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https://www.readbyqxmd.com/read/29217509/macrophage-associated-lipin-1-enzymatic-activity-contributes-to-modified-low-density-lipoprotein-induced-proinflammatory-signaling-and-atherosclerosis
#1
Aimee E Vozenilek, Aaron R Navratil, Jonette M Green, David T Coleman, Cassidy M R Blackburn, Alexandra C Finney, Brenna H Pearson, Roman Chrast, Brian N Finck, Ronald L Klein, A Wayne Orr, Matthew D Woolard
OBJECTIVE: Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine whether macrophage-associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages...
December 7, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29212407/-express-rna-interference-based-functional-knockdown-of-the-voltage-gated-potassium-channel-kv7-2-in-dorsal-root-ganglion-neurons-after-in-vitro-and-in-vivo-gene-transfer-by-adeno-associated-virus-aav-vectors
#2
Markus Valdor, Anke Wagner, Viola Roehrs, Johanna Berg, Henry Fechner, Wolfgang Schroeder, Gregor Bahrenberg, Thomas Tzschentke, Thomas Christoph, Jens Kurreck
No abstract text is available yet for this article.
January 1, 2017: Molecular Pain
https://www.readbyqxmd.com/read/29212391/gene-therapy-successfully-delays-degeneration-in-a-mouse-model-of-pde6a-linked-retinitis-pigmentosa-rp-43
#3
Christian Schön, Vithiyanjali Sothilingam, Regine Mühlfriedel, Marina Garcia Garrido, Susanne C Beck, Naoyuki Tanimoto, Bernd Wissinger, François Paquet-Durand, Martin Biel, Stylianos Michalakis, Mathias W Seeliger, Rd-Cure Consortium
Retinitis pigmentosa type 43 (RP43) is a blinding disease caused by mutations in the gene for rod phosphodiesterase 6 alpha (PDE6A). The disease process begins with a dysfunction of rod photoreceptors, subsequently followed by a currently untreatable progressive degeneration of the entire outer retina. Aiming at a curative approach via PDE6A gene supplementation, we developed a novel adeno-associated viral (AAV) vector for expression of the human PDE6A cDNA under control of the human rhodopsin promotor (rAAV8...
December 7, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29212382/gene-supplementation-rescues-rod-function-and-preserves-photoreceptor-and-retinal-morphology-in-dogs-leading-the-way-towards-treating-human-pde6a-retinitis-pigmentosa
#4
Laurence M Occelli, Christian Schön, Mathias W Seeliger, Martin Biel, Stylianos Michalakis, Simon Petersen-Jones, Rd-Cure Consortium
Mutations in the phosphodiesterase 6A gene (PDE6A) result in retinitis pigmentosa type 43 (RP43) and are responsible for about 4% of autosomal recessive RP. There is currently no treatment for this blinding condition. The aim of this project was to use a large animal model to test a gene supplementation viral vector designed to be translated for use in a clinical trial for the treatment of RP43. Seven Pde6a<sup>-/-</sup> puppies were given subretinal injections of an adeno-associated viral vector serotype 2/8 delivering human PDE6A cDNA under control of a short rhodopsin promoter (AAV8-PDE6A)...
December 6, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29211814/overexpression-of-transmembrane-protein-168-in-the-mouse-nucleus-accumbens-induces-anxiety-and-sensorimotor-gating-deficit
#5
Kequan Fu, Yoshiaki Miyamoto, Kazuyuki Sumi, Eriko Saika, Shin-Ichi Muramatsu, Kyosuke Uno, Atsumi Nitta
Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice)...
2017: PloS One
https://www.readbyqxmd.com/read/29211678/hemophilia-b-gene-therapy-with-a-high-specific-activity-factor-ix-variant
#6
Lindsey A George, Spencer K Sullivan, Adam Giermasz, John E J Rasko, Benjamin J Samelson-Jones, Jonathan Ducore, Adam Cuker, Lisa M Sullivan, Suvankar Majumdar, Jerome Teitel, Catherine E McGuinn, Margaret V Ragni, Alvin Y Luk, Daniel Hui, J Fraser Wright, Yifeng Chen, Yun Liu, Katie Wachtel, Angela Winters, Stefan Tiefenbacher, Valder R Arruda, Johannes C M van der Loo, Olga Zelenaia, Daniel Takefman, Marcus E Carr, Linda B Couto, Xavier M Anguela, Katherine A High
BACKGROUND: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS: We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value...
