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Gene Therapy

E Eriksson, R Moreno, I Milenova, L Liljenfeldt, L C Dieterich, L Christiansson, H Karlsson, G Ullenhag, S Mangsbo, A Dimberg, R Alemany, A Loskog
CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate Th1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer...
December 1, 2016: Gene Therapy
M Alsaggar, M Mills, D Liu
The worldwide prevalence of obesity is increasing, raising health concerns regarding obesity-related complications. Chronic inflammation has been characterized as a major contributor to the development of obesity and obesity-associated metabolic disorders. The purpose of the current study is to assess whether the overexpression of interferon beta (IFNβ1), an immune-modulating cytokine, will attenuate high-fat diet-induced adipose inflammation and protect animals against obesity development. Using hydrodynamic gene transfer to elevate and sustain blood concentration of IFNβ1 in mice fed a high-fat diet, we showed that the overexpression of Ifnβ1 gene markedly suppressed immune cell infiltration into adipose tissue, and attenuated production of pro-inflammatory cytokines...
December 1, 2016: Gene Therapy
M Wang, J Sun, A Crosby, K Woodard, M L Hirsch, R J Samulski, C Li
Recent hemophilia B clinical trials using adeno-associated virus (AAV) gene delivery have demonstrated much lower coagulation factor IX (FIX) production in patients compared with the high levels observed in animal models and AAV capsid-specific cytotoxic T lymphocyte response elicited at high doses of AAV vectors. These results emphasize the necessity to explore effective approaches for enhancement of AAV transduction. Initially, we found that incubation of all AAV vectors with human serum enhanced AAV transduction...
December 1, 2016: Gene Therapy
M Wang, Z A Glass, Q Xu
Manipulating the genetic makeup of mammalian cells using programmable nuclease-based genome-editing technology has recently evolved into a powerful avenue that holds great potential for treating genetic disorders. There are four types of genome-editing nucleases, including meganucleases, zinc finger nucleases, transcription activator-like effector nucleases and clustered, regularly interspaced, short palindromic repeat-associated nucleases such as Cas9. These nucleases have been harnessed to introduce precise and specific changes of the genome sequence at virtually any genome locus of interest...
December 1, 2016: Gene Therapy
E Ilett, T Kottke, J Thompson, K Rajani, S Zaidi, L Evgin, M Coffey, C Ralph, R Diaz, H Pandha, K Harrington, P Selby, R Bram, A Melcher, R Vile
The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity...
December 1, 2016: Gene Therapy
Y Zhang, J Wang, H Cheng, Y Sun, M Liu, Z Wu, R Pei
Numerous synthetic RNA-based controls for integrating sensing switches with function devices have been demonstrated in a variety of organisms for gene regulatory. Although potential advantages of RNA-based genetic control strategies have been shown in clinical applications, successful extending these engineered systems into medical applications has seldom reported. Here, a synthetic RNA-based ribozyme system and its application in advancing rationally designed cellular therapy were described. The theophylline-responsive ribozyme-based device provided a powerful platform for suicide gene expression regulation in tumor cells...
November 22, 2016: Gene Therapy
M Vincent, I de Lázaro, K Kostarelos
Advances in genomics and gene therapy could offer solutions to many diseases that remain incurable today, however one of the critical reasons halting clinical progress is due to the difficulty in designing efficient and safe delivery vectors for the appropriate genetic cargo. Safety and large-scale production concerns counter-balance the high gene transfer efficiency achieved with viral vectors, while non-viral strategies have yet to become sufficiently efficient. The extraordinary physicochemical, optical and photothermal properties of graphene-based materials (GBMs) could offer two-dimensional (2D) components for the design of nucleic acid carrier systems...
November 22, 2016: Gene Therapy
A Kostrzak, V Caval, M Escande, E Pliquet, J Thalmensi, T Bestetti, M Julithe, L Fiette, T Huet, S Wain-Hobson, P L Demoyen
Human APOBEC3A (A3A) cytidine deaminase shows pro-apoptotic properties resulting from hypermutation of genomic DNA, induction of double stranded DNA breaks (DSBs) and G1 cell cycle arrest. Given this we evaluated the anti-tumor efficacy of A3A by intratumoral electroporation of an A3A expression plasmid. DNA was repeatedly electroporated into B16OVA, B16Luc tumors of C57BL/6J mice as well as the aggressive fibrosarcoma Sarc2 tumor of HLA-A*0201/DRB1*0101 transgenic mice using non-invasive plate electrodes. Intratumoral electroporation of A3A plasmid DNA resulted in regression of ~50% of small B16OVA melanoma tumors which did not rebound in the following two months without treatment...
November 18, 2016: Gene Therapy
X Pan, X Liu, J Li, S Zhen, D Liu, Q Feng, W Zhao, Y Luo, Y Zhang, H Li, J Yang
Ras mutations and overexpression of the Ras protein; i.e., p21Ras, are main causes of cancer development and progression, which has made the Ras gene and p21Ras important targets for therapy of Ras-driven cancers. We previously prepared recombinant adenovirus KGHV100 based on replication-defective adenovirus type 5, which could intracellularly express anti-p21Ras single chain fragment viable antibodies (scFv) and repress tumor growth in vitro and in vivo. However, the anti-tumor effects of this anti-p21Ras scFv were limited by short-term scFv expression due to a replication defect of KGHV100...
