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adeno associated virus

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https://www.readbyqxmd.com/read/29155726/visualization-and-live-imaging-of-oligodendrocyte-organelles-in-organotypic-brain-slices-using-adeno-associated-virus-and-confocal-microscopy
#1
Lauritz Hagen Kennedy, Johanne Egge Rinholm
Neurons rely on the electric insulation and trophic support of myelinating oligodendrocytes. Despite the importance of oligodendrocytes, the advanced tools currently used to study neurons, have only partly been taken on by oligodendrocyte researchers. Cell type-specific staining by viral transduction is a useful approach to study live organelle dynamics. This paper describes a protocol for visualizing oligodendrocyte mitochondria in organotypic brain slices by transduction with adeno-associated virus (AAV) carrying genes for mitochondrial targeted fluorescent proteins under the transcriptional control of the myelin basic protein promoter...
October 23, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29154962/a-novel-type-2-diabetes-mouse-model-of-combined-diabetic-kidney-disease-and-atherosclerosis
#2
Karin E Bornfeldt, Farah Kramer, Anna Batorsky, Jinkuk Choi, Kelly L Hudkins, Peter Tontonoz, Charles E Alpers, Jenny E Kanter
Diabetic kidney disease and atherosclerotic disease are major causes of morbidity and mortality associated with type 2 diabetes (T2D), and diabetic kidney disease is a major cardiovascular risk factor. The BTBR mouse strain with leptin-deficiency (Lep(ob)) has emerged as one of the best models of human diabetic kidney disease. However, no T2D mouse model of combined diabetic kidney disease and atherosclerosis exists. Our goal was to generate such a model. To this end, the LDL receptor was targeted for degradation via IDOL (inducible degrader of the LDL receptor) overexpression, using a liver-targeted adeno-associated virus (AAV-DJ/8) in BTBR wild-type (WT) and BTBR Lep(ob) (OB) mice...
November 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29149775/lentiviral-vectors-and-adeno-associated-virus-vectors-useful-tools-for-gene-transfer-in-pain-research
#3
REVIEW
Zheng Chen-Xi, Wang Sheng-Ming, Bai Yun-Hu, Luo Ting-Ting, Wang Jia-Qi, Dai Chun-Qiu, Guo Bao-Lin, Luo Shi-Cheng, Wang Dong-Hui, Yang Yan-Ling, Wang Ya-Yun
Pain, especially chronic pain, has always been a heated point in both basic and clinical researches since it puts heavy burdens on both individuals and the whole society. A better understanding of the role of biological molecules and various ionic channels involved in pain can shed light on the mechanism under pain and advocate the development of pain management. Using viral vectors to transfer specific genes at targeted sites is a promising method for both research and clinical applications. Lentiviral vectors and adeno-associated virus (AAV) vectors which allow stable and long-term expression of transgene in non-dividing cells are widely applied in pain research...
November 17, 2017: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
https://www.readbyqxmd.com/read/29143862/a20-prevents-obesity-induced-development-of-cardiac-dysfunction
#4
Wenjing Xu, Cheng Wang, Minglu Liang, Long Chen, Qin Fu, Fengxiao Zhang, Yan Wang, Dan Huang, Kai Huang
Obesity and an increased free fatty acid (FFA) level are tightly linked, leading to aberrant oxidative stress, inflammation, apoptosis, and progression to cardiovascular disorders. A20 is a ubiquitin-modifying enzyme that plays a significant role in the negative regulation of inflammatory response. Here, we study the role of A20 in obesity-induced heart injury and explore the underlying mechanisms. A20 expression was first increased in mouse hearts after 4 weeks of a high-fat diet (HFD) and then was gradually decreased in the following 20 weeks...
November 16, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29141633/genome-modification-of-cxcr4-by-staphylococcus-aureus-cas9-renders-cells-resistance-to-hiv-1-infection
#5
Qiankun Wang, Shuliang Chen, Qiaoqiao Xiao, Zhepeng Liu, Shuai Liu, Panpan Hou, Li Zhou, Wei Hou, Wenzhe Ho, Chunmei Li, Li Wu, Deyin Guo
BACKGROUND: The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4)-tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4(+) T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question...
November 15, 2017: Retrovirology
https://www.readbyqxmd.com/read/29141514/regulatory-effect-of-neuroglobin-in-the-recovery-of-spinal-cord-injury
#6
Ji-Lin Dai, Yun Lin, Yong-Jian Yuan, Shi-Tong Xing, Yi Xu, Qiang-Hua Zhang, Ji-Kang Min
OBJECTIVE: The present study was aimed to investigate the therapeutic potential of neuroglobin in the recovery of spinal cord injury. METHODS: The male albino Wistar strain rats were used as an experimental model, and adeno associated virus (AAV) was administered in the T12 section of spinal cord ten days prior to the injury. Basso Beattie Bresnahan (BBB) locomotor rating scale was used to determine the recovery of the hind limb during four weeks post-operation...