December 7, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29208777/short-a%C3%AE-peptides-attenuate-a%C3%AE-42-toxicity-in-vivo
#7
Brenda D Moore, Jason Martin, Lorena de Mena, Jonatan Sanchez, Pedro E Cruz, Carolina Ceballos-Diaz, Thomas B Ladd, Yong Ran, Yona Levites, Thomas L Kukar, Justin J Kurian, Robert McKenna, Edward H Koo, David R Borchelt, Christopher Janus, Diego Rincon-Limas, Pedro Fernandez-Funez, Todd E Golde
Processing of amyloid-β (Aβ) precursor protein (APP) by γ-secretase produces multiple species of Aβ: Aβ40, short Aβ peptides (Aβ37-39), and longer Aβ peptides (Aβ42-43). γ-Secretase modulators, a class of Alzheimer's disease therapeutics, reduce production of the pathogenic Aβ42 but increase the relative abundance of short Aβ peptides. To evaluate the pathological relevance of these peptides, we expressed Aβ36-40 and Aβ42-43 in Drosophila melanogaster to evaluate inherent toxicity and potential modulatory effects on Aβ42 toxicity...
December 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29204900/molecular-design-for-recombinant-adeno-associated-virus-raav-vector-production
#8
REVIEW
Juan Jose Aponte-Ubillus, Daniel Barajas, Joseph Peltier, Cameron Bardliving, Parviz Shamlou, Daniel Gold
Recombinant adeno-associated virus (rAAV) vectors are increasingly popular tools for gene therapy applications. Their non-pathogenic status, low inflammatory potential, availability of viral serotypes with different tissue tropisms, and prospective long-lasting gene expression are important attributes that make rAAVs safe and efficient therapeutic options. Over the last three decades, several groups have engineered recombinant AAV-producing platforms, yielding high titers of transducing vector particles. Current specific productivity yields from different platforms range from 103 to 105 vector genomes (vg) per cell, and there is an ongoing effort to improve vector yields in order to satisfy high product demands required for clinical trials and future commercialization...
December 4, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29204648/aav-crispr-cas9-mediated-depletion-of-vegfr2-blocks-angiogenesis-in-vitro
#9
Wenyi Wu, Yajian Duan, Gaoen Ma, Guohong Zhou, Cindy Windhol, Patricia A D'Amore, Hetian Lei
Purpose: Pathologic angiogenesis is a component of many diseases, including neovascular age-related macular degeneration, proliferation diabetic retinopathy, as well as tumor growth and metastasis. The purpose of this project was to examine whether the system of adeno-associated viral (AAV)-mediated CRISPR (clustered regularly interspaced short palindromic repeats)-associated endonuclease (Cas)9 can be used to deplete expression of VEGF receptor 2 (VEGFR2) in human vascular endothelial cells in vitro and thus suppress its downstream signaling events...
December 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29204184/viral-cre-loxp-tools-aid-genome-engineering-in-mammalian-cells
#10
Ranjita Sengupta, Amy Mendenhall, Nandita Sarkar, Chandreyee Mukherjee, Amirali Afshari, Joseph Huang, Biao Lu
Background: Targeted nucleases have transformed genome editing technology, providing more efficient methods to make targeted changes in mammalian genome. In parallel, there is an increasing demand of Cre-LoxP technology for complex genome manipulation such as large deletion, addition, gene fusion and conditional removal of gene sequences at the target site. However, an efficient and easy-to-use Cre-recombinase delivery system remains lacking. Results: We designed and constructed two sets of expression vectors for Cre-recombinase using two highly efficient viral systems, the integrative lentivirus and non-integrative adeno associated virus...
