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[PMID]:28460646
[Au] Autor:Markusic DM; Nichols TC; Merricks EP; Palaschak B; Zolotukhin I; Marsic D; Zolotukhin S; Srivastava A; Herzog RW
[Ad] Endereço:Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. dmarkusic@ufl.edu.
[Ti] Título:Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models.
[So] Source:J Transl Med;15(1):94, 2017 May 01.
[Is] ISSN:1479-5876
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable. METHODS: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B by hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated through molecular evolution. RESULTS: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation FIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however, expression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC capsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog. CONCLUSIONS: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in hepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict efficacy in other species and thus is of limited translational utility.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Fator IX/genética
Técnicas de Transferência de Genes
Engenharia Genética
[Mh] Termos MeSH secundário: Animais
Cães
Vetores Genéticos/metabolismo
Hemofilia B/genética
Hepatócitos/metabolismo
Fígado/metabolismo
Lisina/genética
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Modelos Animais
Mutação/genética
Transdução Genética
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
42HK56048U (Tyrosine); 9001-28-9 (Factor IX); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1186/s12967-017-1200-1


  2 / 25551 MEDLINE  
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[PMID]:29428598
[Au] Autor:Kazemi Oskuee R; Dabbaghi M; Gholami L; Taheri-Bojd S; Balali-Mood M; Mousavi SH; Malaekeh-Nikouei B
[Ad] Endereço:Neurogenic inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: Oskueekr@mums.ac.ir.
[Ti] Título:Investigating the influence of polyplex size on toxicity properties of polyethylenimine mediated gene delivery.
[So] Source:Life Sci;197:101-108, 2018 Mar 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Gene therapy is a promising strategy for the treatment of various diseases. Polyethylenimine (PEI) has received considerable attention for gene delivery applications due to their appropriate properties. However, their toxicity has raised concerns which cause to be used with cautious. This study aimed to prepare different complexes of PEI/DNA and evaluate their parameters affecting in vitro cytotoxicity. Also, apoptosis rate was measured to determine the mechanism of cell toxicity. MATERIALS AND METHODS: The complexes were prepared through conjugation and characterized using dynamic light scattering, MTT and flow cytometry techniques. KEY FINDINGS: The particles' size was from 81 nm to 2785 nm and was increased in the HBS buffer compared to HBG buffer. In the case of branched PEIs, the size of particles was inversely associated with molecular weight. The cytotoxicity results showed that linear 250 KDa PEI was non-toxic whereas branched PEIs with lower molecular weights showed toxicity effects in a concentration dependent manner. Also, the cytotoxicity effects of branched PEIs were proportional with carrier/plasmid (C/P) ratio and were more for the polyplexes prepared in HBG buffer compared to HBS buffer after 24 h incubation. Flow cytometry results confirmed that apoptosis is the main mechanism of cell toxicity produced by polyplexes. SIGNIFICANCE: The results showed the effect of PEI size on its cytotoxicity. Also, the toxicity effects of PEI-derived polyplexes in vivo environment was evaluated.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Técnicas de Transferência de Genes
Teste de Materiais
Polietilenoimina/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Tamanho da Partícula
Polietilenoimina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9002-98-6 (Polyethyleneimine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180212
[St] Status:MEDLINE


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[PMID]:29276826
[Au] Autor:Osawa R; Kamide T; Satoh Y; Kawano Y; Ohtsu I; Dairi T
[Ti] Título:Heterologous and High Production of Ergothioneine in Escherichia coli.
[So] Source:J Agric Food Chem;66(5):1191-1196, 2018 Feb 07.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ergothioneine (ERG) is a histidine-derived thiol compound suggested to function as an antioxidant and cytoprotectant in humans. Therefore, experimental trials have been conducted applying ERG from mushrooms in dietary supplements and as a cosmetic additive. However, this method of producing ERG is expensive; therefore, alternative methods for ERG supply are required. Five Mycobacterium smegmatis genes, egtABCDE, have been confirmed to be responsible for ERG biosynthesis. This enabled us to develop practical fermentative ERG production by microorganisms. In this study, we carried out heterologous and high-level production of ERG in Escherichia coli using the egt genes from M. smegmatis. By high production of each of the Egt enzymes and elimination of bottlenecks in the substrate supply, we succeeded in constructing a production system that yielded 24 mg/L (104 µM) secreted ERG.
[Mh] Termos MeSH primário: Ergotioneína/biossíntese
Escherichia coli/metabolismo
[Mh] Termos MeSH secundário: Antioxidantes
Citoproteção
Escherichia coli/genética
Fermentação
Técnicas de Transferência de Genes
Mycobacterium smegmatis/crescimento & desenvolvimento
Proteínas Recombinantes/biossíntese
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Recombinant Proteins); BDZ3DQM98W (Ergothioneine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171226
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b04924


