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Gene Therapy

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https://www.readbyqxmd.com/read/30242259/scaffold-mediated-delivery-for-non-viral-mrna-vaccines
#1
Ruying Chen, Hong Zhang, Jingxuan Yan, James D Bryers
mRNA is increasingly being recognized as a promising alternative to pDNA in gene vaccinations. Only recently, owing to the needs of cancer immunotherapies, has the biomaterials/gene delivery community begun to develop new biomaterial strategies for immunomodulation. Here, we report a novel way to use implantable porous scaffolds as a local gene delivery depot to enhance mRNA vaccine immunization in vitro, and in vivo when compared with conventional bolus injections. We first evaluated transfection efficiencies of single-stranded mRNA condensed and charge neutralized with two lipids (Lipofectamine Messenger MAXTM LM-MM and StemfectTM SF) and two cationic polymers (in vivo-jetPEI™, Poly (β-amino ester)) as gene carriers...
September 21, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30190607/superior-lentiviral-vectors-designed-for-bsl-0-environment-abolish-vector-mobilization
#2
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...
September 6, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30154525/metabolically-stabilized-double-stranded-mrna-polyplexes
#3
Jacob A Poliskey, Samuel T Crowley, Raghu Ramanathan, Christopher W White, Basil Mathew, Kevin G Rice
The metabolic instability of mRNA currently limits its utility for gene therapy. Compared to plasmid DNA, mRNA is significantly more susceptible to digestion by RNase in the circulation following systemic dosing. To increase mRNA metabolic stability, we hybridized a complementary reverse mRNA with forward mRNA to generate double-stranded mRNA (dsmRNA). RNase A digestion of dsmRNA established a 3000-fold improved metabolic stability compared to single-stranded mRNA (ssmRNA). Formulation of a dsmRNA polyplex using a PEG-peptide further improved the stability by 3000-fold...
August 28, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30108273/in-vivo-delivery-of-pperdby-to-balb-c-mice-by-lacvax-%C3%A2-dna-i-and-comparison-of-elicited-immune-response-with-conventional-immunization-methods
#4
Bhrugu Yagnik, Drashya Sharma, Harish Padh, Priti Desai
The non-invasive food grade Lactococcus lactis (L. lactis) represents a safe and attractive alternative to invasive pathogens for the delivery of plasmid DNA at mucosal sites. We have earlier shown the DNA delivery potential of r-L. lactis harboring DNA vaccine reporter plasmid; pPERDBY in vitro. In the present work, we examined in vivo delivery potential of food grade non-invasive r-L. lactis::pPERDBY (LacVax® DNA-I) in BALB/c mice. Moreover, using EGFP as a model antigen, we also characterized and compared the immune response elicited by LacVax® DNA-I with other conventional vaccination approaches using protein and naked DNA immunization...
August 14, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30097613/diabetic-complication-could-get-a-gene-therapy-boost
#5
Julio Enrique Castañeda-Delgado
No abstract text is available yet for this article.
August 10, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30072816/ectopic-bat-mucp-1-overexpression-in-skm-by-delivering-a-bmp7-prdm16-pgc-1a-gene-cocktail-or-single-prmd16-using-non-viral-utmd-gene-therapy
#6
Shuyuan Chen, Raul A Bastarrachea, Jin-Song Shen, Antonio Laviada-Nagel, Ernesto Rodriguez-Ayala, Edna J Nava-Gonzalez, Pintong Huang, Ralph A DeFronzo, Jack W Kent, Paul A Grayburn
Here we present our progress in inducing an ectopic brown adipose tissue (BAT) phenotype in skeletal muscle (SKM) as a potential gene therapy for obesity and its comorbidities. We used ultrasound-targeted microbubble destruction (UTMD), a novel targeted, non-viral approach to gene therapy, to deliver genes in the BAT differentiation pathway into rodent SKM to engineer a thermogenic BAT phenotype with ectopic mUCP-1 overexpression. In parallel, we performed a second protocol using wild-type Ucp-1-null knockout mice to test whether the effects of the gene therapy are UCP-1 dependent...
August 2, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30072815/serotype-survey-of-aav-gene-delivery-via-subconjunctival-injection-in-mice
#7
Liujiang Song, Telmo Llanga, Laura M Conatser, Violeta Zaric, Brian C Gilger, Matthew L Hirsch
AAV gene therapy approaches in the posterior eye resulted in the first FDA-approved gene therapy-based drug. However, application of AAV vectorology to the anterior eye has yet to enter even a Phase I trial. Furthermore, the simple and safe subconjunctival injection has been relatively unexplored in regard to AAV vector transduction. To determine the utility of this route for the treatment of various ocular disorders, a survey of gene delivery via natural AAV serotypes was performed and correlated to reported cellular attachment factors...