November 16, 2017: Journal of Spinal Cord Medicine
https://www.readbyqxmd.com/read/29140568/crispr-cas9-based-safe-harbor-gene-editing-in-rhesus-ipscs
#7
Ravi Chandra Yada, John W Ostrominski, Ilker Tunc, So Gun Hong, Jizhong Zou, Cynthia E Dunbar
NHP iPSCs provide a unique opportunity to test safety and efficacy of iPSC-derived therapies in clinically relevant NHP models. To monitor these cells in vivo, there is a need for safe and efficient labeling methods. Gene insertion into genomic safe harbors (GSHs) supports reliable transgene expression while minimizing the risk the modification poses to the host genome or target cell. Specifically, this protocol demonstrates targeting of the adeno-associated virus site 1 (AAVS1), one of the most widely used GSH loci in the human genome, with CRISPR/Cas9, allowing targeted marker or therapeutic gene insertion in rhesus macaque induced pluripotent stem cells (RhiPSCs)...
November 15, 2017: Current Protocols in Stem Cell Biology
https://www.readbyqxmd.com/read/29138513/foxa2-alleviates-ccl4-induced-liver-fibrosis-by-protecting-hepatocytes-in-mice
#8
Wei Wang, Li-Jia Yao, Weifeng Shen, Kai Ding, Pei-Mei Shi, Fei Chen, Jin He, Jin Ding, Xin Zhang, Wei-Fen Xie
The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSCs) of mouse fibrotic livers...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29136012/regional-knockdown-of-ndufs4-implicates-a-thalamocortical-circuit-mediating-anesthetic-sensitivity
#9
Renjini Ramadasan-Nair, Jessica Hui, Pavel I Zimin, Leslie S Itsara, Philip G Morgan, Margaret M Sedensky
Knockout of the mitochondrial complex I protein, NDUFS4, profoundly increases sensitivity of mice to volatile anesthetics. In mice carrying an Ndufs4lox/lox gene, adeno-associated virus expressing Cre recombinase was injected into regions of the brain postulated to affect sensitivity to volatile anesthetics. These injections generated otherwise phenotypically wild type mice with region-specific, postnatal inactivation of Ndufs4, minimizing developmental effects of gene loss. Sensitivities to the volatile anesthetics isoflurane and halothane were measured using loss of righting reflex (LORR) and movement in response to tail clamp (TC) as endpoints...
2017: PloS One
https://www.readbyqxmd.com/read/29131863/long-term-retinal-cone-rescue-using-a-capsid-mutant-aav8-vector-in-a-mouse-model-of-cnga3-achromatopsia
#10
Xufeng Dai, Ying He, Hua Zhang, Yangyang Zhang, Yan Liu, Muran Wang, Hao Chen, Ji-Jing Pang
Adeno-associated virus (AAV) vectors are important gene delivery tools for the treatment of many recessively inherited retinal diseases. For example, a wild-type (WT) AAV5 vector can deliver a full-length Cnga3 (cyclic nucleotide-gated channel alpha-3) cDNA to target cells of the cone photoreceptor function loss 5 (cpfl5) mouse, a spontaneous animal model of achromatopsia with a Cnga3 mutation. Gene therapy restores cone-mediated function and blocks cone degeneration in the mice. However, since transgene expression delivered by an AAV vector shows relatively short-term effectiveness, this cannot be regarded as a very successful therapy...
2017: PloS One
https://www.readbyqxmd.com/read/29130354/delivery-of-adeno-associated-viral-vectors-in-adult-mammalian-inner-ear-cell-subtypes-without-auditory-dysfunction
#11
Yong Tao, Mingqian Huang, Yilai Shu, Adam Ruprecht, Hongyang Wang, Yong Tang, Luk H Vandenberghe, Qiuju Wang, Guangping Gao, Wei-Jia Kong, Zheng-Yi Chen
Hearing loss, including genetic hearing loss, is one of the most common forms of sensory deficits in human with limited options of treatment. Adeno-associated virus (AAV)-mediated gene transfer has been shown to effectively recover auditory functions in mouse models of genetic deafness when delivered at neonatal stages. However, the mouse cochlea is still developing at those time points whereas in human the newborn inner ears are already fully mature. For effective gene therapy to treat genetic deafness, it is necessary to determine whether or not AAV-mediated therapy can be equally effective in the fully mature mouse inner ear without causing damages to the inner ear...
November 12, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29130351/the-gene-therapy-resource-program-a-decade-of-dedication-to-translational-research-by-the-national-heart-lung-and-blood-institute
#12
Terence R Flotte, Eric Daniels, Janet Benson, Jenee M Bevett-Rose, Kenneth Cornetta, Margaret Diggins, Julie Johnston, Susan Sepelak, Johannes Van Der Loo, James M Wilson, Cheryl L McDonald
Over a ten-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute (NHLBI) has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice (cGMP) clinical-grade vector cores for recombinant adeno-associated virus (rAAV) and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early phase clinical trials...
