http://precedings.nature.com/tags/gene%20therapy Recently posted documents tagged with 'gene therapy' Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://precedings.nature.com/documents/3307/version/1 Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared to control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR and Ad-hNIS infected cells but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was two-fold and 10-fold higher for Ad-shMDR and Ad-hNIS-infected tumors as compared to tumors infected with a control adenovirus construct that expressed β-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have demonstrated successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes. http://precedings.nature.com/documents/3307/version/1 Tue, 02 Jun 2009 13:29:24 UTC Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model hdl:10101/npre.2009.3307.1 2009-06-02 Yong Hyun Jeon Nature Precedings 2009-06-02T13:29:24Z Manuscript Cancer http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2716/version/1 To examine how heat shock transcription factor 1 (HSF1) protects against maladaptive hypertrophy during pressure overload, we subjected HSF1 transgenic (TG), knockout (KO) and wild type (WT) mice to a constriction of transverse aorta (TAC), and found that cardiac hypertrophy, functions and angiogenesis were well preserved in TG mice but were decreased in KO mice compared to WT ones at 4 weeks, which was related to HIF-1 and p53 expression. Inhibition of angiogenesis suppressed cardiac adaptation in TG mice while overexpression of angiogenesis factors improved maladaptive hypertrophy in KO mice. In vitro formation of vasculatures by microvascular endothelial cells was higher in TG mice but lower in KO mice than in WT ones. A siRNA of p53 but not a HIF-1 gene significantly reversed maladaptive hypertrophy in KO mice whereas a siRNA of HIF-1 but not a p53 gene induced maladaptive hypertrophy in TG mice. Heart microRNA analysis showed that miR-378 and miR-379 were differently changed among the three mice after TAC, and miR-378 or siRNA of miR-379 could maintain cardiac adaptation in WT mice. These results indicate that HSF1 preserves cardiac adaptation during pressure overload through p53-HIF-1-associated angiogenesis, which is controlled by miR-378 and miR-379. http://precedings.nature.com/documents/2716/version/1 Wed, 24 Dec 2008 15:45:13 UTC Heat shock transcription factor 1 preserves cardiac angiogenesis and adaptation during pressure overload hdl:10101/npre.2008.2716.1 2008-12-24 Yunzeng Zou Nature Precedings 2008-12-24T15:45:13Z Manuscript Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2589/version/1 Expression of survivin has been reported to be correlated with shorter survival in patients with non-small cell lung cancer (NSCLC), and overexpression of survivin may lead to radioresistance in various human cancers. In this study, we inhibited survivin expression by using an adenoviral vector (AdsiSurvivin)-mediated RNAi to elucidate the combined effect of survivin-targeting gene therapy and radiotherapy on the NSCLC cells. Our data revealed that AdsiSurvivin exerted survivin gene silencing, induced apoptosis, and significantly attenuated the growth potential in NSCLC cells within 72 hours after infection. The combined treatment modalities with AdsiSurvivin infection and radiation were significantly more potent on cell-growth inhibition than monotherapy. In H1650, H460, A549, and H1975 human NSCLC cells, the survival ratios of AdsiSurvivin-treated groups at m.o.i. of 25 and 50 were significantly lower than those of control groups at varying radiation dose (0~8 Gy; three-way ANOVA, p < 0.05). The cytotoxicity of combined AdsiSurvivin infection and irradiation increased in a dose-dependent manner in both the virus and the irradiation treatment. Knockdown of the survivin gene expression appears to be a promising treatment strategy for NSCLC. Our data warrants the need for further effort to develop survivin-targeted radiosensitizer for lung cancer treatment. http://precedings.nature.com/documents/2589/version/1 Tue, 02 Dec 2008 13:38:52 UTC Adenovirus-mediated transfer of siRNA against survivin enhances the radiosensitivity of human non-small cell lung cancer cells hdl:10101/npre.2008.2589.1 2008-12-02 Cheng-Ta Yang Nature Precedings 2008-12-02T13:38:52Z Manuscript Cancer Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2456/version/1 Vein graft disease is a chronic inflammatory disease and limits the late results of coronary revascularization. Calcitonin gene-related peptide (CGRP) inhibits macrophages infiltrated and inflammatory mediators, we hypothesized that transfected CGRP gene inhibits macrophages infiltrated and inflammatory mediators in vein graft disease. Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of mosaic adeno-associated virus vectors containing CGRP gene (AAV2/1.CGRP) 、escherichia coli lac Z gene (AAV2/1.LacZ) or saline and then interposed in the carotid artery. Intima/media ratio were evaluated at postoperative 4 weeks, Macrophages were marked with CD68 antibody by immunocytochemistry. Inflammatory mediators were mensurated with real-time PCR. Neointimal thickening was significantly suppressed in AAV2/1.CGRP group. Macrophages infiltrated and inflammatory mediators monocyte chemoattractant protein-1 (MCP-1)、tumor necrosis factorα(TNF-α)、inducible nitricoxide synthase (iNOS)、matrix metalloproteinase-9 (MMP-9) was significantly suppressed in AAV2/1.CGRP group.Gene transfected AAV2/1.CGRP suppressed neointimal hyperplasia in vein graft disease by suppressed macrophages infiltrated and inflammatory mediators. http://precedings.nature.com/documents/2456/version/1 Thu, 06 Nov 2008 04:37:12 UTC Gene Transfer of Calcitonin Gene-Related Peptide Inhibits Macrophages and Inflammatory Mediators in Vein Graft Disease hdl:10101/npre.2008.2456.1 2008-11-06 Jian Zhuang Nature Precedings 2008-11-06T04:37:12Z Manuscript Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2395/version/1 Efficient production of eukaryotic expression vectors requires the selection of plasmid-containing bacteria. To avoid the risk of dissemination of antibiotic resistance markers, we developed a new system to produce a family of plasmids Free of Antibiotic Resistance genes, called pFARs. The strategy is based on the suppression of a chromosomal nonsense mutation by a plasmid-borne function. The amber mutation was introduced into the Escherichia coli thyA gene that encodes a thymidylate synthase required for dTMP synthesis, resulting in thymidine auxotrophy. In parallel, a small plasmid vector that carries an amber suppressor t-RNA gene was entirely synthesised. The introduction of pFAR plasmids into an optimised thyA mutant restored normal growth to the auxotrophic strain, and led to an efficient production of monomeric supercoiled plasmids, as required for clinical trials. Luciferase activities measured after intramuscular injection and electrotransfer of LUC-encoding pFAR vector were similar to those obtained with a commercial vector containing the same expression cassette. Interestingly, whereas luciferase activities decreased within three weeks after intradermal electrotransfer of conventional expression vectors, sustained levels were observed with the pFAR derivative. Thus, pFAR plasmids represent a novel family of biosafe eukaryotic expression vectors, suitable for gene therapy. http://precedings.nature.com/documents/2395/version/1 Fri, 17 Oct 2008 19:05:04 UTC pFAR plasmids: New Eukaryotic Expression Vectors for Gene Therapy, devoid of Antibiotic Resistance Markers hdl:10101/npre.2008.2395.1 2008-10-17 Corinne Marie Nature Precedings 2008-10-17T19:05:04Z Manuscript Biotechnology Genetics & Genomics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2262/version/1 Most in vivo gene therapies will require cell-specific targeting. Although vector targeting through ligand attachment has met with success in generating gene delivery particles that are capable of specific cellular interactions, little attention has been given to the possible effects of such ligands on subsequent intracellular processing. In this study, we examine the impact of targeting two distinct endocytic routes-the caveolar and clathrin pathways-on polyethylenimine-mediated gene delivery in HeLa cells. Targeting complexes to the caveolar pathway