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https://www.readbyqxmd.com/read/29779223/gene-editing-vectors-for-studying-nicotinic-acetylcholine-receptors-in-cholinergic-transmission
#1
Can Peng, Yijin Yan, Veronica J Kim, Staci E Engle, Jennifer N Berry, J Michael McIntosh, Rachael L Neve, Ryan M Drenan
Nicotinic acetylcholine receptors (nAChRs), prototype members of the cys-loop ligand gated ion channel family, are key mediators of cholinergic transmission in the central nervous system. Despite their importance, technical gaps exist in our ability to dissect the function of individual subunits in the brain. To overcome these barriers, we designed CRISPR/Cas9 small guide RNA sequences (sgRNAs) for production of loss-of-function alleles in mouse nAChR genes. These sgRNAs were validated in vitro via deep sequencing...
May 19, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29775653/atomic-structure-of-a-rationally-engineered-gene-delivery-vector-aav2-5
#2
Matthew Burg, Claire Rosebrough, Lauren M Drouin, Antonette Bennett, Mario Mietzsch, Paul Chipman, Robert McKenna, Duncan Sousa, Mark Potter, Barry Byrne, R Jude Samulski, Mavis Agbandje-McKenna
AAV2.5 represents the first structure-guided in-silico designed Adeno-associated virus (AAV) gene delivery vector. This engineered vector combined the receptor attachment properties of AAV serotype 2 (AAV2) with the muscle tropic properties of AAV1, and exhibited an antibody escape phenotype because of a modified antigenic epitope. To confirm the design, the structure of the vector was determined to a resolution of 2.78 Å using cryo-electron microscopy and image reconstruction. The structure of the major viral protein (VP), VP3, was ordered from residue 219 to 736, as reported for other AAV structures, and the five AAV2...
May 15, 2018: Journal of Structural Biology
https://www.readbyqxmd.com/read/29766030/cre-recombinase-mediates-the-removal-of-bacterial-backbone-to-efficiently-generate-rsv40
#3
Xiaoxia Shi, Matthew Ryan Ykema, Jaco Hazenoot, Lysbeth Ten Bloemendaal, Irene Mancini, Machteld Odijk, Peter de Haan, Piter J Bosma
Gene therapy has been shown to be a feasible approach to treat inherited disorders in vivo . Among the currently used viral vector systems, adeno-associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of expression upon cell division, while repeating systemic administration lacks efficacy due to the induction of neutralizing antibodies. In addition, a significant percentage of the general population is not eligible for AAV-mediated gene therapy due to pre-existing immunity...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766026/development-of-intrathecal-aav9-gene-therapy-for-giant-axonal-neuropathy
#4
Rachel M Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J Gray
An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766023/adeno-associated-virus-genome-population-sequencing-achieves-full-vector-genome-resolution-and-reveals-human-vector-chimeras
#5
Phillip W L Tai, Jun Xie, Kaiyuen Fong, Matthew Seetin, Cheryl Heiner, Qin Su, Michael Weiand, Daniella Wilmot, Maria L Zapp, Guangping Gao
Recombinant adeno-associated virus (rAAV)-based gene therapy has entered a phase of clinical translation and commercialization. Despite this progress, vector integrity following production is often overlooked. Compromised vectors may negatively impact therapeutic efficacy and safety. Using single molecule, real-time (SMRT) sequencing, we can comprehensively profile packaged genomes as a single intact molecule and directly assess vector integrity without extensive preparation. We have exploited this methodology to profile all heterogeneic populations of self-complementary AAV genomes via bioinformatics pipelines and have coined this approach AAV-genome population sequencing (AAV-GPseq)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766022/influence-of-pre-existing-anti-capsid-neutralizing-and-binding-antibodies-on-aav-vector-transduction
#6
Zachary Fitzpatrick, Christian Leborgne, Elena Barbon, Elisa Masat, Giuseppe Ronzitti, Laetitia van Wittenberghe, Alban Vignaud, Fanny Collaud, Séverine Charles, Marcelo Simon Sola, Fabienne Jouen, Olivier Boyer, Federico Mingozzi
Pre-existing immunity to adeno-associated virus (AAV) is highly prevalent in humans and can profoundly impact transduction efficiency. Despite the relevance to AAV-mediated gene transfer, relatively little is known about the fate of AAV vectors in the presence of neutralizing antibodies (NAbs). Similarly, the effect of binding antibodies (BAbs), with no detectable neutralizing activity, on AAV transduction is ill defined. Here, we delivered AAV8 vectors to mice carrying NAbs and demonstrated that AAV particles are taken up by both liver parenchymal and non-parenchymal cells; viral particles are then rapidly cleared, without resulting in transgene expression...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766021/transduction-patterns-of-adeno-associated-viral-vectors-in-a-laser-induced-choroidal-neovascularization-mouse-model
#7
Si Hyung Lee, Ye Seul Kim, Seung Kwan Nah, Hee Jong Kim, Ha Yan Park, Jin Young Yang, Keerang Park, Tae Kwann Park
