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Gene Therapy

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https://www.readbyqxmd.com/read/29143813/ship1-but-not-an-aml-derived-ship1-mutant-suppresses-myeloid-leukemia-growth-in-a-xenotransplantation-mouse-model
#1
M Täger, S Horn, E Latuske, P Ehm, M Schaks, M Nalaskowski, B Fehse, W Fiedler, C Stocking, J Wellbrock, M Jücker
Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model...
November 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/29106404/strategy-to-detect-pre-existing-immunity-to-aav-gene-therapy
#2
L Falese, K Sandza, B Yates, S Triffault, S Gangar, B Long, L Tsuruda, B Carter, C Vettermann, S J Zoog, S Fong
Gene therapy may offer a new treatment option, particularly for patients with severe hemophilia, based on recent research. However, individuals with pre-existing immunity to adeno-associated viruses (AAVs) may be less likely to benefit from AAV vector-based therapies. To study pre-existing AAV5 immunity in humans, we validated two complementary, sensitive, and scalable in vitro assays to detect AAV5 total antibodies and transduction inhibition (TI). Using these two assays, we found that 53% of samples from 100 healthy male individuals were negative in both assays, 18% were positive in both assays, 5% were positive for total antibodies but negative for TI and, of interest, 24% were negative for total antibodies but positive for TI activity, suggesting the presence of non-antibody‒based neutralizing factors in human plasma...
November 6, 2017: Gene Therapy
https://www.readbyqxmd.com/read/29106403/adipose-tissue-a-new-target-for-electroporation-enhanced-dna-vaccines
#3
P D Fisher, C J Brambila, J R McCoy, W B Kiosses, J M Mendoza, J Oh, B S Yung, K Schultheis, T R F Smith, K E Broderick
DNA vaccines delivered using electroporation (EP) have had clinical success, but these EP methods generally utilize invasive needle electrodes. Here, we demonstrate the delivery and immunogenicity of a DNA vaccine into subcutaneous adipose tissue cells using noninvasive EP. Using finite element analysis, we predicted that plate electrodes, when oriented properly, could effectively concentrate the electric field within adipose tissue. In practice, these electrodes generated widespread gene expression persisting for at least 60 days in vivo within interscapular subcutaneous fat pads of guinea pigs...
November 6, 2017: Gene Therapy
https://www.readbyqxmd.com/read/29057994/effects-of-herpes-simplex-virus-vectors-encoding-poreless-trpv1-or-protein-phosphatase-1%C3%AE-in-a-rat-cystitis-model-induced-by-hydrogen-peroxide
#4
S Takai, T Majima, B Reinhart, W F Goins, Y Funahashi, M Gotoh, P Tyagi, J C Glorioso, N Yoshimura
Enhanced afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS). In addition, transient receptor potential vanilloid-1 (TRPV1) receptors are known to be involved in afferent sensitization. Animals with hydrogen peroxide (HP)-induced cystitis have been used as a model exhibiting pathologic characteristics of chronic inflammatory condition of the bladder. This study investigated the effect of gene therapy with replication-defective herpes simplex virus (HSV) vectors encoding poreless TRPV1 (PL) or protein phosphatase 1 α (PP1α), a negative regulator of TRPV1, using a HP-induced rat model of cystitis...
October 20, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28984845/site-directed-rna-editing-by-adenosine-deaminase-acting-on-rna-adar1-for-correction-of-the-genetic-code-in-gene-therapy
#5
T A Azad, S Bhakta, T Tsukahara
Site-directed RNA editing is an important technique for correcting gene sequences and ultimately tuning protein function. In this study, we engineered the deaminase domain of adenosine deaminase acting on RNA (ADAR1) and the MS2 system to target specific adenosines, with the goal of correcting G-to-A mutations at the RNA level. For this purpose, the ADAR1 deaminase domain was fused downstream of the RNA-binding protein MS2, which has affinity for the MS2 RNA. To direct editing to specific targets, we designed guide RNAs complementary to target RNAs...