  4 / 25551 MEDLINE  
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[PMID]:28748978
[Au] Autor:Song L; Ding AX; Zhang KX; Gong B; Lu ZL; He L
[Ad] Endereço:Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China. luzl@bnu.edu.cn.
[Ti] Título:Degradable polyesters via ring-opening polymerization of functional valerolactones for efficient gene delivery.
[So] Source:Org Biomol Chem;15(31):6567-6574, 2017 Aug 09.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Degradable polymers as gene and drug carriers are emerging as one of the most promising types of materials in the biomedical and pharmaceutical areas. Herein, we report the synthesis of a series of block co-polyesters (B1-B6) and random co-polyesters (C1-C4) via ring-opening polymerization of tertiary amine-bearing valerolactone and alkylated valerolactone monomers. These polymers can completely inhibit the electrophoretic migrations of plasmid DNAs (pDNAs) at a w/w ratio of 2-6. The polyplexes of these polymers with pDNAs were steadily formed in a narrow range of sizes (75 to 220 nm) and could be effectively internalized into the cytoplasm. The results of transfection experiments showed that the block copolymers generally exhibited better performance than their random counterparts and the aliphatic chain lengths on the backbone of the polymers obviously affected the transfection efficiency (TE). Block copolymer B5 with n-octyl chains generated the best TE in Hek293T cells, which was 2.2 fold that of polyethylenimine (PEI) 25k under the optimal conditions. Moreover, these polymers were found to be more biocompatible compared to PEI 25k, and showed degradable properties. Our results suggest that these polymers are potentially reliable/efficient non-viral gene vectors.
[Mh] Termos MeSH primário: DNA/administração & dosagem
Técnicas de Transferência de Genes
Lactonas/química
Plasmídeos/administração & dosagem
Poliésteres/química
[Mh] Termos MeSH secundário: DNA/genética
Vetores Genéticos/administração & dosagem
Vetores Genéticos/genética
Células HEK293
Seres Humanos
Lactonas/síntese química
Plasmídeos/genética
Poliésteres/síntese química
Polimerização
Transfecção/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lactones); 0 (Polyesters); 9007-49-2 (DNA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob00822h


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[PMID]:29269254
[Au] Autor:Begum AA; Wan Y; Toth I; Moyle PM
[Ad] Endereço:School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia.
[Ti] Título:Bombesin/oligoarginine fusion peptides for gastrin releasing peptide receptor (GRPR) targeted gene delivery.
[So] Source:Bioorg Med Chem;26(2):516-526, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin peptide ligand (BBN(6-14)), to selectively target the gastrin releasing peptide receptor (GRPR); oligoarginine peptides (hexa- (R ) and nona-arginine (R )), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6-14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.
[Mh] Termos MeSH primário: Arginina/farmacologia
Bombesina/farmacologia
Técnicas de Transferência de Genes
Receptores da Bombesina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Arginina/análogos & derivados
Arginina/química
Bombesina/química
Células CACO-2
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Ligantes
Estrutura Molecular
Tamanho da Partícula
Receptores da Bombesina/genética
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Bombesin); 94ZLA3W45F (Arginine); PX9AZU7QPK (Bombesin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE


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[PMID]:29229392
[Au] Autor:Zhou A; Sun H; Feng S; Zhou M; Gong S; Wang J; Zhang S
[Ad] Endereço:College of Horticulture and Landscape Architecture, Northeast Agricultural University, Harbin 150030, China. Electronic address: aiminzhou@neau.edu.cn.
[Ti] Título:A novel cold-regulated gene from Phlox subulata, PsCor413im1, enhances low temperature tolerance in Arabidopsis.
[So] Source:Biochem Biophys Res Commun;495(2):1688-1694, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Low temperature stress adversely affects plant growth, development, and crop productivity. Analysis of the function of genes in the response of plants to low temperature stress is essential for understanding the mechanism of chilling and freezing tolerance. In this study, PsCor413im1, a novel cold-regulated gene isolated from Phlox subulata, was transferred to Arabidopsis to investigate its function under low temperature stress. Real-time quantitative PCR analysis revealed that PsCor413im1 expression was induced by cold and abscisic acid. Subcellular localization revealed that PsCor413im1-GFP fusion protein was localized to the periphery of the chloroplast, consistent with the localization of chloroplast inner membrane protein AtCor413im1, indicating that PsCor413im1 is a chloroplast membrane protein. Furthermore, the N-terminal of PsCor413im1 was determined to be necessary for its localization. Compared to the wild-type plants, transgenic plants showed higher germination and survival rates under cold and freezing stress. Moreover, the expression of AtCor15 in transgenic plants was higher than that in the wild-type plants under cold stress. Taken together, our results suggest that the overexpression of PsCor413im1 enhances low temperature tolerance in Arabidopsis.
[Mh] Termos MeSH primário: Aclimatação/genética
Arabidopsis/genética
Ericales/genética
Genes de Plantas
[Mh] Termos MeSH secundário: Aclimatação/fisiologia
Sequência de Aminoácidos
Arabidopsis/crescimento & desenvolvimento
Arabidopsis/fisiologia
Proteínas de Arabidopsis/genética
Proteínas de Arabidopsis/metabolismo
Temperatura Baixa
Ericales/fisiologia
Técnicas de Transferência de Genes
Filogenia
Proteínas de Plantas/genética
Proteínas de Plantas/metabolismo
Plantas Geneticamente Modificadas
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Homologia de Sequência de Aminoácidos
Frações Subcelulares/metabolismo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (Plant Proteins); 0 (Recombinant Fusion Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE


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[PMID]:29355529
[Au] Autor:Wang X; Wang JG; Geng YY; Wang JJ; Zhang XM; Yang SS; Jiang W; Liu WQ
[Ad] Endereço:State Key Laboratories of Agrobiotechnology, College of Biological Sciences, China Agricultural University, PR China.
[Ti] Título:An enhanced anti-tumor effect of apoptin-cecropin B on human hepatoma cells by using bacterial magnetic particle gene delivery system.
[So] Source:Biochem Biophys Res Commun;496(2):719-725, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The gene therapy of cancer, due to the limit of its efficiency and safety, has not been widely used in clinical. Recently, bacterial magnetic particles (BMPs), which are membrane-bound nanocrystals found in magnetotactic bacteria, have been exploited as a new gene delivery system. However, its application on gene therapy remains to be explored. In our previous study, we found that a combination of cecropin B (ABPs) and apoptin (VP3) could serve as an effective gene therapeutic agent. Thus, in this study, we used BMPs to deliver the co-expression plasmid of these two gene, namely pVAX1-VA, and evaluated its therapeutic effect on human hepatocellular carcinoma (HepG2). Our results showed that BMPs significantly improved the efficiency of gene transfection (almost 3-fold than Lipofectamine 2000 at 48 h, P < .001), which led to stronger apoptosis (in a peak almost 2-fold than Lipofectamine 2000-pVAX1-VA, P < .01) and growth inhibition of HepG2 cells. More importantly, compared with Lipofectamine 2000-pVAX1-VA group, BMP-pVAX1-VA strikingly inhibited tumor growth (0.60 ±â€¯0.09 g vs. 0.88 ±â€¯0.11 g, P < .05) in nude mouse tumor models and increased the tumor-infiltrating lymphocytes considerably without apparent cytotoxicity. These findings suggest that BMPs could be an attractive gene delivery system for gene therapy and provide a potential available treatment for human hepatocellular carcinoma and maybe some other kinds of tumors.
[Mh] Termos MeSH primário: Proteínas do Capsídeo/genética
Carcinoma Hepatocelular/terapia
Técnicas de Transferência de Genes
Vetores Genéticos/administração & dosagem
Proteínas de Insetos/genética
Neoplasias Hepáticas/terapia
Magnetossomos/química
Magnetospirillum/química
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/metabolismo
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/patologia
Portadores de Fármacos/química
Feminino
Terapia Genética/métodos
Vetores Genéticos/genética
Vetores Genéticos/uso terapêutico
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Camundongos Endogâmicos BALB C
Camundongos Nus
Transfecção/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Capsid Proteins); 0 (Drug Carriers); 0 (Insect Proteins); 0 (VP3 protein, Chicken anemia virus); 80451-05-4 (cecropin B protein, Insecta)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29262710
[Au] Autor:Liu Y; Liu G; Yang Y; Niu S; Yang F; Yang S; Tang J; Chen J
[Ad] Endereço:1 Department of Biotechnology, Faculty of Agricultural Science, Guang Dong Ocean University , Zhanjiang, Guangdong , P.R. China.
[Ti] Título:Establishment of an efficient plant regeneration culture protocol and achievement of successful genetic transformation in Jatropha curcas L.
[So] Source:Acta Biol Hung;68(4):428-442, 2017 Dec.
[Is] ISSN:0236-5383
[Cp] País de publicação:Hungary
[La] Idioma:eng
[Ab] Resumo:An efficient and reproducible protocol is described for shoot-bud regeneration and Agrobacterium tumefaciens-mediated genetic transformation of J. curcas. Treating the explants with high concentrations (5-120 mg/L) of TDZ for short durations (5-80 min) before inoculation culture increased significantly the regeneration frequency and improved the quality of the regenerated buds. The highest shoot-buds induction rate (87.35%) was achieved when petiole explants were treated with 20 mg/L TDZ solution for 20 min and inoculated on hormone-free MS medium for 30 days. Regenerated shoots of 0.5 cm or a little longer were isolated and grafted to seedling stocks of the same species, and then the grafted plantlets were planted on half-strength MS medium containing 0.1 mg/L IBA and 2 mg/L sodium nitroprusside (SNP). This grafting strategy was found to be very effective, to obtain that healthy grafted plantlets ready for acclimatization within 20 days. By the above mentioned protocol and with general Agrobacterium - mediated genetic transformation methods only 65 days were needed to obtain intact transgenic plants.
[Mh] Termos MeSH primário: Técnicas de Cultura de Células/métodos
Técnicas de Transferência de Genes
Jatropha
Células Vegetais/metabolismo
Brotos de Planta
Transformação Genética
[Mh] Termos MeSH secundário: Agrobacterium tumefaciens/genética
Agrobacterium tumefaciens/metabolismo
Jatropha/genética
Jatropha/crescimento & desenvolvimento
Brotos de Planta/genética
Brotos de Planta/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1556/018.68.2017.4.8


