Regulation of Gene Expression with Double-Stranded Phosphorothioate Oligonucleotides

Bielinska, Anna U.; Shivdasani, Ramesh A.; Zhang, Liquan; Nabel, Gary J.

doi:10.1126/science.2237444

Cited by 373 publications

(261 citation statements)

References 31 publications

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“…[11][12][13] Recently, a few studies have described application of the 'decoy' ODN strategy as in vivo gene therapy. 14,15 The present study provides the first evidence of in vivo application of this novel molecular approach as a therapeutic strategy for cancer cachexia.…”

Section: Discussionmentioning

confidence: 99%

“…Transfection of cis-element double-stranded oligodeoxynucleotides (ODN) as decoy has been reported to be a powerful new tool for the study of transcriptional regulation. [11][12][13] Transfection of double-stranded ODN corresponding to the cis sequence results in attenuation of the authentic cis-trans interaction, leading to the removal of the trans-factors from the endogenous ciselement, with subsequent modulation of gene expression. Therefore, the decoy approach enables us to treat diseases by modulation of endogenous transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Kawamura¹,

et al. 1999

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Cancer cachexia, characterized by anorexia, weight loss muscle mass and food intake, which were induced by the and progressive tissue wasting, has been postulated to be tumor presence. Interleukin 6 mRNA in the tumor was also mediated by various cytokines. However, the precise markedly decreased by the transfection of NF B decoy mechanism of cachexia induction is not fully explained. We ODN. It is known that the transcriptional factor E2F plays have developed synthetic double-stranded oligodeoxynua pivotal role in the coordinated transactivation of cell cycle cleotides (ODN) as 'decoy' cis-elements that block the regulatory genes. Therefore, we hypothesized that the binding of nuclear factors to promoter regions of targeted introduction of synthetic double-stranded DNA with high genes, resulting in the inhibition of gene transactivation in affinity for E2F in vivo as 'decoy' cis-elements might inhibit vivo as well as in vitro. This novel molecular strategy could the tumor growth of colon26, resulting in turn in inhibition of be useful for treating a broad range of human diseases cachexia induction. However, injection of E2F decoy ODN including cancer. In this study, we injected decoy ODN tarfailed to inhibit tumor growth and cachexia induction, as geting the transcriptional factor, NF-kappaB (NF B) bindcompared with mismatched decoy ODN. Overall, the ing cis-elements, which are essential for transactivation of present study demonstrated that cachexia induced by gene expression of cytokines, directly into tumors of adenocarcinoma colon26 was inhibited by blocking of adenocarcinoma colon26 in mice, in order to examine NF B, using a novel molecular decoy strategy, without an whether or not cachexia is alleviated by inhibiting the action effect on tumor growth, and also that tumor growth and of cytokines. Tumor growth was not affected by transfeccachexia induction in the colon26 model were not affected tion of NF B decoy ODN as compared with scrambled by E2F decoy ODN. These results suggest that cytokines decoy ODN. Nevertheless, transfection of NF B decoy, but regulated by NF B may play a pivotal role in the induction not scrambled decoy, ODN resulted in attenuation of the of cachexia by colon26, providing a new therapeutic reductions in body weight, epididymal fat, gastrocnemius strategy for cancer cachexia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Kawamura¹,

et al. 1999

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“…Polycations used for gene therapy studies to date include poly(L-lysine), poly(L-ornithine), both linear and branched polyethyleneimine) (PEL), diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). [1][2][3][4][5][6] They usually carry protonable amine groups, which gives positive charge, and therefore form particulated complexes (or 'condensates') with negatively charged DNA enabling its effective transport through the negatively charged cell membrane, usually by endocytosis. In addition, the amine groups exhibit a buffering effect (also called the 'proton sponge' effect) in the endosome in which as a result of the pH-mediated influx of chloride ions, osmotic swelling and rupture lysosome/endosome occur, which in turn allows the vector and its cargo to be safely released in the cytosol.…”

