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adeno-associated viral

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https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#1
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28549772/codon-optimized-rpgr-improves-stability-and-efficacy-of-aav8-gene-therapy-in-two-mouse-models-of-x-linked-retinitis-pigmentosa
#2
M Dominik Fischer, Michelle E McClements, Cristina Martinez-Fernandez de la Camara, Julia-Sophia Bellingrath, Daniyar Dauletbekov, Simon C Ramsden, Doron G Hickey, Alun R Barnard, Robert E MacLaren
X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGR(ORF15)). Despite successful RPGR(ORF15) gene replacement with adeno-associated viral (AAV) vectors being established in a number of animal models of XLRP, progression to human trials has not yet been possible. The inherent sequence instability in the purine-rich region of RPGR(ORF15) (which contains highly repetitive nucleotide sequences) leads to unpredictable recombination errors during viral vector cloning...
May 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28549257/human-somatic-cells-deficient-for-rad52-are-impaired-for-viral-integration-and-compromised-for-most-aspects-of-homology-directed-repair
#3
Yinan Kan, Nizar N Batada, Eric A Hendrickson
Homology-directed repair (HDR) maintains genomic integrity by eliminating lesions such as DNA double-strand breaks (DSBs), interstrand crosslinks (ICLs) and stalled replication forks and thus a deficiency in HDR is associated with genomic instability and cancer predisposition. The mechanism of HDR is best understood and most rigorously characterized in yeast. The inactivation of the fungal radiation sensitive 52 (RAD52) gene, which has both recombination mediator and single-strand annealing (SSA) activities in vitro, leads to severe HDR defects in vivo...
May 10, 2017: DNA Repair
https://www.readbyqxmd.com/read/28540323/neuroglobin-can-prevent-or-reverse-glaucomatous-progression-in-dba-2j-mice
#4
Hélène Cwerman-Thibault, Christophe Lechauve, Sébastien Augustin, Delphine Roussel, Élodie Reboussin, Ammara Mohammad, Julie Degardin-Chicaud, Manuel Simonutti, Hong Liang, Françoise Brignole-Baudouin, Anne Maron, Thomas Debeir, Marisol Corral-Debrinski
Mitochondrial dysfunction is responsible for hereditary optic neuropathies. We wished to determine whether preserving mitochondrial bioenergetics could prevent optic neuropathy in a reliable model of glaucoma. DBA/2J mice exhibit elevated intraocular pressure, progressive degeneration of their retinal ganglion cells, and optic neuropathy that resembles glaucoma. We established that glaucoma in these mice is directly associated with mitochondrial dysfunction: respiratory chain activity was compromised in optic nerves 5 months before neuronal loss began, and the amounts of some mitochondrial proteins were reduced in retinas of glaucomatous mice...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28527664/a-new-hdv-mouse-model-identifies-mitochondrial-antiviral-signaling-protein-mavs-as-a-key-player-in-ifn-%C3%AE-induction
#5
Lester Suárez-Amarán, Carla Usai, Marianna Di Scala, Cristina Godoy, Yi Ni, Mirja Hommel, Laura Palomo, Víctor Segura, Cristina Olagüe, Africa Vales, Alicia Ruiz-Ripa, Maria Buti, Eduardo Salido, Jesús Prieto, Stephan Urban, Francisco Rodríguez-Frias, Rafael Aldabe, Gloria González-Aseguinolaza
BACKGROUND & AIMS: Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the limited availability of small animal models. Here a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented. METHODS: HDV- and HBV-replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV) (AAV-HDV and AAV-HBV). Viral load, antigen expression and genomes were quantified at different time points after AAV injection...
May 17, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28523568/role-of-dopamine-projections-from-ventral-tegmental-area-to-nucleus-accumbens-and-medial-prefrontal-cortex-in-reinforcement-behaviors-assessed-using-optogenetic-manipulation
#6
Xiao Han, Man-Yi Jing, Tai-Yun Zhao, Ning Wu, Rui Song, Jin Li
Dopamine (DA) neurons in the ventral tegmental area (VTA) are predicted to play important roles in reward. In pharmacological studies, the rewarding effects of methamphetamine are mediated by DA neurons localized in the VTA. The nucleus accumbens (NAc) and medial prefrontal cortices (mPFC) are the main projections from the VTA. However, the role of these projections remains unclear, particularly the mPFC projections. In the present study, DAT-Cre transgenic mice received an injection of adeno-associated viral vectors encoding channelrhodopsin2 (ChR2) or control vector into the VTA resulting in the selective expression of these opsins in DA neurons...