  9 / 25551 MEDLINE  
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[PMID]:29326244
[Au] Autor:Dunbar CE; High KA; Joung JK; Kohn DB; Ozawa K; Sadelain M
[Ad] Endereço:Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA. dunbarc@nhlbi.nih.gov m-sadelain@ski.mskcc.org.
[Ti] Título:Gene therapy comes of age.
[So] Source:Science;359(6372), 2018 01 12.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss emerging genome editing technologies that should further advance the scope and efficacy of gene therapy approaches.
[Mh] Termos MeSH primário: Terapia Genética
[Mh] Termos MeSH secundário: Animais
Edição de Genes
Técnicas de Transferência de Genes
Doenças Genéticas Inatas/terapia
Engenharia Genética
Terapia Genética/efeitos adversos
Vetores Genéticos
Doenças Hematológicas/terapia
Seres Humanos
Neoplasias/terapia
Doenças Neuromusculares/terapia
Pesquisa Médica Translacional
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE


  10 / 25551 MEDLINE  
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[PMID]:29260200
[Au] Autor:Reid CA; Ertel KJ; Lipinski DM
[Ad] Endereço:Department of Ophthalmology, Eye Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
[Ti] Título:Improvement of Photoreceptor Targeting via Intravitreal Delivery in Mouse and Human Retina Using Combinatory rAAV2 Capsid Mutant Vectors.
[So] Source:Invest Ophthalmol Vis Sci;58(14):6429-6439, 2017 Dec 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Effective intravitreal gene delivery to cells of the central retina (i.e., photoreceptors) would be of substantial benefit for treating patients with retinal diseases, such as achromatopsia, where retinal detachment from a subretinal may be harmful. Previous studies demonstrated that mutation of the recombinant adeno-associated virus (rAAV) capsid through introduction of peptide insertions or amino acid substitutions dramatically alters vector tropism. Herein, we evaluate the photoreceptor transduction efficiency of three rAAV2/2-based capsid mutant vectors: rAAV2/2[7m8], rAAV2/2[QuadYF+TV], and a chimeric vector incorporating both mutations (termed rAAV2/2[MAX]) following intravitreal delivery in mice. Furthermore, we evaluate the transduction efficiency of rAAV2/2[MAX] using explanted human central retinal samples to address clinical translatability. Methods: Vectors containing a GFP or mCherry reporter gene were intravitreally injected into C57BL/6J or Nrl-EGFP mice, respectively. Transduction was assessed in vivo utilizing a custom multiline confocal scanning laser ophthalmoscope. Injected Nrl-EGFP mouse retinas were used to quantify transduced photoreceptors using flow cytometry. Postmortem human retinal tissue was cultured following administration of rAAV2/2[MAX]. C57BL/6J retinas and human explants were cryosectioned to determine vector tropism. Results: The chimeric vector rAAV2/2[MAX] transduced significantly higher proportions of the retina than did either single mutant serotypes following intravitreal delivery in murine retina, including inner retinal cells and photoreceptors. Vector rAAV2[MAX] demonstrated transduction of human photoreceptors and ganglion cells. Conclusions: Transduction observed via rAAV2/2[MAX] indicates that combining mutations with complementary mechanisms of action in a single vector results in enhanced transduction. rAAV2/2[MAX] also presented the ability to transduce human photoreceptors and ganglion cells, indicating potential for efficient intravitreal vector delivery.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Técnicas de Transferência de Genes
Terapia Genética/métodos
Vetores Genéticos/administração & dosagem
Células Fotorreceptoras de Vertebrados/metabolismo
Retina/metabolismo
[Mh] Termos MeSH secundário: Animais
Dependovirus/fisiologia
Seres Humanos
Injeções Intravítreas
Camundongos
Camundongos Endogâmicos C57BL
Regiões Promotoras Genéticas/genética
Transdução Genética
Tropismo Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22281



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