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Gene Therapy

Marianne Lehmann, Martina Canatelli-Mallat, Priscila Chiavellini, Gustavo R Morel, Paula C Reggiani, Claudia B Hereñú, Rodolfo G Goya
Biological rejuvenation by partial cell reprogramming is an emerging avenue of research. In this context, regulatable pluripotency gene expression systems are the most widely used at present. We have constructed a regulatable bidirectional adenovector expressing the humanized green fluorescent protein (GFP) and oct4, sox2, klf4, and c-myc genes (known as the Yamanaka genes or OSKM). The OSKM genes are arranged as a bicistronic tandem (hSTEMCCA tandem), which is under the control of a Tet-Off bidirectional promoter that also controls the expression of the gFP gene...
February 15, 2019: Gene Therapy
Bianca Ferrarini Zanetti, Camila Pontes Ferreira, José Ronnie Carvalho de Vasconcelos, Sang Won Han
The carcinoembryonic antigen (CEA) is the main tumor-associated antigen of colorectal cancers. Previously, we developed a DNA vaccine using scFv6.C4, a CEA surrogate, against CEA-expressing tumors; 40% of the vaccinated mice were tumor-free after tumor challenge. In order to enhance vaccine efficacy, fragment C of Tetanus Toxin (FrC) was tested as adjuvant. C57BL/6J-CEA2682 mice were electroporated intramuscularly 4 times with uP-PS/scFv6.C4-FrC or uP-PS/scFv6.C4, challenged by s.c. injection of 1 × 105 MC38-CEA cells, and tumor growth was monitored over 100 days...
February 15, 2019: Gene Therapy
Qi Wang, Alanna Vossen, Yasuhiro Ikeda, Patricia Devaux
Induced pluripotent stem cells (iPSCs) provide a unique platform for individualized cell therapy approaches. Currently, episomal DNA, mRNA, and Sendai virus-based RNA reprogramming systems are widely used to generate iPSCs. However, they all rely on the use of multiple (three to six) components (vectors/plasmids/mRNAs) leading to the production of partially reprogrammed cells, reducing the efficiency of the systems. We produced a one-cycle measles virus (MV) vector by substituting the viral attachment protein gene with the green fluorescent protein (GFP) gene...
February 4, 2019: Gene Therapy
Eleonora Leggiero, Giuseppe Labruna, Laura Iaffaldano, Barbara Lombardo, Adelaide Greco, Dario Fiorenza, Matteo Gramanzini, Donatella Montanaro, Alfonso Baldi, Vincenzo Cerullo, Lucia Sacchetti, Lucio Pastore
Familial hypercholesterolemia (FH) is a genetic hyperlipidemia characterized by elevated concentrations of plasma LDL cholesterol. Statins are not always effective for the treatment of FH patients; unresponsive patients have poor prognosis and rely on LDL apheresis. In the past, we developed safe and effective gene therapy strategies for the expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We recently developed a HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDL receptor (LDLR) fused with a rabbit transferrin dimer (LDLR-TF)...
January 30, 2019: Gene Therapy
Xu Cao, Jasmine Yung, Heather Mak, Christopher K S Leung
Efficient transduction of the retinal ganglion cells (RGCs) is a prerequisite to maximize therapeutic outcomes in any form of gene therapy for optic neuropathies. Whereas subretinal injection of adeno-associated virus 2 (AAV2) has been well-characterized, the serotype, viral load, and promoter combinations that govern RGC transduction efficiency following intravitreal injection remains poorly understood. We evaluated the transduction efficiency of seven AAV2 serotypes (AAV2/1, AAV2/2, AAV2/4, AAV2/5, AAV2/6, AAV2/8, and AAV2/9) for the RGCs at 4 weeks following intravitreal injection in C57BL/6J mice...
January 28, 2019: Gene Therapy
Mira Cho, Kwangsoo Jung, Seung-Hyun Kim, Il-Sun Kim, Miri Kim, Mikyung Shin, Haeshin Lee, Kook In Park, Jae-Hyung Jang
Gene therapy technologies are inevitably required to boost the therapeutic performance of cell therapies; thus, validating the efficacy of gene carriers specifically used for preparing cellular therapeutics is a prerequisite for evaluating the therapeutic capabilities of gene and cell combinatorial therapies. Herein, the efficacy of a recombinant adeno-associated virus derivative (rAAVr3.45) was examined to evaluate its potential as a gene carrier for genetically manipulating interleukin-10 (IL10)-secreting human neural stem cells (hNSCs) that can potentially treat ischemic injuries or neurological disorders...