November 12, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29130152/combining-engineered-nucleases-with-adeno-associated-viral-vectors-for-therapeutic-gene-editing
#13
Benjamin E Epstein, David V Schaffer
With the recent advent of several generations of targeted DNA nucleases, most recently CRISPR/Cas9, genome editing has become broadly accessible across the biomedical community. Importantly, the capacity of these nucleases to modify specific genomic loci associated with human disease could render new classes of genetic disease, including autosomal dominant or even idiopathic disease, accessible to gene therapy. In parallel, the emergence of adeno-associated virus (AAV) as a clinically important vector raises the possibility of integrating these two technologies towards the development of gene editing therapies...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29120948/parvalbumin-containing-gaba-cells-and-schizophrenia-experimental-model-based-on-targeted-gene-delivery-through-adeno-associated-viruses
#14
Marta U Woloszynowska-Fraser, Peer Wulff, Gernot Riedel
Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted cell-type selective interferences, for example by expression of light-sensitive channels followed by optogenetic stimulation in behaviourally meaningful settings or by engineered channels termed DREADDS that respond to peripherally administered drugs...
December 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29119608/synthetic-aav-crispr-vectors-for-blocking-hiv-1-expression-in-persistently-infected-astrocytes
#15
Christine Kunze, Kathleen Börner, Eike Kienle, Tanja Orschmann, Ejona Rusha, Martha Schneider, Milena Radivojkov-Blagojevic, Micha Drukker, Sabrina Desbordes, Dirk Grimm, Ruth Brack-Werner
Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes...
November 9, 2017: Glia
https://www.readbyqxmd.com/read/29117317/superior-retinal-gene-transfer-and-biodistribution-profile-of-subretinal-versus-intravitreal-delivery-of-aav8-in-nonhuman-primates
#16
Immanuel P Seitz, Stylianos Michalakis, Barbara Wilhelm, Felix F Reichel, G Alex Ochakovski, Eberhart Zrenner, Marius Ueffing, Martin Biel, Bernd Wissinger, Karl U Bartz-Schmidt, Tobias Peters, M Dominik Fischer
Purpose: To investigate shedding and biodistribution characteristics of recombinant adeno-associated virus serotype 8 (rAAV8) after single-dose subretinal or intravitreal injection in nonhuman primates (NHP, Macaca fascicularis) as a surrogate for environmental hazard and patient safety. Methods: In a study for regulatory submission, 22 NHP were divided into four cohorts receiving either single subretinal injections of vehicle or clinical grade rAAV8 (1 × 1011 or 1 × 1012 vector genomes [vg]) versus single intravitreal application of 1 × 1012 vg...
November 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29116375/uncoupling-n-acetylaspartate-from-brain-pathology-implications-for-canavan-disease-gene-therapy
#17
Georg von Jonquieres, Ziggy H T Spencer, Benjamin D Rowlands, Claudia B Klugmann, Andre Bongers, Anne E Harasta, Kristina E Parley, Jennie Cederholm, Orla Teahan, Russell Pickford, Fabien Delerue, Lars M Ittner, Dominik Fröhlich, Catriona A McLean, Anthony S Don, Miriam Schneider, Gary D Housley, Caroline D Rae, Matthias Klugmann
N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation...
November 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29116194/site-specific-modification-of-adeno-associated-virus-enables-both-fluorescent-imaging-of-viral-particles-and-characterization-of-the-capsid-interactome
#18
Jayanth S Chandran, Paul S Sharp, Evangelia Karyka, João Miguel da Conceição Aves-Cruzeiro, Ian Coldicott, Lydia Castelli, Guillaume Hautbergue, Mark O Collins, Mimoun Azzouz
Adeno-associated viruses (AAVs) are attractive gene therapy vectors due to their low toxicity, high stability, and rare integration into the host genome. Expressing ligands on the viral capsid can re-target AAVs to new cell types, but limited sites have been identified on the capsid that tolerate a peptide insertion. Here, we incorporated a site-specific tetracysteine sequence into the AAV serotype 9 (AAV9) capsid, to permit labelling of viral particles with either a fluorescent dye or biotin. We demonstrate that fluorescently labelled particles are detectable in vitro, and explore the utility of the method in vivo in mice with time-lapse imaging...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29106404/strategy-to-detect-pre-existing-immunity-to-aav-gene-therapy
#19
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/29106384/hepatic-neuregulin-4-signaling-defines-an-endocrine-checkpoint-for-steatosis-to-nash-progression
#20
Liang Guo, Peng Zhang, Zhimin Chen, Houjun Xia, Siming Li, Yanqiao Zhang, Sune Kobberup, Weiping Zou, Jiandie D Lin
Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue-enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH...
November 6, 2017: Journal of Clinical Investigation
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