November 11, 2016: Gene Therapy
A B Plonka, B Khorsand, N Yu, J V Sugai, A K Salem, W V Giannobile, S Elangovan
Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) promotes soft tissue and bone healing, and is FDA-approved for treatment of diabetic ulcers and periodontal defects. The short half-life of topical rhPDGF-BB protein application necessitates bolus, high-dose delivery. Gene therapy enables sustained local growth factor production. A novel gene activated matrix delivering polyplexes of polyethylenimine (PEI)-plasmid DNA (pDNA) encoding PDGF was evaluated for promotion of periodontal wound repair in vivo...
November 8, 2016: Gene Therapy
A M Shaw, G L Joseph, A C Jasti, L Sastry-Dent, S Witting, K Cornetta
A variety of mutations in lentiviral vector expression systems have been shown to generate a non-integrating phenotype. We studied a novel 12 base-pair U3-LTR integrase attachment site deletion (U3-LTR att site) mutant and found similar physical titers to the previously reported integrase catalytic core mutant IN/D116N. Both mutations led to a greater than two log reduction in vector integration; with IN/D116N providing lower illegitimate integration frequency, while the U3-LTR att site mutant provided a higher level of transgene expression...
September 28, 2016: Gene Therapy
S Chen, X Chen, X Wu, S Wei, W Han, J Lin, M Kang, L Chen
Accumulative evidence demonstrated that mesenchymal stem cell (MSC) engraftment could protect tissue injury from ischemia/reperfusion (I/R). Hepatocyte growth factor (HGF) has important roles in the cell and tissue repairment and regeneration. Here we investigated the enhanced effects of HGF-modified MSCs on I/R-induced acute lung injury. Rat bone marrow-derived MSCs were successfully transfected to express HGF. HGF modification did not affect the characteristics of MSCs, and increased MSC viability, and inhibit the proinflammatory phenotype of MSCs in the inflammatory condition...
September 22, 2016: Gene Therapy
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
Leber congenital amaurosis is a group of inherited retinal dystrophies that cause severe sight impairment in childhood; RPE65-deficiency causes impaired rod photoreceptor function from birth and progressive impairment of cone photoreceptor function associated with retinal degeneration. In animal models of RPE65 deficiency, subretinal injection of recombinant adeno-associated virus (AAV) 2/2 vectors carrying RPE65 cDNA improves rod photoreceptor function, and intervention at an early stage of disease provides sustained benefit by protecting cone photoreceptors against retinal degeneration...
December 2016: Gene Therapy
S K Jones, O M Merkel
Breast cancer is the leading cancer diagnosed in women and the second leading cause of cancer-related deaths in women. Current limitations to standard chemotherapy in the clinic are extensively researched, including problems arising from repeated treatments with the same drugs. The phenomenon that cancer cells become resistant toward certain chemo drugs is called chemotherapy resistance. In this review, we are focusing on nanoformulation of siRNA for the fight against breast cancer chemoresistance.
December 2016: Gene Therapy
W-H Wang, C-H Zhou, J Ding, Y-X Zhang, L-L Zheng, S-F Chen, W Zhang
The immune effect and safety evaluation of rAAV (recombinant adeno-associated virus)-containing Bcsg1 (breast cancer-specific gene 1) (rAAV/Bcsg1)-transfected DC (dendritic cell) (rAAV/Bcsg1-DC) vaccine in immunotherapy for (BCSG1) (+) BC was assessed. Immune effect of cytotoxic T lymphocytes (CTLs) on Bcsg1 (+) BC cells, and rAAV gene residuals in mature CTL cells and culture medium were determined. Nude mouse xenograft tumor model was established to assess the inhibition effects of DC-activated CTLs on tumor growth...
December 2016: Gene Therapy
H Khonsari, M Schneider, S Al-Mahdawi, Y G Chianea, M Themis, C Parris, M A Pook, M Themis
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron-sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress...
December 2016: Gene Therapy
G Liang, Y Zhu, A Jing, J Wang, F Hu, W Feng, Z Xiao, B Chen
Manipulation of tumor microRNAs (miRNAs) may offer novel avenues for treatment of cancer. However, development of safe, robust, non-viral delivery methods remains a main challenge to obtain the promise of gene therapy. The miR-145 is dysregulated in many cancers, including colon carcer, and further in vitro investigation established antiproliferative and proapoptotic roles of miR-145. Herein, we study a PLGA/PEI (poly (d, l-lactide-co-glycolide)/polyethylenimine)-mediated miRNA vector delivery system; the validation of the method was carried out using a colon cancer xenograft model with miR-145 vector encoding for the expression of miR-145 (pDNA)...
December 2016: Gene Therapy
E Hudry, C Martin, S Gandhi, B György, D I Scheffer, D Mu, S F Merkel, F Mingozzi, Z Fitzpatrick, H Dimant, M Masek, T Ragan, S Tan, A R Brisson, S H Ramirez, B T Hyman, C A Maguire
No abstract text is available yet for this article.
November 2016: Gene Therapy
D Vavrincova-Yaghi, L E Deelman, H van Goor, M A Seelen, P Vavrinec, I P Kema, P Gomolcak, A Benigni, R H Henning, M Sandovici
No abstract text is available yet for this article.
November 2016: Gene Therapy
S K Powell, N Khan, C L Parker, R J Samulski, G Matsushima, S J Gray, T J McCown
No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression...
November 2016: Gene Therapy
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