Adeno-associated virus (AAV) vector is a promising platform technology for ocular gene therapy. Recently clinical successes to treat choroidal neovascularization (CNV) in wet type age-related macular degeneration have been reported. However, because pathologic conditions of the retina may alter the tropism of viral vectors, it is necessary to evaluate the transduction efficiency of different serotypes of AAV vectors in the retinas with CNVs. Here, we show the patterns and efficacy of transduction of AAV2, -5, and -8 vectors in a laser-induced CNV mouse model...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29766020/amelioration-of-muscle-and-nerve-pathology-in-lama2-muscular-dystrophy-by-aav9-mini-agrin
#8
Chunping Qiao, Yi Dai, Viktoriya D Nikolova, Quan Jin, Jianbin Li, Bin Xiao, Juan Li, Sheryl S Moy, Xiao Xiao
LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin α2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1)...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29764210/curative-ex-vivo-hepatocyte-directed-gene-editing-in-a-mouse-model-of-hereditary-tyrosinemia-type-1
#9
Caitlin VanLith, Rebekah Guthman, Clara T Nicolas, Kari Allen, Zeji Du, Dong Jin Joo, Scott L Nyberg, Joseph B Lillegard, Raymond Daniel Hickey
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small and large animal models of HT1. In this study, we hypothesized that ex vivo hepatocyte-directed gene editing using CRISPR-Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function...
May 15, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29763576/g-i-protein-functions-in-thalamic-neurons-to-decrease-orofacial-nociceptive-response
#10
Jennifer Strand, Crystal Stinson, Larry L Bellinger, Yuan Peng, Phillip R Kramer
Orofacial pain includes neuronal pathways that project from the trigeminal nucleus to and through the thalamus. What role the ventroposterior thalamic complex (VP) has on orofacial pain transmission is not understood. To begin to address this question an inhibitory G protein (Gi) designer receptor exclusively activated by a designer drug (DREADD) was transfected in cells of the VP using adeno-associated virus isotype 8. Virus infected cells were identified by a fluorescent tag and immunostaining. Cells were silenced after injecting the designer drug clozapine-n-oxide, which binds the designer receptor activating Gi ...
May 12, 2018: Brain Research
https://www.readbyqxmd.com/read/29754775/in-situ-gene-therapy-via-aav-crispr-cas9-mediated-targeted-gene-regulation
#11
Ana M Moreno, Xin Fu, Jie Zhu, Dhruva Katrekar, Yu-Ru V Shih, John Marlett, Jessica Cabotaje, Jasmine Tat, John Naughton, Leszek Lisowski, Shyni Varghese, Kang Zhang, Prashant Mali
Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice...
April 25, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29742436/the-assembly-activating-protein-promotes-stability-and-interactions-between-aav-s-viral-proteins-to-nucleate-capsid-assembly
#12
Anna C Maurer, Simon Pacouret, Ana Karla Cepeda Diaz, Jessica Blake, Eva Andres-Mateos, Luk H Vandenberghe
The adeno-associated virus (AAV) vector is a preferred delivery platform for in vivo gene therapy. Natural and engineered variations of the AAV capsid affect a plurality of phenotypes relevant to gene therapy, including vector production and host tropism. Fundamental to these aspects is the mechanism of AAV capsid assembly. Here, the role of the viral co-factor assembly-activating protein (AAP) was evaluated in 12 naturally occurring AAVs and 9 putative ancestral capsid intermediates. The results demonstrate increased capsid protein stability and VP-VP interactions in the presence of AAP...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29740452/interleukin-27-gene-therapy-prevents-the-development-of-autoimmune-encephalomyelitis-but-fails-to-attenuate-established-inflammation-due-to-the-expansion-of-cd11b-gr-1-myeloid-cells
#13
Jianmin Zhu, Jin-Qing Liu, Zhihao Liu, Lisha Wu, Min Shi, Jianchao Zhang, Jonathan P Davis, Xue-Feng Bai
Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown to inhibit autoimmunity and have been suggested as potential immunotherapeutic for autoimmune diseases such as multiple sclerosis (MS). However, the potential of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not been fully understood. In this study, we evaluated the efficacy of adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30 (AAV-IL-30) in a murine model of MS. We found that one single administration of AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental autoimmune encephalomyelitis (EAE)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29723270/creating-an-arsenal-of-adeno-associated-virus-aav-gene-delivery-stealth-vehicles
#14
J Kennon Smith, Mavis Agbandje-McKenna
The Adeno-associated virus (AAV) gene delivery system is ushering in a new and exciting era in the United States; following the first approved gene therapy (Glybera) in Europe, the FDA has approved a second therapy, Luxturna [1]. However, challenges to this system remain. In viral gene therapy, the surface of the capsid is an important determinant of tissue tropism, impacts gene transfer efficiency, and is targeted by the human immune system. Preexisting immunity is a significant challenge to this approach, and the ability to visualize areas of antibody binding ("footprints") can inform efforts to improve the efficacy of viral vectors...
