-Pfizer monkey virus, used in first generation bidirectional LV vectors, improved gene expression. Titers of bidirectional vectors were B10-fold reduced in comparison to unidirectional vectors, independent of the Rev/RRE interaction. We reasoned that titer reductions were due to the formation of interfering double-stranded RNA in packaging cells. Indeed, cotransfection of Nodamuravirus B2 protein, an RNA interference suppressor, increased bidirectional vector titers at least fivefold. We validated the potential of high titer bidirectional vectors by coexpressing a fluorescent marker with O 6 -methylguanine-DNA methyltransferase from integrating, or with Cre recombinase from integrating and non-integrating GV and LV backbones. This allowed for the tracking of chemoprotected and recombined cells by fluorescence marker expression.

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Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state

Cited by 506 publications

References 59 publications

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Efficient in vivo microRNA targeting of liver metastasis

Mechanisms controlling titer and expression of bidirectional lentiviral and gammaretroviral vectors

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