January 28, 2019: Gene Therapy
Sarah Urnauer, Kathrin A Schmohl, Mariella Tutter, Christina Schug, Nathalie Schwenk, Stephan Morys, Sibylle Ziegler, Peter Bartenstein, Dirk-André Clevert, Ernst Wagner, Christine Spitzweg
Tumor heterogeneity, within and between tumors, may have severe implications for tumor therapy, especially for targeted gene therapy, where single-targeted approaches often result in limited efficacy and therapy resistance. Polymer-formulated nonviral vectors provide a potent delivery platform for cancer therapy. To improve applicability for future clinical use in a broad range of patients and cancer types, a dual-targeting approach was performed. Synthetic LPEI-PEG2kDa -based polymer backbones were coupled to two tumor-specific peptide ligands GE11 (EGFR-targeting) and cMBP (cMET-targeting)...
January 25, 2019: Gene Therapy
Rajvinder Karda, John R Counsell, Kinga Karbowniczek, Lisa J Caproni, John P Tite, Simon N Waddington
The manufacture of large quantities of high-quality DNA is a major bottleneck in the production of viral vectors for gene therapy. Touchlight Genetics has developed a proprietary abiological technology that addresses the major issues in commercial DNA supply. The technology uses 'rolling-circle' amplification to produce large quantities of concatameric DNA that is then processed to create closed linear double-stranded DNA by enzymatic digestion. This novel form of DNA, Doggybone™ DNA (dbDNA™), is structurally distinct from plasmid DNA...
January 14, 2019: Gene Therapy
Jack W Hickmott, Uvini Gunawardane, Kimberly Jensen, Andrea J Korecki, Elizabeth M Simpson
This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
January 2, 2019: Gene Therapy
Chunbo Zhang, Guisheng Zhang, Dexi Liu
Gene silencing for plasmid-based vectors and the underlying mechanism are critical factors for development of effective gene therapy. The objective of this study is to explore the role of epigenetic regulation for transgene expression. Two reporter genes, mouse interleukin 10 and human secreted alkaline phosphatase under the control of human cytomegalovirus immediate early promoter for expression, were delivered to mouse liver by hrodydynamics-based procedure and reporter gene expression was monitored. Reporter gene expression reached its peak level one day after gene delivery and declined progressively thereafter, reaching the minimal level in about 3 weeks...
December 11, 2018: Gene Therapy
Luis Quintino, Martino Avallone, Emil Brännstrom, Patrick Kavanagh, Marcus Lockowandt, Patricia Garcia Jareño, Ludivine S Breger, Cecilia Lundberg
Glial cell-line derived neurotrophic factor (GDNF) is a promising therapeutic molecule to treat Parkinson's disease. Despite an excellent profile in experimental settings, clinical trials testing GDNF have failed. One of the theories to explain these negative outcomes is that the clinical trials were done in late-stage patients that have advanced nigrostriatal degeneration and may therefore not respond to a neurotrophic factor therapy. Based on this idea, we tested if the stage of nigrostriatal degeneration is important for GDNF-based therapies...
December 7, 2018: Gene Therapy
Asha Recino, Shu Uin Gan, Kian Chuan Sia, Yvonne Sawyer, Jenny Trendell, Richard Kay, Fiona M Gribble, Frank Reimann, Rob Foale, Maria Notaridou, Nick Holmes, Andrew Lever, Kok Onn Lee, Amit Nathwani, Anne Cooke, Roy Calne, Maja Wallberg
We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were no immunological barriers to efficacy of insulin gene therapy in chemically induced C57BL/6 mice, which enjoyed long-lasting correction of hyperglycaemia after therapy, up to 250 days...
December 4, 2018: Gene Therapy
(no author information available yet)
We would like to thank all those listed below for taking the time to review for Gene Therapy in 2017-your generosity is much appreciated and we hope your association with the journal continues in the future.Editor-in-Chief: Rafael Yáñez-MuñozWe will be awarding the top reviewers with a 1-year gratis subscription to Gene Therapy and Nature as a special thank you for their time.Nevertheless the support from all of you is vital to the journal and we wish to sincerely thank you all too.
