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adeno associated virus

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https://www.readbyqxmd.com/read/28934386/expression-of-the-neuropathy-associated-mtmr2-gene-rescues-mtm1-associated-myopathy
#1
Matthieu A Raess, Belinda S Cowling, Dimitri L Bertazzi, Christine Kretz, Bruno Rinaldi, Jean-Marie Xuereb, Pascal Kessler, Norma B Romero, Bernard Payrastre, Sylvie Friant, Jocelyn Laporte
Myotubularins (MTMs) are active or dead phosphoinositides phosphatases defining a large protein family conserved through evolution and implicated in different neuromuscular diseases. Loss-of-function mutations in MTM1 cause the severe congenital myopathy called myotubular myopathy (or X-linked centronuclear myopathy) while mutations in the MTM1-related protein MTMR2 cause a recessive Charcot-Marie-Tooth peripheral neuropathy. Here we aimed to determine the functional specificity and redundancy of MTM1 and MTMR2, and to assess their abilities to compensate for a potential therapeutic strategy...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28926997/effects-of-cellular-methylation-on-transgene-expression-and-site-specific-integration-of-adeno-associated-virus
#2
Diptiman Chanda, Jonathan A Hensel, Jerome T Higgs, Rajat Grover, Niroop Kaza, Selvarangan Ponnazhagan
DNA methylation is a major epigenetic event that affects not only cellular gene expression but that also has the potential to influence bacterial and viral DNA in their host-dependent functions. Adeno-associated virus (AAV) genome contains a high degree of CpG sequences capable of methylation in its terminal repeat sequences, which are the sole elements retained in AAV-based vectors used in gene therapy. The present study determined the influence of methylation status of the host cell on wild type (wt) AAV integration and recombinant (r) AAV transgene expression in HeLa cells...
September 18, 2017: Genes
https://www.readbyqxmd.com/read/28922943/differential-prevalence-of-antibodies-against-adeno-associated-virus-in-healthy-children-and-patients-with-mucopolysaccharidosis-iii-perspective-for-aav-mediated-gene-therapy
#3
Haiyan Fu, Aaron S Meadows, Ricardo J Pineda, Krista L Kunkler, Kristen V Truxal, Kim L McBride, Kevin Flanigan, Douglas M McCarty
Recombinant AAV vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating MPS III patients, we investigated the seroprevalence profiles of AAV1-9 and rh74 in MPS IIIA/IIIB patients and in healthy children. Using ELISA for αAAV-IgG, we observed significantly higher sero-prevalence for AAV1 and AAVrh74 in 2-7y-old MPS III patients than in healthy controls...
September 19, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28919107/combination-of-a%C3%AE-suppression-and-innate-immune-activation-in-the-brain-significantly-attenuates-amyloid-plaque-deposition
#4
Christophe Verbeeck, Anna Carrano, Paramita Chakrabarty, Joanna L Jankowsky, Pritam Das
Anti-Aβ clinical trials are currently underway to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and pre-clinical studies suggest that anti-amyloid strategies are only effective if started at very early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and improve pathological outcomes in mice with moderate amyloid pathology...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28918073/a-directed-evolution-approach-to-select-for-novel-adeno-associated-virus-capsids-on-an-hiv-1-producer-t-cell-line
#5
Dawn P Wooley, Priyanka Sharma, John R Weinstein, Poornima Kotha Lakshmi Narayan, David V Schaffer, Katherine J D A Excoffon
A directed evolution approach was used to select for Adeno-associated virus (AAV) capsids that would exhibit more tropism toward an HIV-1 producer T cell line with the long-term goal of developing improved gene transfer vectors. A library of AAV variants was used to infect H9T cells previously infected or uninfected by HIV-1 followed by AAV amplification with wild-type adenovirus. Six rounds of biological selection were performed, including negative selection and diversification after round three. The H9T cells were successfully infected with all three wild-type viruses (AAV, adenovirus, and HIV-1)...