October 6, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28937681/primary-t-cells-for-mrna-mediated-immunotoxin-delivery
#6
R Eggers, A Philippi, M O Altmeyer, F Breinig, M J Schmitt
Immune cells become increasingly attractive as delivery system for immunotoxins in cancer therapy in order to reduce the intrinsic toxicity and severe side effects of chimeric protein toxins. In this study, we investigated the potential of human primary T cells to deliver a secreted immunotoxin through transient mRNA transfection. The chimeric protein toxin was directed towards the neovasculature of cancer cells by fusing a truncated version of Pseudomonas exotoxin A (PE38) to human vascular endothelial growth factor (VEGF) and to the single chain variable fragment (scFv) of anti-Her2/neu...
September 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28925992/efficacy-of-combining-ing4-and-trail-genes-in-cancer-targeting-gene-virotherapy-strategy-first-evidence-in-preclinical-hepatocellular-carcinoma
#7
A G El-Shemi, A M Ashshi, E Oh, B-K Jung, M Basalamah, A Alsaegh, C-O Yun
Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4); as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); as potent-apoptosis inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono-and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC...
September 19, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28905887/an-efficient-non-viral-dendritic-vector-for-gene-delivery-in-tissue-engineering
#8
D P Walsh, A Heise, F J O'Brien, S-A Cryan
Recent developments within the field of tissue engineering (TE) have shown that biomaterial scaffold systems can be augmented via the incorporation of gene therapeutics. The objective of this study was to assess the potential of the activated polyamidoamine dendrimer (dPAMAM) transfection reagent (Superfect(TM)) as a gene delivery system to mesenchymal stem cells (MSCs) in both monolayer and 3D culture on collagen based scaffolds. dPAMAM-pDNA polyplexes at a mass ratio (M:R) 10:1 (dPAMAM : pDNA) (1 ug pDNA) were capable of facilitating prolonged reporter gene expression in monolayer MSCs which was superior to that facilitated using polyethylenimine (PEI)-pDNA polyplexes (2 ug pDNA)...
September 14, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28905885/long-term-correction-of-hemophilia-a-mice-following-lentiviral-mediated-delivery-of-an-optimized-canine-factor-viii-gene
#9
J M Staber, M J Pollpeter, C-G Anderson, M Burrascano, A L Cooney, P L Sinn, D T Rutkowski, W C Raschke, P B McCray
Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes...
September 14, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28880021/long-term-expression-of-melanopsin-and-channelrhodopsin-causes-no-gross-alterations-in-the-dystrophic-dog-retina
#10
B Ameline, K-T Tshilenge, M Weber, M Biget, L Libeau, R Caplette, A Mendes-Madeira, N Provost, C Guihal, S Picaud, P Moullier, V Pichard, T Cronin, C Isiegas
Several preclinical studies have investigated the potential of algal channelrhodopsin and human melanopsin as optogenetic tools for vision restoration. In the present study, we assessed the potentially deleterious effects of long-term expression of these optogenes on the diseased retina in a large animal model of retinal degeneration, the RPE65-deficient Briard dog model of Leber congenital amaurosis. Intravitreal injection of adeno-associated virus vectors expressing channelrhodopsin and melanopsin had no effect on retinal thickness over a 16-month period post injection...
September 7, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28880019/market-access-of-spinraza-nusinersen-for-spinal-muscular-atrophy-intellectual-property-rights-pricing-value-and-coverage-considerations
#11
S Simoens, I Huys
No abstract text is available yet for this article.
September 7, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28880018/spinraza-the-patient-perspective
#12
S Madipalli
No abstract text is available yet for this article.
September 7, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28880017/will-rising-prices-and-budget-constraints-prevent-patients-from-accessing-novel-gene-therapies
#13
A Kent, J Spink
No abstract text is available yet for this article.
September 7, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28726798/gene-therapy-research-in-asia
#14
REVIEW
H-X Deng, Y Wang, Q-R Ding, D-L Li, Yu-Quan Wei
Gene therapy has shown great potential for the treatment of diseases that previously were either untreatable or treatable but not curable with conventional schemes. Recent progress in clinical gene therapy trials has emerged in various severe diseases, including primary immunodeficiencies, leukodystrophies, Leber's congenital amaurosis, haemophilia, as well as retinal dystrophy. The clinical transformation and industrialization of gene therapy in Asia have been remarkable and continue making steady progress...