Section: Nonviral Vectorsmentioning

confidence: 99%

“…Although it was originally devised for the treatment of inherited genetic disorders, recent work has expanded the applications of gene therapy to develop strategies for treatment of a wide range of metabolic, infectious, and inflammatory diseases. [1][2][3] All these novel therapeutics including plasmid DNA carrying genetic information are 'fragile', in other terms they are faced with biodegradation within the body before they reach their target. A 'carrier vehicle' or a 'vector' is needed that allows targeted and intracellular delivery.…”

Section: Introductionmentioning

confidence: 99%

Intelligent polymers as nonviral vectors

2005

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The successful gene therapy largely depends on the vector type that allows a selective and efficient gene delivery to target cells with minimal toxicity. Nonviral vectors are much safer and cheaper, can be produced easily in large quantities, and have higher genetic material carrying capacity. However, they are generally less efficient in delivering DNA and initiating gene expression as compared to viral vectors, particularly when used in vivo. As nonviral vectors, polycations may work well for efficient cell uptake and endosomal escape, because they do form compact and smaller complexes with plasmid DNA and carry amine groups, which give positive charge and buffering ability that allows safe escape from endosome/lysosome. However, this is a disadvantage in the following step, which is releasing the plasmid DNA within the cytosol. In order to initiate transcription and enhance gene expression, the polymer/plasmid complex should dissociate after releasing from endosome safely and effectively. There are also other limitations with some of the polycationic carriers, for example, aggregation, toxicity, etc. Intelligent polymers, also called as 'stimuli responsive polymers', have a great potential as nonviral vectors to obtain site-, timing-, and duration period-specific gene expression, which is already exhibited in recent studies that are briefly summarized here. Gene Therapy (2005) 12, S139-S145.

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“…It blocks the binding of nuclear factors to promoter regions of targeted genes, resulting in inhibition of gene transactivation in vitro and in vivo. 21,22 Such a decoy strategy has been proposed for the treatment of some human diseases represented by animal models. 23,24 Recently, we developed decoy ciselements oligo deoxyribonucleic acid against NFkB (NFkB-decoy), which inhibited the production of major inflammatory cytokines and expression of adhesion molecules in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts

et al. 2003

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Nuclear factor kB (NFkB) plays a pivotal role in the coordinated transactivation of a series of genes of cytokines and adhesion molecules that are highly involved in the onset of acute rejection in organ transplantation. We previously developed decoy cis-elements oligo deoxyribonucleic acid against NFkB (NFkB-decoy) that effectively inhibited the activation of major inflammatory mediators in vitro and in vivo. Accordingly, we hypothesized that transfection of NFkB-decoy into the donor kidney would prevent acute rejection and prolong graft survival, and thus provide effective therapy for renal acute rejection. To transfect NFkB-decoy, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison, and clearly demonstrated successful transfection of NFkB-decoy into renal tissue. The therapeutic effect of NFkB-decoy on renal allografts was then evaluated in a rat renal allograft model (Wistar-Lewis). In the control group, graft function significantly deteriorated with marked destruction of renal tissue, accompanied by increased production of major inflammatory mediators, and all animals died of renal failure by 9 days. In contrast, graft function (serum creatinine on day 2, NFkB-treated: 0.9770.16 versus control: 1.8470.23 mg/dl, Po0.01) and histological structure were well preserved with significantly decreased expression of NFkB-regulated cytokines and adhesion molecules, including IL-1, iNOS, MCP-1, TNF-a, and ICAM-1, in allografts transfected with NFkB-decoy. As a result, animal survival was significantly prolonged in this group as compared to controls (14.275.2 versus 7.171.2 days, Po0.01). Thus, we established a novel ultrasound-Optison-mediated gene transfection approach and demonstrated the significant prolongation of graft survival by the successful transfection of NFkB-decoy into the donor kidney in a rat renal allograft model. Gene Therapy (2003) 10, 415-425.

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Regulation of Gene Expression with Double-Stranded Phosphorothioate Oligonucleotides

Cited by 373 publications

References 31 publications

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Intelligent polymers as nonviral vectors

Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts

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