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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
Jack W Hickmott, Uvini Gunawardane, Kimberly Jensen, Andrea J Korecki, Elizabeth M Simpson
The small eye (Sey) mouse is a model of PAX6-aniridia syndrome (aniridia). Aniridia, a congenital ocular disorder caused by heterozygous loss-of-function mutations in PAX6, needs new vision saving therapies. However, high phenotypic variability in Sey mice makes development of such therapies challenging. We hypothesize that genetic background is a major source of undesirable variability in Sey mice. Here we performed a systematic quantitative examination of anatomical, histological, and molecular phenotypes on the inbred C57BL/6J, hybrid B6129F1, and inbred 129S1/SvImJ backgrounds...
September 26, 2018: Gene Therapy
Wei Wei, Yong Huang, Dan Li, Hong-Feng Gou, Wei Wang
Mesenchymal stem cells (MSCs), well-studied adult stem cells in various tissues, possess multi-lineage differentiation potential and anti-inflammatory properties. MSCs have been approved to regenerate lineage-specific cells to replace injured cells in tissues. MSCs are approved to treat inflammatory diseases. With the discovery of genes important for the repair of damaged tissues, MSCs genetically modified by such genes hold improved therapeutic potential. In this review, we summarised the uses of genetically modified MSCs to treat different diseases, including bone diseases, cardiovascular diseases, autoimmune diseases, central nervous system disorders, and cancer...
September 25, 2018: Gene Therapy
Anna Egorova, Mariya Petrosyan, Marianna Maretina, Natalia Balashova, Lyudmila Polyanskih, Vladislav Baranov, Anton Kiselev
Development of gene therapy for endometriosis requires inhibition of vascularization in endometrial lesions. We have previously developed CXCR4 receptor-targeted siRNA carrier L1 and observed efficient RNAi-mediated down-regulation of VEGFA gene expression in endothelial cells followed by decrease in VEGFA protein production and inhibition of cell migration. In this study we evaluated L1 carrier as non-viral vector for anti-VEGFA siRNA delivery into endometrial implants in rat subcutaneous endometriosis model created by subcutaneous auto-transplantation of uterus horn's fragments...
September 25, 2018: Gene Therapy
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
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
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...
October 2018: Gene Therapy
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...
October 2018: Gene Therapy
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...
October 2018: Gene Therapy
Julio Enrique Castañeda-Delgado
No abstract text is available yet for this article.
August 10, 2018: Gene Therapy
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
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
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
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
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
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...
August 2018: Gene Therapy
Yi Yang, Jinpei Zhang, Xi Chen, Xin Xu, Gang Cao, Hua Li, Tao Wu
Recent researches have reported that long noncoding RNA (lncRNA) five prime to Xist (FTX) plays a crucial role in the initiation and progression of cancers. In the current study, the clinical significance and functional roles of lncRNA FTX in colorectal cancer (CRC) progression were investigated. A significant increase of lncRNA FTX expression in CRC tissue and cell lines was observed. Overexpression of lncRNA FTX was significantly associated with the bigger tumor diameter, the advanced TNM stage, the lymph node, and distant metastasis, and also predicted poor prognosis of patients with CRC...
August 2018: Gene Therapy
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