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https://www.readbyqxmd.com/read/27910044/cell-based-measurement-of-neutralizing-antibodies-against-adeno-associated-virus-aav
#1
Andreas Jungmann, Oliver Müller, Kleopatra Rapti
In recent years gene therapy using adeno-associated viral (AAV) vectors to treat cardiac disease has seen an unprecedented surge, owing to its safety, low immunogenicity relative to other vectors and high and long-term transduction efficiency. This field has also been hampered by the presence of preexisting neutralizing antibodies, not only in patients participating in clinical trials but also in preclinical large animal models. These conflicting circumstances have generated the need for a simple, efficient, and fast assay to screen subjects for the presence of neutralizing antibodies, or lack thereof, in order for them to be included in gene therapy trials...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27910043/production-and-characterization-of-vectors-based-on-the-cardiotropic-aav-serotype-9
#2
Erik Kohlbrenner, Thomas Weber
Vectors based on adeno-associated virus serotype 9 (AAV9) efficiently transduce cardiomyocytes in both rodents and large animal models upon either systemic or regional vector delivery. In this chapter, we describe the most widely used production and purification method of AAV9. This production approach does not depend on the use of a helpervirus but instead on transient transfection of HEK293T cells with a plasmid containing the recombinant AAV genome and a second plasmid encoding the AAV9 capsid proteins, the AAV Rep proteins and the adenoviral helper functions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27910040/generation-of-efficient-mirna-inhibitors-using-tough-decoy-constructs
#3
Jimeen Yoo, Roger J Hajjar, Dongtak Jeong
Over the last decade a previously unappreciated mechanism of gene regulation has been uncovered that is mediated by a large class of small noncoding RNAs known as microRNAs (miRNAs), and this mechanism is utilized by organisms ranging from plants to humans. MiRNAs are important downregulators of gene expression and are seen to be dysregulated in disease development. Thus inhibition of aberrantly upregulated miRNAs as a therapeutic approach has become a promising field.Many models of miRNA inhibitors currently exist, with decoy models being the most successful in current research...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27910039/silencing-genes-in-the-heart
#4
Henry Fechner, Roland Vetter, Jens Kurreck, Wolfgang Poller
Silencing of cardiac genes by RNA interference (RNAi) has developed into a powerful new method to treat cardiac diseases. Small interfering (si)RNAs are the inducers of RNAi, but cultured primary cardiomyocytes and heart are highly resistant to siRNA transfection. This can be overcome by delivery of small hairpin (sh)RNAs or artificial microRNA (amiRNAs) by cardiotropic adeno-associated virus (AAV) vectors. Here we describe as example of the silencing of a cardiac gene, the generation and cloning of shRNA, and amiRNAs directed against the cardiac protein phospholamban...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27909699/aav-mediated-sirt1-overexpression-in-skeletal-muscle-activates-oxidative-capacity-but-does-not-prevent-insulin-resistance
#5
Laia Vilà, Carles Roca, Ivet Elias, Alba Casellas, Ricardo Lage, Sylvie Franckhauser, Fatima Bosch
Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, Sirt1 up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation. Here we examined whether Sirt1 overexpression mediated by adeno-associated viral vectors of serotype 1 (AAV1) specifically in skeletal muscle can counteract the development of insulin resistance induced by a high fat diet in mice...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27903748/hepatic-expression-of-adenovirus-36-e4orf1-improves-glycemic-control-and-promotes-glucose-metabolism-via-akt-activation
#6
Travis B McMurphy, Wei Huang, Run Xiao, Xianglan Liu, Nikhil V Dhurandhar, Lei Cao
Considering that impaired proximal insulin signaling is linked with diabetes, approaches that enhance glucose disposal independent of insulin signaling are attractive. In vitro data indicate that the E4ORF1 peptide derived from human adenovirus 36 (Ad36) interacts with cells from adipose tissue, skeletal muscle and liver to enhance glucose disposal, independent of proximal insulin signaling. Adipocyte-specific expression of Ad36E4ORF1 improved hyperglycemia in mice. To determine the hepatic interaction of Ad36E4ORF1 in enhancing glycemic control, we expressed E4ORF1 of Ad36 or adenovirus 5, or fluorescent tag alone using recombinant adeno-associated viral vector in the livers of three mouse models...
November 30, 2016: Diabetes
https://www.readbyqxmd.com/read/27903483/therapeutic-benefits-and-adverse-effects-of-combined-pro-angiogenic-gene-therapy-in-mouse-critical-leg-ischemia
#7
Benoît Lebas, Julien Galley, Edith Renaud-Gabardos, Françoise Pujol, Françoise Lenfant, Barbara Garmy-Susini, Xavier Chaufour, Anne-Catherine Prats
OBJECTIVE: Critical leg ischemia (CLI) represents the ultimate stage of peripheral arterial disease. Despite current surgery advances, patients with CLI have limited therapeutic options. Therapeutic angiogenesis thus appears as a powerful approach, aiming to stimulate vessel formation by angiogenic molecules administration. In this context, combined gene therapy has proved the most efficient. The present study aims to compare, in a preclinical mouse model, the therapeutic benefit of a combination of two angiogenic factors FGF2 (fibroblast growth factor 2) and Cyr61 using plasmid and viral vectors, able to generate short or long-term transgene expression in the leg, respectively...
November 26, 2016: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/27903222/sustained-elabela-gene-therapy-in-high-salt-induced-hypertensive-rats
#8
Claire A Schreiber, Sara J Holditch, Alex Generous, Yasuhiro Ikeda
BACKGROUND: Elabela (ELA) is a recently identified apelin receptor agonist essential for cardiac development, but its biology and therapeutic potential are unclear. In humans ELA transcripts are detected in embryonic stem cells, induced pluripotent stem cells, kidney, heart and blood vessels. ELA through the apelin receptor promotes angiogenesis in vitro, relaxes murine aortic blood vessels and attenuates high blood pressure in vivo. The apelin receptor when bound to its original ligand, apelin, exerts peripheral vasodilatory and positive inotropic effects, conferring cardioprotection in vivo...
November 21, 2016: Current Gene Therapy
https://www.readbyqxmd.com/read/27903072/a-5-non-coding-exon-containing-engineered-intron-enhances-transgene-expression-from-recombinant-aav-vectors-in-vivo
#9
Jiamiao Lu, James A Williams, James Luke, Feijie Zhang, Kirk Chu, Mark A Kay
We previously developed a mini-intronic plasmid (MIP) expression system in which the essential bacterial elements for plasmid replication and selection are placed within an engineered intron contained within a universal 5'UTR non-coding exon. Like minicircle DNA plasmids (devoid of bacterial backbone sequences), MIP plasmids overcome transcriptional silencing of the transgene. However, in addition MIP plasmids increase transgene expression by 2 and often >10 times higher than minicircle vectors in vivo and in vitro...
November 30, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27898094/crispr-cas9-aav-mediated-knock-in-at-nrl-locus-in-human-embryonic-stem-cells
#10
Xianglian Ge, Haitao Xi, Fayu Yang, Xiao Zhi, