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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
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...
September 22, 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.Gene Therapy accepted article preview online, 20 September 2016...
September 20, 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...
September 15, 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) plays 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...
August 24, 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/Bcsg1-DC vaccine in immunotherapy for BCSG1 (+) breast cancer (BC) was assessed. Immune effect of 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 inhibition effects of DC activated CTLs on tumor growth. DC cell surface markers were highly expressed in rAAV/Bcsg1 group and Lysate-DC group, and rAAV/Bcsg1-DC-CTL showed stronger cytotoxic activity targeting Bcsg1 (+) BC cells...
August 24, 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 (DRG) and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron-sulphur 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 (ROS) and sensitivity to oxidative stress...
August 12, 2016: Gene Therapy
B Tockner, T Kocher, S Hainzl, J Reichelt, J W Bauer, U Koller, E M Murauer
RNA trans-splicing has become a versatile tool in the gene therapy of monogenetic diseases. This technique is especially valuable for the correction of mutations in large genes such as COL7A1, which underlie the dystrophic subtype of the skin blistering disease epidermolysis bullosa. Over 800 mutations spanning the entire length of the COL7A1 gene have been associated with defects in type VII collagen, leading to excessive fragility of epithelial tissues, the hallmark of dystrophic epidermolysis bullosa (DEB)...
August 11, 2016: Gene Therapy
Y Ikawa, T Uchiyama, G J Jagadeesh, F Candotti
Integrating vectors based on γ-retroviruses and containing full-length long terminal repeats (LTRs) have been associated with activation of oncogene expression and leukemogenesis in human gene therapy trials. Identification of the specific molecular elements of the LTRs that have a role in insertional oncogenesis events is important as it can lead to the development of safer gene transfer vectors. The negative control region (NCR) of the LTR is a particularly well-conserved sequence among mammalian γ-retroviruses with demonstrated regulatory activity of gene transcription in hematopoietic cells, which led us to hypothesize that this region may have a role in insertional oncogenesis after γ-retroviral vector (GV)-mediated gene transfer into hematopoietic progenitors...
August 4, 2016: Gene Therapy
N Avaliani, M Andersson, A H Runegaard, D Woldbye, M Kokaia
Epilepsy is a neurological disorder with a prevalence of ≈1% of general population. Available antiepileptic drugs (AEDs) have multiple side effects and are ineffective in 30% of patients. Therefore, development of effective treatment strategies is highly needed, requiring drug-screening models that are relevant and reliable. We investigated novel chemogenetic approach, using DREADDs (designer receptors exclusively activated by designer drugs) as possible inhibitor of epileptiform activity in organotypic hippocampal slice cultures (OHSCs)...
August 4, 2016: Gene Therapy
G Liang, Y Zhu, A Jing, J Wang, F Hu, W Feng, Z Xiao, B Chen
Manipulation of tumor microRNAs (miRNA) may offer novel avenues for cancer treatment. However, development of safe, robust, nonviral delivery methods remains a main challenge in order 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 pro-apoptotic roles of miR-145. Herein, we study a PLGA/polyethylenimine (PEI)-mediated miRNA vector delivery system, validating the method employing colon cancer xenograf model with miR-145 vector encoding for the expression of miR-145 (pDNA)...
August 2, 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
Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and gene therapy with IDO inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline...
July 25, 2016: Gene Therapy
V A Dolgachev, R Goldberg, M V Suresh, B Thomas, N Talarico, M R Hemmila, K Raghavendran, D Machado-Aranda
Injured patients with lung contusion (LC) are at risk of developing bacterial pneumonia (PNA) followed by sepsis and death. A recent Genome-wide Association Study, showed FER gene expression positively correlating with survival rates among individuals with above conditions. We sought to determine if electroporation-mediated (EP) delivery of FER gene could indeed improve survival, in a lethal model of combined LC and PNA. C57BL/6 mice sustained unilateral LC, which preceded a 500 Klebsiella CFU inoculation by 6 hrs...