September 13, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28918031/anti-adenoviral-artificial-micrornas-expressed-from-aav9-vectors-inhibit-human-adenovirus-infection-in-immunosuppressed-syrian-hamsters
#6
Katrin Schaar, Anja Geisler, Milena Kraus, Sandra Pinkert, Markian Pryshliak, Jacqueline F Spencer, Ann E Tollefson, Baoling Ying, Jens Kurreck, William S Wold, Robert Klopfleisch, Karoly Toth, Henry Fechner
Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28918027/adeno-associated-viral-vector-mediated-mtor-inhibition-by-short-hairpin-rna-suppresses-laser-induced-choroidal-neovascularization
#7
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/28918020/rationally-engineered-aav-capsids-improve-transduction-and-volumetric-spread-in-the-cns
#8
Nicholas M Kanaan, Rhyomi C Sellnow, Sanford L Boye, Ben Coberly, Antonette Bennett, Mavis Agbandje-McKenna, Caryl E Sortwell, William W Hauswirth, Shannon E Boye, Fredric P Manfredsson
Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited spread and transduction efficacy in large regions of the human brain. Using rationally designed modifications of the capsid, novel AAV capsids have been generated that improve intracellular processing and result in increased transgene expression...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28918015/a-microrna124-target-sequence-restores-astrocyte-specificity-of-gfaabc1d-driven-transgene-expression-in-aav-mediated-gene-transfer
#9
Grit Taschenberger, Julia Tereshchenko, Sebastian Kügler
Experimentally restricting transgene expression exclusively to astrocytes has proven difficult. Using adeno-associated-virus-mediated gene transfer, we assessed two commonly used glial fibrillary acidic protein promoters: the full-length version gfa2 (2,210-bp human glial fibrillary acidic protein [GFAP] promoter) and the truncated variant gfaABC1D (681-bp GFAP promoter). The capacity to drive efficient, but also cell-type specific, expression of the EGFP in astrocytes was tested both in vitro in rat primary cortical cultures as well as in vivo in the rat striatum...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28902707/impact-of-human-ca8-on-thermal-antinociception-in-relation-to-morphine-equivalence-in-mice
#10
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/28894301/lateral-hypothalamic-glp-1-receptors-are-critical-for-the-control-of-food-reinforcement-ingestive-behavior-and-body-weight
#11
L López-Ferreras, J E Richard, E E Noble, K Eerola, R H Anderberg, K Olandersson, L Taing, S E Kanoski, M R Hayes, K P Skibicka
Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH...
September 12, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28888955/distinct-roles-of-neuronal-and-microglial-cb2-cannabinoid-receptors-in-the-mouse-hippocampus
#12
Yong Li, Jimok Kim
The effects of cannabinoids are primarily mediated by type-1 cannabinoid receptors in the brain and type-2 cannabinoid receptors (CB2Rs) in the peripheral immune system. However, recent evidence demonstrates that CB2Rs are also expressed in the brain and implicated in neuropsychiatric effects. Diverse types of cells in various regions in the brain express CB2Rs but the cellular loci of CB2Rs that induce specific behavioral effects have not been determined. To manipulate CB2R expression in specific types of cells in the dorsal hippocampus of adult mice, we used Cre-dependent overexpression and CRISPR-Cas9 genome-editing techniques in combination with adeno-associated viruses and transgenic mice...
September 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28887535/metabolic-stress-induced-cardiomyopathy-is-caused-by-mitochondrial-dysfunction-due-to-attenuated-erk5-signaling
#13
Wei Liu, Andrea Ruiz-Velasco, Shoubao Wang, Saba Khan, Min Zi, Andreas Jungmann, Maria Dolores Camacho-Muñoz, Jing Guo, Guanhua Du, Liping Xie, Delvac Oceandy, Anna Nicolaou, Gina Galli, Oliver J Müller, Elizabeth J Cartwright, Yong Ji, Xin Wang
The prevalence of cardiomyopathy from metabolic stress has increased dramatically; however, its molecular mechanisms remain elusive. Here, we show that extracellular signal-regulated protein kinase 5 (Erk5) is lost in the hearts of obese/diabetic animal models and that cardiac-specific deletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractility and mitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). Erk5 regulation of peroxisome proliferator-activated receptor γ co-activator-1α (Pgc-1α) is critical for cardiac mitochondrial functions...
