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adeno-associated viral

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https://www.readbyqxmd.com/read/28918027/adeno-associated-viral-vector-mediated-mtor-inhibition-by-short-hairpin-rna-suppresses-laser-induced-choroidal-neovascularization
#1
Tae Kwann Park, Si Hyung Lee, Jun Sub Choi, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Heuiran Lee, Steven Hyun Seung Lee, Keerang Park
Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28912572/follistatin-n-terminus-differentially-regulates-muscle-size-and-fat-in-vivo
#2
Hui Zheng, Chunping Qiao, Ruhang Tang, Jianbin Li, Karen Bulaklak, Zhenhua Huang, Chunxia Zhao, Yi Dai, Juan Li, Xiao Xiao
Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno-associated viral vector (AAV)...
September 15, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28902707/impact-of-human-ca8-on-thermal-antinociception-in-relation-to-morphine-equivalence-in-mice
#3
Eugene S Fu, Diana M Erasso, Gerald Z Zhuang, Udita Upadhyay, Mehtap Ozdemir, Timothy Wiltshire, Konstantinos D Sarantopoulos, Shad B Smith, William Maixner, Eden R Martin, Roy C Levitt
Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice...
September 11, 2017: Neuroreport
https://www.readbyqxmd.com/read/28895845/nonintegrating-gene-therapy-vectors
#4
REVIEW
Takis Athanasopoulos, Mustafa M Munye, Rafael J Yáñez-Muñoz
Gene delivery vectors that do not rely on host cell genome integration offer several advantages for gene transfer, chiefly the avoidance of insertional mutagenesis and position effect variegation. However, unless engineered for replication and segregation, nonintegrating vectors will dilute progressively in proliferating cells, and are not exempt of epigenetic effects. This article provides an overview of the main nonintegrating viral (adenoviral, adeno-associated viral, integration-deficient retro-lentiviral, poxviral), and nonviral (plasmid vectors, artificial chromosomes) vectors used for preclinical and clinical cell and gene therapy applications...
October 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28890324/direct-head-to-head-evaluation-of-recombinant-adeno-associated-viral-vectors-manufactured-in-human-versus-insect-cells
#5
Oleksandr Kondratov, Damien Marsic, Sean M Crosson, Hector R Mendez-Gomez, Oleksandr Moskalenko, Mario Mietzsch, Regine Heilbronn, Jonathan R Allison, Kari B Green, Mavis Agbandje-McKenna, Sergei Zolotukhin
The major drawback of the Baculovirus/Sf9 system for recombinant adeno-associated viral (rAAV) manufacturing is that most of the Bac-derived rAAV vector serotypes, with few exceptions, demonstrate altered capsid compositions and lower biological potencies. Here, we describe a new insect cell-based production platform utilizing attenuated Kozak sequence and a leaky ribosome scanning to achieve a serotype-specific modulation of AAV capsid proteins stoichiometry. By way of example, rAAV5 and rAAV9 were produced and comprehensively characterized side by side with HEK293-derived vectors...
August 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28888664/regulatory-t-cells-and-tlr9-activation-shape-antibody-formation-to-a-secreted-transgene-product-in-aav-muscle-gene-transfer
#6
Roland W Herzog, Mario Cooper, George Q Perrin, Moanaro Biswas, Ashley T Martino, Laurence Morel, Cox Terhorst, Brad E Hoffman
Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response...
August 1, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28882452/aav-php-b-mediated-global-scale-expression-in-the-mouse-nervous-system-enables-gba1-gene-therapy-for-wide-protection-from-synucleinopathy
#7
Giuseppe Morabito, Serena G Giannelli, Gabriele Ordazzo, Simone Bido, Valerio Castoldi, Marzia Indrigo, Tommaso Cabassi, Stefano Cattaneo, Mirko Luoni, Cinzia Cancellieri, Alessandro Sessa, Marco Bacigaluppi, Stefano Taverna, Letizia Leocani, José L Lanciego, Vania Broccoli
The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern...
August 10, 2017: Molecular Therapy: the Journal of the American Society of 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
#8
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/28851809/postnatal-cardiac-gene-editing-using-crispr-cas9-with-aav9-mediated-delivery-of-short-guide-rnas-results-in-mosaic-gene-disruption
#9
Anne K Johansen, Bas Molenaar, Danielle Versteeg, Ana R Leitoguinho, Charlotte J Demkes, Bastiaan Spanjaard, Hesther de Ruiter, Farhad A Akbari Moqadam, Lieneke Kooijman, Lorena Zentilin, Mauro Giacca, Eva van Rooij
Rationale: CRISPR/Cas9-based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. Objective: To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. Methods and Results: We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression...