September 7, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28872643/tropism-of-engineered-and-evolved-recombinant-aav-serotypes-in-the-rd1-mouse-and-ex-vivo-primate-retina
#15
D G Hickey, T L Edwards, A R Barnard, M S Singh, S R de Silva, M E McClements, J G Flannery, M W Hankins, R E MacLaren
There is much debate on the adeno-associated virus (AAV) serotype that best targets specific retinal cell types and the route of surgical delivery-intravitreal or subretinal. This study compared three of the most efficacious AAV vectors known to date in a mouse model of retinal degeneration (rd1 mouse) and macaque and human retinal explants. GFP driven by a ubiquitous promoter was packaged into three AAV capsids: AAV2/8(Y733F), AAV2/2(quad Y-F) and AAV2/2(7m8). Overall AAV2/2(7m8) transduced the largest area of retina and resulted in the highest level of GFP expression, followed by AAV2/2(quad Y-F) and AAV2/8(Y733F)...
September 5, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28853717/in-utero-delivery-of-raav2-9-induces-neuronal-expression-of-the-transgene-in-the-brain-towards-new-models-of-parkinson-s-disease
#16
L Chansel-Debordeaux, M Bourdenx, S Dovero, V Grouthier, N Dutheil, A Espana, L Groc, C Jimenez, E Bezard, B Dehay
Animal models are essential tools for basic pathophysiological research as well as validation of therapeutic strategies for curing human diseases. However, technical difficulties associated with classical transgenesis approaches in rodent species higher than mus musculus have prevented this long-awaited development. The availability of viral-mediated gene delivery systems in the past few years has stimulated the production of viruses with unique characteristics. For example, the recombinant adeno-associated virus serotype 9 (rAAV2/9) crosses the blood-brain barrier, is capable of transducing developing cells and neurons after intravenous injection and mediates long-term transduction...
August 30, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28846076/a-new-combination-therapy-for-asthma-using-dual-function-dexamethsone-conjugated-polyethylenimine-and-vitamin-d-binding-protein-sirna
#17
M Choi, J Gu, M Lee, T Rhim
Asthma is a multifactorial disease that is influenced by the interaction of genetic and environmental factors. Due to its complex nature, there is no cure for asthma currently. Instead, reliever and controller medications are used to treat asthma. Unfortunately, conventional treatments do not work in some severe cases of asthma. In addition, there may be adverse, systemic effects of long-term treatment with high-dose inhaled corticosteroids as a controller medication. Therefore, we attempted to develop a novel combination therapy for asthma...
August 28, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28832561/stent-based-delivery-of-adeno-associated-viral-vectors-with-sustained-vascular-transduction-and-inos-mediated-inhibition-of-in-stent-restenosis
#18
I Fishbein, D T Guerrero, I S Alferiev, J B Foster, N G Minutolo, M Chorny, A M Monteys, K H Driesbaugh, C Nagaswami, R J Levy
In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab)...
August 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28905886/time-series-oligonucleotide-count-to-assign-antiviral-sirnas-with-long-utility-fit-in-the-big-data-era
#19
K Wada, Y Wada, Y Iwasaki, T Ikemura
Oligonucleotides are key elements of nucleic acid therapeutics such as small interfering RNAs (siRNAs). Influenza and Ebolaviruses are zoonotic RNA viruses mutating very rapidly, and their sequence changes must be characterized intensively to design therapeutic oligonucleotides with long utility. Focusing on a total of 182 experimentally validated siRNAs for influenza A, B and Ebolaviruses compiled by the siRNA database, we conducted time-series analyses of occurrences of siRNA targets in these viral genomes...
October 2017: Gene Therapy
https://www.readbyqxmd.com/read/28880020/novel-gp64-envelope-variants-for-improved-delivery-to-human-airway-epithelial-cells
#20
P L Sinn, B-Y Hwang, N Li, J L S Ortiz, E Shirazi, K R Parekh, A L Cooney, D V Schaffer, P B McCray
Lentiviral vectors pseudotyped with the baculovirus envelope protein GP64 transduce primary cultures of human airway epithelia (HAE) at their apical surface. Our goal in this study was to harness a directed evolution approach to develop a novel envelope glycoprotein with increased transduction properties for HAE. Using error-prone PCR, a library of GP64 mutants was generated and used to prepare a diverse pool of lentiviral virions pseudotyped with GP64 variants. The library was serially passaged on HAE and three GP64 mutations were recovered...
October 2017: Gene Therapy
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