with folic acid and the clathrin pathway with transferrin yields enhanced gene delivery relative to unmodified polyethylenimine. Colocalization studies with caveolin-1 and clathrin heavy chain indicate that the ligands successfully deliver their cargo to the intended pathways. However, inhibition of only the caveolar pathway-whether through the use of small molecule drugs or RNA interference-reduces gene delivery efficiency, suggesting that successful polyethylenimine-mediated gene delivery proceeds via a caveolar pathway in HeLa cells. Transfections in the presence of chloroquine and pH tracking studies suggest that a contributing factor to the success of the caveolar pathway is avoidance of lysosomes. Collectively, these data demonstrate that uptake mechanism and subsequent endocytic processing are important design parameters for gene delivery materials. http://precedings.nature.com/documents/2262/version/1 Mon, 08 Sep 2008 16:36:00 UTC Efficient polyethylenimine-mediated gene delivery proceeds via a caveolar pathway in HeLa cells. hdl:10101/npre.2008.2262.1 2008-09-08 Daniel W. Pack Nature Precedings 2008-09-08T16:36:00Z Manuscript Biotechnology Cancer http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2036/version/1 The accumulation and infiltration of eosinophils in airways is one of the most important characteristics of asthma, and is mediated partly by secretion of IL-5 from Th2 lymphocytes. It is well known that interleukin-5 (IL-5) played an important role in the regulation of eosinophils. In this study, an anti-sense IL-5 gene transferred by recombinant adeno-associated virus (rAAV-ASIL-5) was prepared to transfect allergic rats. It was found that the expression of IL-5 protein in plasma and BALF were inhibited significantly. The rAAV-ASIL-5-mediated suppression of total cell counts in peripheral blood and BALF were also observed. Moreover, rAAV-ASIL-5 remarkably reduced the eosinophil counts in peripheral blood and BALF, as well as the expression of ECP protein in plasma and BALF. The inflammation in lungs of rAAV-ASIL-5 pretreated rats also became slighter when compared with allergic rats. Otherwise, no apparent pathological damage to vital organs of rats was found. In conclusion, recombinant adeno-associated virus-mediated delivery of anti-sense IL-5 gene inhibited the accumulation of eosinophils and the airways inflammation in rat model of allergic asthma via suppressing IL-5 expression. It suggested the feasibility of rAAV-ASIL-5 in the gene therapy for allergic asthma and other eosinophilic diseases. http://precedings.nature.com/documents/2036/version/1 Wed, 09 Jul 2008 17:10:57 UTC The effects of anti-sense interleukin-5 gene transferred by recombinant adeno-associated virus in allergic rats hdl:10101/npre.2008.2036.1 2008-07-09 Weining Xiong Nature Precedings 2008-07-09T17:10:57Z Manuscript Biotechnology Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2007.1299.1 The successful use of small interfering RNAs (siRNAs) for therapeutic purposes requires safe and efficient delivery to specific cells and tissues. Here we demonstrate cell type-specific delivery of anti-HIV siRNAs via fusion to an anti-gp120 aptamer. The envelope glycoprotein is expressed on the surface of HIV-1 infected cells, allowing binding and interalization of the aptamer-siRNA chimeric molecules. We demonstrate that the anti-gp120 aptamer-siRNA chimera is specifically taken up by cells expressing HIV-1 gp120, and the appended siRNA is processed by Dicer, releasing an anti-tat/rev siRNA which in turn inhibits HIV replication. We show for the first time a dual functioning aptamer-siRNA chimera in which both the aptamer and the siRNA portions have potent anti-HIV activities and that gp120 expressed on the surface of HIV infected cells can be used for aptamer mediated delivery of anti-HIV siRNAs. http://dx.doi.org/10.1038/npre.2007.1299.1 Wed, 14 Nov 2007 20:51:10 UTC Novel Cell type-specific aptamer-siRNA delivery system for HIV-1 therapy doi:10.1038/npre.2007.1299.1 2007-11-14 John Rossi Nature Precedings 2007-11-14T20:51:10Z Manuscript Biotechnology Molecular Cell Biology http://creativecommons.org/licenses/by/2.5/