May 19, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28515305/cell-cycle-dependent-expression-of-aav2-rep-in-hsv-1-co-infections-gives-rise-to-a-mosaic-of-cells-replicating-either-aav2-or-hsv-1
#7
Francesca D Franzoso, Michael Seyffert, Rebecca Vogel, Artur Yakimovich, Bruna de Andrade Pereira, Anita F Meier, Sereina O Sutter, Kurt Tobler, Bernd Vogt, Urs F Greber, Hildegard Büning, Mathias Ackermann, Cornel Fraefel
Adeno-associated virus 2 (AAV2) depends for productive replication on the simultaneous presence of a helper virus such as herpes simplex virus type 1 (HSV-1). At the same time, AAV2 efficiently blocks the replication of HSV-1, which would eventually limit its own replication by diminishing the helper virus reservoir. This discrepancy begs the question how AAV2 and HSV-1 can co-exist in a cell population. Here we show that in co-infected cultures, AAV2 DNA replication takes place almost exclusively in S/G2 cells, while HSV-1 DNA replication is restricted to G1...
May 17, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28497073/integrase-deficient-lentiviral-vector-as-an-all-in-one-platform-for-highly-efficient-crispr-cas9-mediated-gene-editing
#8
Pavel I Ortinski, Bernadette O'Donovan, Xiaoyu Dong, Boris Kantor
The CRISPR/Cas9 systems have revolutionized the field of genome editing by providing unprecedented control over gene sequences and gene expression in many species, including humans. Lentiviral vectors (LVs) are one of the primary delivery platforms for the CRISPR/Cas9 system due to their ability to accommodate large DNA payloads and sustain robust expression in a wide range of dividing and non-dividing cells. However, long-term expression of LV-delivered Cas9/guide RNA may lead to undesirable off-target effects characterized by non-specific RNA-DNA interactions and off-target DNA cleavages...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28497072/improved-mecp2-gene-therapy-extends-the-survival-of-mecp2-null-mice-without-apparent-toxicity-after-intracisternal-delivery
#9
Sarah E Sinnett, Ralph D Hector, Kamal K E Gadalla, Clifford Heindel, Daphne Chen, Violeta Zaric, Mark E S Bailey, Stuart R Cobb, Steven J Gray
Intravenous administration of adeno-associated virus serotype 9 (AAV9)/hMECP2 has been shown to extend the lifespan of Mecp2(-/y) mice, but this delivery route induces liver toxicity in wild-type (WT) mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM). AAV9/hMECP2 (1 × 10(12) viral genomes [vg]; ICM) extended Mecp2(-/y) survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 10(12) vg of AAV9/hMECP2 induced clasping and abnormal gait...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28494738/smart-and-controllable-raav-gene-delivery-carriers-in-progenitor-cells-for-human-musculoskeletal-regenerative-medicine-with-a-focus-on-the-articular-cartilage
#10
Ana Rey-Rico, Magali Cucchiarini
Cell therapy using mesenchymal stem cells (MSCs) is a powerful tool for the treatment of various diseases and injuries. Still, important limitations including the large amounts of cells required for application in vivo and the age-related decline in lifespan, proliferation, and potency may hinder the use of MSCs in patients. In this regard, gene therapy may offer strong approaches to optimize the use of MSCs for regenerative medicine. Diverse nonviral and viral gene vehicles have been manipulated to genetically modify MSCs, among which the highly effective and relatively safe recombinant adeno-associated viral (rAAV) vectors that emerged as the preferred gene delivery system to treat human disorders...