2017: Journal of Biological Engineering
https://www.readbyqxmd.com/read/29202463/patients-and-animal-models-of-cng%C3%AE-1-deficient-retinitis-pigmentosa-support-gene-augmentation-approach
#11
Simon M Petersen-Jones, Laurence M Occelli, Paige A Winkler, Winston Lee, Janet R Sparrow, Mai Tsukikawa, Sanford L Boye, Vince Chiodo, Jenina E Capasso, Elvir Becirovic, Christian Schön, Mathias W Seeliger, Alex V Levin, Stylianos Michalakis, William W Hauswirth, Stephen H Tsang
Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease...
November 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29199855/the-hierarchy-of-proinflammatory-cytokines-in-ocular-inflammation
#12
A P Da Cunha, Q Zhang, M Prentiss, X Q Wu, V Kainz, Y Y Xu, J Vrouvlianis, H Li, N Rangaswamy, B Leehy, T L McGee, C L Bell, C E Bigelow, V Kansara, Q Medley, Q Huang, H Y Wu
PURPOSE: The concept of tissue-dependent cytokine hierarchy has been demonstrated in a number of diseases, but it has not been investigated in ophthalmic diseases. Here, we evaluated the functional hierarchy of interleukin-1β (IL-1β), IL-6, IL-17A, and tumor necrosis factor (TNF) in the induction of ocular inflammation. MATERIALS AND METHODS: We delivered adeno-associated virus (AAV) vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer...
December 4, 2017: Current Eye Research
https://www.readbyqxmd.com/read/29195742/preclinical-models-to-assess-the-immunogenicity-of-aav-vectors
#13
Hildegund C J Ertl
Although gene transfer using adeno-associated virus (AAV) vectors has made tremendous progress in recent years, challenges remain due to vector-specific adaptive immune responses. Specifically, AAV-neutralizing antibodies reduce AAV-transduction rates, while CD8+ T cells directed to AAV capsid antigens cause rejection of AAV-transduced cells. This has been addressed clinically by excluding humans with pre-existing AAV-neutralizing antibodies from gene transfer trials or by using immunosuppression or reduced doses of vectors expressing improved transgene products to blunt or circumvent destructive T cell responses...
November 23, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/29192808/a-splice-site-variant-in-flvcr1-produces-retinitis-pigmentosa-without-posterior-column-ataxia
#14
Imran H Yusuf, Morag E Shanks, Penny Clouston, Robert E MacLaren
FLVCR1 (feline leukemia virus subgroup c receptor 1) is a transmembrane protein involved in the trafficking of intracellular heme. Homozygous variants in FLVCR1 have been described in association with a clinical syndrome of posterior column ataxia with retinitis pigmentosa (PCARP). Here, we describe a patient with non-syndromic retinitis pigmentosa homozygous for a splice-site variant in FLVCR1 (c.1092 + 5G>A) without evidence of posterior column ataxia or cerebellar degeneration. We suggest an association between intronic splice-site variants in FLVCR1 and the absence of posterior column degeneration and suggest a hypothesis to explain this observation...
December 1, 2017: Ophthalmic Genetics
https://www.readbyqxmd.com/read/29191939/effects-of-hypothalamic-leptin-gene-therapy-on-osteopetrosis-in-leptin-deficient-mice
#15
Kenneth A Philbrick, Stephen A Martin, Amy R Colagiovanni, Adam J Branscum, Russell T Turner, Urszula T Iwaniec
Impaired resorption of cartilage matrix deposited during endochondral ossification is a defining feature of juvenile osteopetrosis. Growing, leptin-deficient ob/ob mice exhibit a mild form of osteopetrosis. However, the extent to which the disease is (1) self-limiting and (2) reversible by leptin treatment is unknown. We addressed the first question by performing histomorphometric analysis of femurs in rapidly growing (2-month-old), slowly growing (4-month-old), and skeletally mature (6-month-old) wild type (WT) and ob/ob male mice...