December 2018: Gene Therapy
Avtandil Nanobashvili, Esbjörn Melin, Dwaine Emerich, Jens Tornøe, Michele Simonato, Lars Wahlberg, Merab Kokaia
Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. This neurological disorder is characterized by focal seizures originating in the temporal lobe, often with secondary generalization. A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the epilepsy patients. Thus, developing more targeted and effective treatment strategies for focal seizures, originating from, e...
November 21, 2018: Gene Therapy
Lei Chen, Shiqi Zhang, Xiaoyong Pan, XiaoHua Hu, Yu-Hang Zhang, Fei Yuan, Tao Huang, Yu-Dong Cai
Many complex diseases or traits are the results of both genetic and environmental factors. The environmental factors affect the human body by modifying its epigenetics, which controls the activity of genomes without mutating it. Viral infection is one of the common environmental factors for complex diseases. For example, the human immunodeficiency virus (HIV) infection can cause acquired immune deficiency syndrome (AIDS), HBV, and HCV infections are associated with hepatocellular carcinoma, and human papillomavirus infection is a causal factor in cervical carcinoma...
November 15, 2018: Gene Therapy
Bin Ren, Volker M Betz, Christian Thirion, Michael Salomon, Volkmar Jansson, Peter E Müller, Oliver B Betz
Bone can be engineered in vivo by implantation of gene-activated muscle tissue fragments. This expedited approach may be further improved by use of muscle tissue with attached fascia. The aim of this in vitro study was to provide an in depth comparison of the osteogenic differentiation capacity of muscle alone and muscle with fascia after BMP-2 transduction. Skeletal muscle tissue from rats was cut into pieces with and without a fascia layer on the surface. Adenoviral BMP-2 or GFP vectors were used for transduction...
October 27, 2018: Gene Therapy
Anandaroop Mukhopadhyay, Jocelyn Wright, Shawna Shirley, David A Canton, Christoph Burkart, Richard J Connolly, Jean S Campbell, Robert H Pierce
Intratumoral electroporation-mediated IL-12 gene therapy (IT-pIL12/EP) has been shown to be safe and effective in clinical trials, demonstrating systemic antitumor effects with local delivery of this potent cytokine. We recently optimized our IL-12 gene delivery platform to increase transgene expression and efficacy in preclinical models. Here we analyze the immunological changes induced with the new IT-pIL12/EP platform in both electroporated and distant, non-electroporated lesions. IT-pIL12/EP-treated tumors demonstrated rapid induction of IL-12-regulated pathways, as well as other cytokines and chemokines pathways, and upregulation of antigen presentation machinery...
October 15, 2018: Gene Therapy
Hongchun Wu, Zhen-Ao Zhao, Junwei Liu, Kaili Hao, You Yu, Xinglong Han, Jingjing Li, Yixuan Wang, Wei Lei, Nianguo Dong, Zhenya Shen, Shijun Hu
Myocardial infarction (MI), with a major process of cardiomyocyte death, remains a leading cause of morbidity and mortality worldwide. To date, it has been shown that lncRNAs play important roles in cardiovascular pathology. However, the detailed studies on lncRNAs regulating cardiomyocyte death in myocardial infarction are still limited. In this study, we found a progressively upregulated expression of Meg3 in mouse injured heart after MI. Gain-of-function and loss-of-function approaches further revealed pro-apoptotic functions of Meg3 in rodent cardiomyocytes...
October 4, 2018: Gene Therapy
Charles Coutelle
No abstract text is available yet for this article.
October 2018: Gene Therapy
Peirong Hu, Yanmin Bi, Hong Ma, Thipparat Suwanmanee, Brian Zeithaml, Nate J Fry, Donald B Kohn, Tal Kafri
Lentiviral vector mobilization following HIV-1 infection of vector-transduced cells poses biosafety risks to vector-treated patients and their communities. The self-inactivating (SIN) vector design has reduced, however, not abolished mobilization of integrated vector genomes. Furthermore, an earlier study demonstrated the ability of the major product of reverse transcription, a circular SIN HIV-1 vector comprising a single- long terminal repeat (LTR) to support production of high vector titers. Here, we demonstrate that configuring the internal vector expression cassette in opposite orientation to the LTRs abolishes mobilization of SIN vectors...
October 2018: Gene Therapy
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