May 10, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/28488944/a-scalable-and-accurate-method-for-quantifying-vector-genomes-of-recombinant-adeno-associated-viruses-in-crude-lysate
#11
Jianzhong Ai, Raed Ibraheim, Phillip W L Tai, Guangping Gao
Increasing interest and application of recombinant adeno-associated viruses (rAAVs) in basic and clinical research have urged efforts to improve rAAV production quality and yield. Standard vector production workflows call for genome titration of purified vectors at the endpoint of production to assess yield. Unfortunately, quality control measures for preparations during mid-production steps and economical means to assess the fidelity of multiple batches of rAAV preparations are lacking. Here we describe a scalable and accurate method for the direct quantitative polymerase chain reaction (qPCR) titration of rAAV genomes in crude lysate...
April 13, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28487469/phosphoinositide-3-kinase-p110%C3%AE-gene-delivery-limits-diabetes-induced-cardiac-nadph-oxidase-and-cardiomyopathy-in-a-mouse-model-with-established-diastolic-dysfunction
#12
Darnel Prakoso, Miles J DeBlasio, Chengxue Qin, Sarah Rosli, Helen Kiriazis, Hongwei Qian, Xiao-Jun Du, Kate L Weeks, Paul Gregorevic, Julie R McMullen, Rebecca H Ritchie
Phosphoinositide 3-kinase [PI3K (p110α)] is able to negatively regulate the diabetes-induced increase in NADPH oxidase in the heart. Patients affected by diabetes exhibit significant cardiovascular morbidity and mortality, at least in part due to a cardiomyopathy characterised by oxidative stress and left ventricular (LV) dysfunction. Thus, PI3K (p110α) may represent a novel approach to protect the heart from diabetes-induced cardiac oxidative stress and dysfunction. In the current study, we investigated the therapeutic potential of a delayed intervention with cardiac-targeted PI3K gene therapy, administered to mice with established diabetes-induced LV diastolic dysfunction...
May 9, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28482158/magnetically-guided-viral-transduction-of-gene-based-sensitization-for-localized-photodynamic-therapy-to-overcome-multidrug-resistance-in-breast-cancer-cells
#13
Zi-Xian Liao, Ivan M Kempson, Yu-Chen Fa, Meng-Chia Liu, Li-Chen Hsieh, Kuo-Yen Huang, Li-Feng Wang
Chemotherapy represents a conventional treatment for many cancers at different stages and is either solely prescribed or concomitant to surgery, radiotherapy, or both. However, treatment is tempered in instances of acquired drug resistance in response to either chemotherapy or targeted therapy, leading to therapeutic failure. To overcome this challenge, many studies focus on how cancer cells manipulate their genomes and metabolism to prevent drug influx and facilitate the efflux of accumulated chemotherapy drugs...
May 15, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28480299/the-2-8%C3%A2-%C3%A3-electron-microscopy-structure-of-adeno-associated-virus-dj-bound-by-a-heparinoid-pentasaccharide
#14
Qing Xie, John M Spear, Alex J Noble, Duncan R Sousa, Nancy L Meyer, Omar Davulcu, Fuming Zhang, Robert J Linhardt, Scott M Stagg, Michael S Chapman
Atomic structures of adeno-associated virus (AAV)-DJ, alone and in complex with fondaparinux, have been determined by cryoelectron microscopy at 3 Å resolution. The gene therapy vector, AAV-DJ, is a hybrid of natural serotypes that was previously derived by directed evolution, selecting for hepatocyte entry and resistance to neutralization by human serum. The structure of AAV-DJ differs from that of parental serotypes in two regions where neutralizing antibodies bind, so immune escape appears to have been the primary driver of AAV-DJ's directed evolution...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28468798/plasmacytoid-and-conventional-dendritic-cells-cooperate-in-cross-priming-aav-capsid-specific-cd8-t-cells
#15
Geoffrey L Rogers, Jamie L Shirley, Irene Zolotukhin, Sandeep R P Kumar, Alexandra Sherman, George Q Perrin, Brad E Hoffman, Arun Srivastava, Etiena Basner-Tschakarjan, Mark A Wallet, Cox Terhorst, Moanaro Biswas, Roland W Herzog
Adeno-associated virus (AAV) is a replication-deficient parvovirus that is extensively used as a gene therapy vector. CD8(+) T cell responses against the AAV capsid protein can, however, affect therapeutic efficacy. Little is known about the in vivo mechanism that leads to the cross-priming of CD8(+) T cells against the input viral capsid antigen. Here we report that the TLR9-MyD88 pattern-recognition receptor pathway is uniquely capable of initiating this response. By contrast, the absence of TLR2, STING, or addition of TLR4 agonist has no effect...