August 2, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30069004/optimization-of-viral-protein-ratios-for-production-of-raav-serotype-5-in-the-baculovirus-system
#8
Bas Bosma, Francois du Plessis, Erich Ehlert, Bart Nijmeijer, Martin de Haan, Harald Petry, Jacek Lubelski
Recombinant adeno-associated virus (rAAV) has become the vector of choice for the development of novel human gene therapies. High-yield manufacturing of high-quality vectors can be achieved using the baculovirus expression vector system. However, efficient production of rAAV in this insect cell-based system requires a genetic redesign of the viral protein 1 (VP1) operon. In this study, we generated a library of rationally designed rAAV serotype 5 variants with modulations in the translation-initiation region of VP1 and investigated the potency of the resulting vectors...
August 1, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30046128/correction-development-of-an-optimized-aav2-5-gene-therapy-vector-for-leber-congenital-amaurosis-owing-to-defects-in-rpe65
#9
A Georgiadis, Y Duran, J Ribeiro, L Abelleira-Hervas, S J Robbie, B Sünkel-Laing, S Fourali, A Gonzalez-Cordero, E Cristante, M Michaelides, J W B Bainbridge, A J Smith, R R Ali
The authors originally published this article under the incorrect license type; this has now been corrected and is published under the CC-BY license.
July 25, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29955127/nanosphere-mediated-co-delivery-of-vegf-a-and-pdgf-b-genes-for-accelerating-diabetic-foot-ulcers-healing-in-rats
#10
Rongfeng Shi, Weishuai Lian, Shilong Han, Chuanwu Cao, Yinpeng Jin, Yifeng Yuan, Hui Zhao, Maoquan Li
Diabetic ischemic ulcer is an intractable diabetic complication. Angiogenesis is a critical factor for wound healing in patients with diabetic foot wounds. Sustained gene delivery could be notably necessary in modulating gene expression in chronic ulcer healing and might be a promising approach for diabetic foot ulcers. In the present study, Sprague-Dawley rats were used to establish diabetic foot ulcer models by streptozotocin and skin biopsy punch. The plasmids expressing VEGF-A and PDGF-B were prepared and then incorporated with polylactic-co-glycolic acid (PLGA) nanospheres to upregulate genes expression...
June 28, 2018: Gene Therapy
https://www.readbyqxmd.com/read/30022127/the-murine-lung-as-a-factory-to-produce-secreted-intrapulmonary-and-circulatory-proteins
#11
Michael C Paul-Smith, Kamila M Pytel, Jean-François Gelinas, Jenny McIntosh, Ian Pringle, Lee Davies, Mario Chan, Cuixiang Meng, Robyn Bell, Lidia Cammack, Caroline Moran, Loren Cameron, Makoto Inoue, Shu Tsugumine, Takashi Hironaka, Deborah R Gill, Stephen C Hyde, Amit Nathwani, Eric W F W Alton, Uta Griesenbach
We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using human α1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV...
August 2018: Gene Therapy
https://www.readbyqxmd.com/read/30013187/characterization-of-a-replicating-expanded-tropism-oncolytic-reovirus-carrying-the-adenovirus-e4orf4-gene
#12
Vera Kemp, Iris J C Dautzenberg, Steve J Cramer, Rob C Hoeben, Diana J M van den Wollenberg
While the mammalian orthoreovirus type 3 dearing (reovirus T3D) infects many different tumour cells, various cell lines resist the induction of reovirus-mediated cell death. In an effort to increase the oncolytic potency, we introduced transgenes into the S1 segment of reovirus T3D. The adenovirus E4orf4 gene was selected as transgene since the encoded E4orf4 protein induces cell death in transformed cells. The induction of cell death by E4orf4 depends in part on its binding to phosphatase 2A (PP2A). In addition to the S1-E4orf4 reovirus, two other reoviruses were employed in our studies...
August 2018: Gene Therapy
https://www.readbyqxmd.com/read/30013186/more-expansive-gene-transfer-to-the-rat-cns-aav-php-eb-vector-dose-response-and-comparison-to-aav-php-b
#13
Robert D Dayton, Mychal S Grames, Ronald L Klein
Engineered recombinant adeno-associated virus (AAV) vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis since the papers first using AAV9 for this purpose. Wide-scale CNS expression is relevant to gene therapy as well as indispensable for basic studies such as disease modeling. For example, the wide-scale gene transfer approach could expedite hypothesis testing in vivo relative to the generation of germ-line transgenic mice for all of the genes of interest. Wide-scale gene transfer is more efficient in neonates than in adults, so improving gene transfer efficiency in adults is an important goal...
August 2018: Gene Therapy
https://www.readbyqxmd.com/read/29973656/downreguation-of-foxm1-by-mir-214-inhibits-proliferation-and-migration-in-hepatocellular-carcinoma
#14
Chuan Tian, Haixia Wu, Chan Li, Xia Tian, Yong Sun, Enqiang Liu, Xiuyong Liao, Wei Song
The FoxM1 transcription factor plays an important role in the progression of HCC. Therefore, it is necessary to study cell regulation of FoxM1. In this study, we determined the expression of miR-214 and it was inversely associated with FoxM1 protein level in HCC; and suppression of FoxM1 translation by miR-214 mimics. We found that miR-214 targeted the 3'untranslated region of FoxM1 mRNA. In addition, the study found that DLX1 was the direct target of FoxM1 in HCC. Downregulation of FoxM1 inhibits the proliferation, migration, and invasion of HCC cells by miR-214...