September 8, 2017: Nature Communications
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
#14
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/28882310/studying-tau-protein-propagation-and-pathology-in-the-mouse-brain-using-adeno-associated-viruses
#15
Susanne Wegmann, Rachel E Bennett, Ana S Amaral, Bradley T Hyman
The progressive spread of pathological brain lesions containing aggregated tau protein is a hallmark of Alzheimer's disease and other neurodegenerative diseases. In AD, this process follows a distinct pattern along neuronal connections from the entorhinal cortex to hippocampal areas and further on through the limbic system. In other tauopathies, the spread of tau appears less hierarchical throughout the brain, and also nonpathological tau is reported to cross-synaptic connections in the brain. To be able to study the process of cell-to-cell transport of tau and the associated neurotoxicity in the brain in vivo, adeno-associated virus-mediated expression of tau can be used to express different forms of tau in distinct brain areas in rodent models...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28880021/long-term-expression-of-melanopsin-and-channelrhodopsin-causes-no-gross-alterations-in-the-dystrophic-dog-retina
#16
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/28878120/mdm2-regulates-cardiac-contractility-by-inhibiting-grk2-mediated-desensitization-of-%C3%AE-adrenergic-receptor-signaling
#17
Pierre-Yves Jean-Charles, Samuel Mon-Wei Yu, Dennis Abraham, Reddy Peera Kommaddi, Lan Mao, Ryan T Strachan, Zhu-Shan Zhang, Dawn E Bowles, Leigh Brian, Jonathan A Stiber, Stephen N Jones, Walter J Koch, Howard A Rockman, Sudha K Shenoy
The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, thereby regulating β-adrenergic receptor (βAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects βAR signaling and cardiac function in adult mice...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28872643/tropism-of-engineered-and-evolved-recombinant-aav-serotypes-in-the-rd1-mouse-and-ex-vivo-primate-retina
#18
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/28872640/nectin-3-modulates-the-structural-plasticity-of-dentate-granule-cells-and-long-term-memory
#19
X-X Wang, J-T Li, X-M Xie, Y Gu, T-M Si, M V Schmidt, X-D Wang
Nectin-3, a cell adhesion molecule enriched in hippocampal neurons, has been implicated in stress-related cognitive disorders. Nectin-3 is expressed by granule cells in the dentate gyrus (DG), but it remains unclear whether nectin-3 in DG modulates the structural plasticity of dentate granule cells and hippocampus-dependent memory. In this study, we found that DG nectin-3 expression levels were developmentally regulated and reduced by early postnatal stress exposure in adult mice. Most importantly, knockdown of nectin-3 levels in all DG neuron populations by adeno-associated virus (AAV) mimicked the cognitive effects of early-life stress, and impaired long-term spatial memory and temporal order memory...
September 5, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28872135/methods-and-tips-for-intravenous-administration-of-adeno-associated-virus-to-rats-and-evaluation-of-central-nervous-system-transduction
#20
Mychal S Grames, Kasey L Jackson, Robert D Dayton, John A Stanford, Ronald L Klein
Adeno-associated virus (AAV) vectors are a key reagent in the neurosciences for clustered regularly interspaced short palindromic repeats (CRISPR), optogenetics, cre-lox targeting, etc. The purpose of this manuscript is to aid the investigator attempting expansive central nervous system (CNS) gene transfer in the rat via tail vein injection of AAV. Wide-scale expression is relevant for conditions with widespread pathology, and a rat model is significant due to its greater size and physiologic similarities to humans compared to mice...
August 25, 2017: Journal of Visualized Experiments: JoVE
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