November 30, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/29191753/melanin-concentrating-hormone-acts-through-hypothalamic-kappa-opioid-system-and-p70s6k-to-stimulate-acute-food-intake
#16
Amparo Romero-Picó, Estrella Sanchez-Rebordelo, Monica Imbernon, David González-Touceda, Cintia Folgueira, Ana Senra, Johan Fernø, Clémence Blouet, Roberto Cabrera, Margriet van Gestel, Roger A Adan, Miguel López, Rafael Maldonado, Ruben Nogueiras, Carlos Diéguez
Melanin-Concentrating Hormone (MCH) is one of the most relevant orexigenic factors specifically located in the lateral hypothalamic area (LHA), with its physiological relevance demonstrated in studies using several genetically manipulated mice models. However, the central mechanisms controlling MCH-induced hyperphagia remain largely uncharacterized. Here, we show that central injection of MCH in mice deficient for kappa opoid receptor (k-OR) failed to stimulate feeding. To determine the hypothalamic area responsible for this MCH/k-OR interaction, we performed virogenetic studies and found that downregulation of k-OR by adeno-associated viruses (shOprk1-AAV) in LHA, but not in other hypothalamic nuclei, was sufficient to block MCH-induced food intake...
December 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29191327/optogenetic-modulation-of-cardiac%C3%A2-sympathetic-nerve-activity-to%C3%A2-prevent-ventricular%C3%A2-arrhythmias
#17
Lilei Yu, Liping Zhou, Gang Cao, Sunny S Po, Bing Huang, Xiaoya Zhou, Menglong Wang, Shenxu Yuan, Zhuo Wang, Songyun Wang, Hong Jiang
BACKGROUND: Studies have shown that left stellate ganglion (LSG) suppression protects against ventricular arrhythmias (VAs). Optogenetics is a novel technique to reversibly regulate the activity of the targeted neurons. OBJECTIVES: This study aimed to investigate whether an optogenetically silenced LSG could protect against VAs induced by myocardial ischemia. METHODS: Adeno-associated virus (AAV) was used as the vector to deliver ArchT, an inhibitory light-sensitive opsin, to the LSG neurons...
December 5, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/29188522/human-retinal-explant-culture-for-ex-vivo-validation-of-aav-gene-therapy
#18
Harry O Orlans, Thomas L Edwards, Samantha R De Silva, Maria I Patrício, Robert E MacLaren
Recombinant adeno-associated viral (AAV) vectors have been successfully employed as the mode of gene delivery in several clinical trials for the treatment of inherited retinal diseases to date. The design of such vectors is critical in determining cellular tropism and level of subsequent gene expression that may be achieved following viral delivery. Here we describe a system for living retinal tissue extraction, ex vivo culture, viral transduction and assessment of transgene expression that may be used to assess viral constructs for gene therapy in the human retina at a preclinical stage...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29188521/aav-serotype-testing-on-cultured-human-donor-retinal-explants
#19
Thilo M Buck, Lucie P Pellissier, Rogier M Vos, Elon H C van Dijk, Camiel J F Boon, Jan Wijnholds
This protocol details on a screening method for infectivity and tropism of different serotypes of adeno-associated viruses (AAVs) on human retinal explants with cell-type specific or ubiquitous green fluorescent protein (GFP) expression vectors. Eyes from deceased adult human donors are enucleated and the retinas are isolated. Each retina is punched into eight to ten 6-mm equal pieces. Whatman™ paper punches are placed on the retinas and the stack is transferred onto 24-well culture inserts with the photoreceptors facing the membrane...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29188520/production-of-ips-derived-human-retinal-organoids-for-use-in-transgene-expression-assays
#20
Peter M Quinn, Thilo M Buck, Charlotte Ohonin, Harald M M Mikkers, Jan Wijnholds
In vitro retinal organoid modeling from human pluripotent stem cells is becoming more common place in many ophthalmic laboratories worldwide. These organoids mimic human retinogenesis through formation of organized layered retinal structures that display markers for typical retinal cell types. Pivotally these humanized retinal models provide a stepping stone to the clinic as therapeutic tools and are expected to provide a promising alternative to current animal models. Thus pluripotent stem cell based healthy as well as diseased human retinal organoids are attractive for use in drug potency assays and gene augmentation therapeutics...
2018: Methods in Molecular Biology
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