August 29, 2017: Circulation Research
https://www.readbyqxmd.com/read/28842419/repulsive-guidance-molecule-a-rgma-induces-neuropathological-and-behavioral-changes-that-closely-resemble-parkinson-s-disease
#10
J A Korecka, E B Moloney, R Eggers, B Hobo, S Scheffer, N Ras-Verloop, R J Pasterkamp, D F Swaab, A B Smit, R E Van Kesteren, K Bossers, J Verhaagen
Repulsive guidance molecule member a (RGMa) is a membrane-associated or released guidance molecule that is involved in axon guidance, cell patterning and cell survival. In our previous work we showed that RGMa is significantly upregulated in the substantia nigra of patients with Parkinson's disease. Here we demonstrate the expression of RGMa in midbrain human dopaminergic neurons. To investigate whether RGMa might model aspects of the neuropathology of Parkinson's disease in mouse, we targeted RGMa to adult midbrain dopaminergic neurons using adeno-associated viral vectors...
August 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28841687/a-trp53fl-flptenfl-fl-mouse-model-of-undifferentiated-pleomorphic-sarcoma-mediated-by-adeno-cre-injection-and-in-vivo-bioluminescence-imaging
#11
Marisa R Buchakjian, Nicole M Merritt, Devon L Moose, Adam J Dupuy, Munir R Tanas, Michael D Henry
Genetic mouse models of soft tissue sarcoma provide critical insights into disease pathophysiology, which are oftentimes unable to be extracted from human tumor samples or xenograft models. In this study we describe a mouse model of soft tissue sarcoma mediated by adenoviral-Cre recombinase injection into Trp53fl/fl/Ptenfl/fl lox-stop-lox luciferase mice. Injection of adenovirus expressing Cre recombinase, either subcutaneously or intramuscularly in two experimental groups, results in viral infection and gene recombination with 100% penetrance within the first 24 hours following injection...
2017: PloS One
https://www.readbyqxmd.com/read/28835123/advances-in-gene-therapy-for-haemophilia
#12
Amit C Nathwani, Andrew M Davidoff, Edward G D Tuddenham
Gene therapy provides hope for a cure for patients with haemophilia by establishing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene copy to replace the haemophilic patient's own defective gene. Haemophilia may be considered a 'low hanging fruit' for gene therapy because a small increment in blood factor levels (≥2% of normal) significantly improves the bleeding tendency from severe to moderate, eliminating most spontaneous bleeds. After decades of research, the first trial to provide clear evidence of efficiency after gene transfer in patients with haemophilia B using adeno-associated viral (AAV) vectors was reported by our group in 2011...
August 23, 2017: Human 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
#13
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/28831096/inflammatory-cytokine-induced-changes-in-neural-network-activity-measured-by-waveform-analysis-of-high-content-calcium-imaging-in-murine-cortical-neurons
#14
Benjamin D S Clarkson, Robert J Kahoud, Christina B McCarthy, Charles L Howe
During acute neuroinflammation, increased levels of cytokines within the brain may contribute to synaptic reorganization that results in long-term changes in network hyperexcitability. Indeed, inflammatory cytokines are implicated in synaptic dysfunction in epilepsy and in an array of degenerative and autoimmune diseases of the central nervous system. Current tools for studying the impact of inflammatory factors on neural networks are either insufficiently fast and sensitive or require complicated and costly experimental rigs...