May 3, 2017: Blood
https://www.readbyqxmd.com/read/28463571/accurate-identification-and-quantification-of-dna-species-by-next-generation-sequencing-in-adeno-associated-viral-vectors-produced-in-insect-cells
#16
Magalie Penaud-Budloo, Emilie Lecomte, Aurélien Guy-Duché, Sylvie Saleun, Alain Roulet, Céline Lopez-Roques, Benoît Tournaire, Benjamin Cogné, Adrien Léger, Veronique Blouin, Pierre Lindenbaum, Philippe Moullier, Eduard Ayuso
Recombinant adeno-associated viral vectors (rAAV) have proven excellent tools for the treatment of many genetic diseases and other complex diseases. However, the illegitimate encapsidation of DNA contaminants within viral particles constitutes a major safety concern for rAAV-based therapies. Moreover, the development of rAAV vectors for early-phase clinical trials has revealed the limited accuracy of the analytical tools used to characterize these new and complex drugs. While most published data concerning residual DNA in rAAV preparations have been generated by quantitative PCR, we recently developed a novel single-strand virus sequencing (SSV-Seq) method for quantification of DNA contaminants in AAV vectors produced in mammalian cells by next-generation sequencing (NGS)...
May 2, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28462820/short-dna-hairpins-compromise-recombinant-adeno-associated-virus-genome-homogeneity
#17
Jun Xie, Qin Mao, Phillip W L Tai, Ran He, Jianzhong Ai, Qin Su, Ye Zhu, Hong Ma, Jia Li, Shoufang Gong, Dan Wang, Zhen Gao, Mengxin Li, Li Zhong, Heather Zhou, Guangping Gao
Short hairpin (sh)RNAs delivered by recombinant adeno-associated viruses (rAAVs) are valuable tools to study gene function in vivo and a promising gene therapy platform. Our data show that incorporation of shRNA transgenes into rAAV constructs reduces vector yield and produces a population of truncated and defective genomes. We demonstrate that sequences with hairpins or hairpin-like structures drive the generation of truncated AAV genomes through a polymerase redirection mechanism during viral genome replication...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28462816/in-utero-transfer-of-adeno-associated-viral-vectors-produces-long-term-factor-ix-levels-in-a-cynomolgus-macaque-model
#18
Citra N Z Mattar, Irene Gil-Farina, Cecilia Rosales, Nuryanti Johana, Yvonne Yi Wan Tan, Jenny McIntosh, Christine Kaeppel, Simon N Waddington, Arijit Biswas, Mahesh Choolani, Manfred Schmidt, Amit C Nathwani, Jerry K Y Chan
The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28460646/evaluation-of-engineered-aav-capsids-for-hepatic-factor-ix-gene-transfer-in-murine-and-canine-models
#19
David M Markusic, Timothy C Nichols, Elizabeth P Merricks, Brett Palaschak, Irene Zolotukhin, Damien Marsic, Sergei Zolotukhin, Arun Srivastava, Roland W Herzog
BACKGROUND: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable...
May 1, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28453362/a-novel-mutation-in-the-dominantly-inherited-topors-gene-supports-haploinsufficiency-as-the-mechanism-of-retinitis-pigmentosa
#20
Marta Latasiewicz, Anna Paola Salvetti, Robert E MacLaren
BACKGROUND: Inherited retinal degenerations are a major cause of untreatable blindness in the younger age group. Recent advances in gene therapy using adeno-associated viral (AAV) vectors have raised the possibility of slowing or stopping retinal degenerations with gene replacement in cases of gene deficiency. MATERIALS AND METHODS: In this report, we present a family with autosomal dominant retinitis pigmentosa. A screen for common ADRP genes was performed with 105 genes targeted...
April 28, 2017: Ophthalmic Genetics
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