July 25, 2016: Gene Therapy
A Baoutina, S Bhat, M Zheng, L Partis, M Dobeson, I E Alexander, K R Emslie
There is a recognised need for standardisation of protocols for vector genome analysis used in vector manufacturing, to establish dosage, in biodistribution studies and to detect gene doping in sport. Analysis of vector genomes and transgene expression is typically performed by qPCR using plasmid-based calibrants incorporating transgenic sequences. These often undergo limited characterisation and differ between manufacturers, potentially leading to inaccurate quantification, inconsistent inter-laboratory results and affecting clinical outcomes...
October 2016: Gene Therapy
R Kaminski, R Bella, C Yin, J Otte, P Ferrante, H E Gendelman, H Li, R Booze, J Gordon, W Hu, K Khalili
No abstract text is available yet for this article.
August 2016: Gene Therapy
R Kaminski, R Bella, C Yin, J Otte, P Ferrante, H E Gendelman, H Li, R Booze, J Gordon, W Hu, K Khalili
A CRISPR/Cas9 gene editing strategy has been remarkable in excising segments of integrated HIV-1 DNA sequences from the genome of latently infected human cell lines and by introducing InDel mutations, suppressing HIV-1 replication in patient-derived CD4+ T-cells, ex vivo. Here, we employed a short version of the Cas9 endonuclease, saCas9, together with a multiplex of guide RNAs (gRNAs) for targeting the viral DNA sequences within the 5'-LTR and the Gag gene for removing critically important segments of the viral DNA in transgenic mice and rats encompassing the HIV-1 genome...
August 2016: Gene Therapy
P N Matkar, H Leong-Poi, K K Singh
The incidence of cardiovascular disease (CVD) is increasing throughout the world and is associated with elevated morbidity and mortality. Gene therapy to treat cardiac dysfunction is gaining importance because of the limited therapeutic benefit offered by pharmacotherapies. The growing knowledge of the complex signaling pathways and the development of sophisticated vectors and delivery systems, are facilitating identification and targeting of specific molecular candidates involved in initiation and progression of CVDs...
August 2016: Gene Therapy
Q Lu, T H Ganjawala, E Ivanova, J G Cheng, D Troilo, Z-H Pan
Adeno-associated virus (AAV) vectors have been a powerful gene delivery vehicle to the retina for basic research and gene therapy. For many of these applications, achieving cell type-specific targeting and high transduction efficiency is desired. Recently, there has been increasing interest in AAV-mediated gene targeting to specific retinal bipolar cell types. A 200-bp enhancer in combination with a basal SV40 promoter has been commonly used to target transgenes into ON-type bipolar cells. In the current study, we searched for additional cis-regulatory elements in the mGluR6 gene for improving AAV-mediated transduction efficiency into retinal bipolar cells...
August 2016: Gene Therapy
E Bôle-Richard, C Gamonet, J-M Certoux, I Idirene, F Larosa, E Deconinck, A-M Mosseley, P Tiberghien, C Borg, C Ferrand, M Deschamps
Anti-tumor cellular immunotherapies that implement a suicide gene system can limit potential undesirable effects. In a haplo-identical bone marrow transplant clinical trial, over 90% of iCaspase-9-expressing cells were eradicated after AP1903 exposure, and signs of graft-versus-host disease disappeared. Nevertheless, low numbers of genetically modified T cells survived this treatment. We studied genetically modified cell lines (GMCL) that carried a dual iCaspase-9/ΔCD19 DNA construct (ΔCD19=truncated CD19)...
August 2016: Gene Therapy
M B Heckmann, R Bauer, A Jungmann, L Winter, K Rapti, K-H Strucksberg, C S Clemen, Z Li, R Schröder, H A Katus, O J Müller
Mutations of the human desmin (DES) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice...
August 2016: Gene Therapy
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