July 2018: Gene Therapy
https://www.readbyqxmd.com/read/29802374/effect-of-pak1-gene-silencing-on-proliferation-and-apoptosis-in-hepatocellular-carcinoma-cell-lines-mhcc97-h-and-hepg2-and-cells-in-xenograft-tumor
#15
Zhi-Lei Zhang, Guang-Chao Liu, Li Peng, Chong Zhang, Yu-Ming Jia, Wu-Han Yang, Lei Mao
This study intends to explore the effect of the PAK1 gene silencing on apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H and HepG2 cells and cells in xenograft tumor. MHCC97-H and HepG2 cells and mice with xenograft tumor in vivo were randomly divided into control, empty vector and PAK1 shRNA groups. Morphology and the expression of green fluorescent protein of MHCC97-H and HepG2 cells and cells in xenograft tumor were observed. MTT assay and flow cytometry were used to detect proliferation, cell cycle and apoptosis of MHCC97-H and HepG2 cells and cells in xenograft tumor...
July 2018: Gene Therapy
https://www.readbyqxmd.com/read/29789638/human-carbonic-anhydrase-8-aav8-gene-therapy-inhibits-nerve-growth-factor-signaling-producing-prolonged-analgesia-and-anti-hyperalgesia-in-mice
#16
Gerald Z Zhuang, Udita Upadhyay, Xiaoying Tong, Yuan Kang, Diana M Erasso, Eugene S Fu, Konstantinos D Sarantopoulos, Eden R Martin, Tim Wiltshire, Luda Diatchenko, Shad B Smith, William Maixner, Roy C Levitt
Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8WT ), but not the reported CA8 S100P loss-of-function mutation (CA8MT ), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro...
July 2018: Gene Therapy
https://www.readbyqxmd.com/read/29535374/aav-mediated-nt-3-overexpression-protects-cochleae-against-noise-induced-synaptopathy
#17
Hengchao Chen, Yazhi Xing, Li Xia, Zhengnong Chen, Shankai Yin, Jian Wang
The synapse between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) has been identified as a sensitive structure to noise-induced damage in the mammalian cochlea. Since this synapse provides the major information pathway from the cochlea to the auditory brain, it is important to maintain its integrity. Neurotrophin-3 (NT-3) has been known to play an important role in the development and the functional maintenance of this synapse. Application of exogenous NT-3, or overexpression of this gene in a transgenic animal model, have shown the value to protect this synapse from noise-induced damage...
July 2018: Gene Therapy
https://www.readbyqxmd.com/read/29523882/hiv-based-lentivirus-mediated-vasoactive-intestinal-peptide-gene-delivery-protects-against-dio-animal-model-of-type-2-diabetes
#18
Hale M Tasyurek, Yunus E Eksi, Ahter D Sanlioglu, Hasan A Altunbas, Mustafa K Balci, Thomas S Griffith, Salih Sanlioglu
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, glucose intolerance and beta cell loss leading to hyperglycemia. Vasoactive intestinal peptide (VIP) has been regarded as a novel therapeutic agent for the treatment of T2DM because of its insulinotropic and anti-inflammatory properties. Despite these beneficial properties, VIP is extremely sensitive to peptidases (DPP-4) requiring constant infusion or multiple injections to observe any therapeutic benefit. Thus, we constructed an HIV-based lentiviral vector encoding human VIP (LentiVIP) to test the therapeutic efficacy of VIP peptide in a diet-induced obesity (DIO) animal model of T2DM...
July 2018: Gene Therapy
https://www.readbyqxmd.com/read/29941984/additive-effects-of-the-combined-expression-of-soluble-forms-of-gas1-and-pten-inhibiting-glioblastoma-growth
#19
Laura Sánchez-Hernández, Justino Hernández-Soto, Paula Vergara, Rosa O González, José Segovia
The overexpression of GAS1 (Growth Arrest Specific 1) in glioma cells induces cell cycle arrest and apoptosis. We previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity to inhibit the Glial cell-derived neurotrophic factor (GDNF)-mediated intracellular survival signaling pathway. Whereas on the other hand, PTEN is a tumor suppressor, inactive in many tumors, and both GAS1 and PTEN inhibit the PI3K/AKT pathway. Therefore, it is relevant to investigate the potential additive effect of the overexpression of GAS1 and PTEN on tumor growth...
June 25, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29930343/stable-and-reproducible-transgene-expression-independent-of-proliferative-or-differentiated-state-using-bac-tg-embed
#20
Pankaj Chaturvedi, Binhui Zhao, David L Zimmerman, Andrew S Belmont
Reproducible and stable transgene expression is an important goal in both basic research and biotechnology, with each application demanding a range of transgene expression. Problems in achieving stable transgene expression include multi-copy transgene silencing, chromosome-position effects, and loss of expression during long-term culture, induced cell quiescence, and/or cell differentiation. Previously, we described the "BAC TG-EMBED" method for copy-number dependent, chromosome position-independent expression of embedded transgenes within a BAC containing ~170 kb of the mouse Dhfr locus...
June 21, 2018: Gene Therapy
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