August 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28828391/minimal-purkinje-cell-specific-pcp2-l7-promoter-virally-available-for-rodents-and-non-human-primates
#15
Keisuke Nitta, Yasunori Matsuzaki, Ayumu Konno, Hirokazu Hirai
Cell-type-specific promoters in combination with viral vectors and gene-editing technology permit efficient gene manipulation in specific cell populations. Cerebellar Purkinje cells play a pivotal role in cerebellar functions. Although the Purkinje cell-specific L7 promoter is widely used for the generation of transgenic mice, it remains unsuitable for viral vectors because of its large size (3 kb) and exceedingly weak promoter activity. Here, we found that the 0.8-kb region (named here as L7-6) upstream of the transcription initiation codon in the first exon was alone sufficient as a Purkinje cell-specific promoter, presenting a far stronger promoter activity over the original 3-kb L7 promoter with a sustained significant specificity to Purkinje cells...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28825979/covalent-coupling-of-high-affinity-ligands-to-the-surface-of-viral-vector-particles-by-protein-trans-splicing-mediates-cell-type-specific-gene-transfer
#16
Alexander Muik, Johanna Reul, Thorsten Friedel, Anke Muth, Karen Patricia Hartmann, Irene C Schneider, Robert C Münch, Christian J Buchholz
We have established a novel approach for the covalent coupling of large polypeptides to the surface of fully assembled adeno-associated viral gene transfer vector (AAV) particles via split-intein mediated protein-trans-splicing (PTS). This way, we achieved selective gene transfer to distinct cell types. Single-chain variable fragments (scFvs) or designed ankyrin repeat proteins (DARPins), exhibiting high-affinity binding to cell surface receptors selectively expressed on the surface of target cells, were coupled to AAV particles harboring mutations in the capsid proteins which ablate natural receptor usage...
July 25, 2017: Biomaterials
https://www.readbyqxmd.com/read/28822689/cholesterol-lowering-gene-therapy-counteracts-the-development-of-non-ischemic-cardiomyopathy-in-mice
#17
Ilayaraja Muthuramu, Ruhul Amin, Andrey Postnov, Mudit Mishra, Joseph Pierre Aboumsallem, Tom Dresselaers, Uwe Himmelreich, Paul P Van Veldhoven, Olivier Gheysens, Frank Jacobs, Bart De Geest
A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.8% (p < 0.0001) reduction of plasma cholesterol compared with controls. Mortality rate was lower (p < 0.05) in AAV8-LDLr TAC mice compared with control TAC mice (hazard ratio for mortality 0...
August 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28820183/technique-of-retinal-gene-therapy-delivery-of-viral-vector-into-the-subretinal-space
#18
K Xue, M Groppe, A P Salvetti, R E MacLaren
PurposeSafe and reproducible delivery of gene therapy vector into the subretinal space is essential for successful targeting of the retinal pigment epithelium (RPE) and photoreceptors. The success of surgery is critical for the clinical efficacy of retinal gene therapy. Iatrogenic detachment of the degenerate (often adherent) retina in patients with hereditary retinal degenerations and small volume (eg, 0.1 ml) subretinal injections pose new surgical challenges.MethodsOur subretinal gene therapy technique involved pre-operative planning with optical coherence tomography (OCT) and autofluorescence (AF) imaging, 23 G pars plana vitrectomy, internal limiting membrane staining with Membrane Blue Dual (DORC BV, Zuidland, Netherlands), a two-step subretinal injection using a 41 G Teflon tipped cannula (DORC) first with normal saline to create a parafoveal bleb followed by slow infusion of viral vector via the same self-sealing retinotomy...
September 2017: Eye
https://www.readbyqxmd.com/read/28810808/advances-and-challenges-in-cardiovascular-gene-therapy
#19
Seppo Ylä-Herttuala, Johanna Lähteenvuo
25 years of gene therapy have not yet yielded standard therapeutic solutions for clinical use in cardiovascular medicine, but several therapeutic targets have been identified and foundations for future therapies have been set. The safety of viral gene therapy has been established with a wide variety of vectors and transgenes. Adenoviruses and adeno-associated viruses have established their role as vectors of choice for many cardiovascular applications and appropriate viral doses have been established for several tissues and applications...
August 16, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28809089/inverted-quasi-spherical-droplets-on-polydopamine-tio2-substrates-for-enhancing-gene-delivery
#20
Seung-Hyun Kim, Mihyun Lee, Mira Cho, Il-Sun Kim, Kook In Park, Haeshin Lee, Jae-Hyung Jang
Devising efficient gene delivery systems is crucial to enhancing the therapeutic efficacy of gene-cell therapy approaches. Herein, inverted quasi-spherical (iQS) droplet systems, which enhance gene delivery efficiencies by reducing the path lengths of gene vectors, mediating motions of vectors at early stages, and raising the contact frequencies of vectors with cells, are developed by adopting the principle of 3D hanging-drop cell culture. Micrometer-sized polydopamine (pDA) holes are created on superhydrophobic titanium isopropoxide (TiO2 )-coated substrates by physical scraping; droplets are loaded on the pDA holes, and inversion of the substrate generates iQS droplets with large contact angles...
August 15, 2017: Macromolecular Bioscience
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