May 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29721930/mutation-independent-gene-therapies-for-rod-cone-dystrophies
#15
Cécile Fortuny, John G Flannery
The clinical success of gene replacement therapies in recent years has served as a proof of concept for the treatment of inherited retinal degenerations using adeno-associated virus (AAV) as viral vector. However, inherited retinal degenerative diseases showcase a broad genetic and mechanistic heterogeneity, challenging the development of mutation-specific therapies for each specific mutation. Mutation-independent approaches must be developed to slow down retinal degeneration regardless of the underlying genetic mutation and onset of the disease...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29720499/gene-transfer-of-engineered-calmodulin-alleviates-ventricular-arrhythmias-in-a-calsequestrin-associated-mouse-model-of-catecholaminergic-polymorphic-ventricular-tachycardia
#16
Bin Liu, Shane D Walton, Hsiang-Ting Ho, Andriy E Belevych, Svetlana B Tikunova, Ingrid Bonilla, Vikram Shettigar, Bjorn C Knollmann, Silvia G Priori, Pompeo Volpe, Przemysław B Radwański, Jonathan P Davis, Sándor Györke
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases...
May 2, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29717624/chondrogenic-differentiation-processes-in-human-bone-marrow-aspirates-seeded-in-three-dimensional-woven-poly-%C3%AE%C2%B5-caprolactone-scaffolds-enhanced-by-raav-mediated-sox9-gene-transfer
#17
Jagadeesh Kumar Venkatesan, Franklin T Moutos, Ana Rey-Rico, Bradley T Estes, Janina Frisch, Gertrud Schmitt, Henning Madry, Farshid Guilak, Magali Cucchiarini
Combining gene therapy approaches with tissue engineering procedures is an active area of translational research for the effective treatment of articular cartilage lesions, especially to target chondrogenic progenitor cells such as those derived from the bone marrow. Here, we evaluated the effect of genetically modifying concentrated human mesenchymal stem cells from bone marrow to induce chondrogenesis by recombinant adeno-associated viral (rAAV) vector gene transfer of the sex-determining region Y-type high-mobility group box 9 (SOX9) factor upon seeding in three-dimensional (3D) woven poly(ε-caprolactone) (PCL) scaffolds that provide mechanical properties mimicking those of native articular cartilage...
May 2, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29717546/the-dorsal-column-lesion-model-of-spinal-cord-injury-and-its-use-in-deciphering-the-neuron-intrinsic-injury-response
#18
REVIEW
Callan L Attwell, Mike van Zwieten, Joost Verhaagen, Matthew Rj Mason
The neuron-intrinsic response to axonal injury differs markedly between neurons of the peripheral and central nervous system. Following a peripheral lesion a robust axonal growth program is initiated, whereas neurons of the central nervous system do not mount an effective regenerative response. Increasing the neuron-intrinsic regenerative response would therefore be one way to promote axonal regeneration in the injured central nervous system. The large diameter sensory neurons located in the dorsal root ganglia are pseudo-unipolar neurons that project one axon branch into the spinal cord, and, via the dorsal column to the brain stem, and a peripheral process to the muscles and skin...
May 1, 2018: Developmental Neurobiology
https://www.readbyqxmd.com/read/29716522/the-cytidine-deaminase-under-representation-reporter-cdur-as-a-tool-to-study-evolution-of-sequences-under-deaminase-mutational-pressure
#19
Maxwell Shapiro, Stephen Meier, Thomas MacCarthy
BACKGROUND: Activation induced deaminase (AID) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) are deaminases that mutate C to U on single-stranded DNA (ssDNA). AID is expressed primarily in germinal center B-cells, where it facilitates affinity maturation and class-switch recombination. APOBEC3 are a family of anti-viral proteins that act as part of the intrinsic immune response. In both cases, there are particular sequence motifs, also known as "mutation motifs", to which these deaminases prefer to bind and mutate...
May 2, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29709207/viral-strategies-for-targeting-the-central-and-peripheral-nervous-systems
#20
Claire N Bedbrook, Benjamin E Deverman, Viviana Gradinaru
Recombinant viruses allow for targeted transgene expression in specific cell populations throughout the nervous system. The adeno-associated virus (AAV) is among the most commonly used viruses for neuroscience research. Recombinant AAVs (rAAVs) are highly versatile and can package most cargo composed of desired genes within the capsid's ∼5-kb carrying capacity. Numerous regulatory elements and intersectional strategies have been validated in rAAVs to enable cell type-specific expression. rAAVs can be delivered to specific neuronal populations or globally throughout the animal...
April 25, 2018: Annual Review of Neuroscience
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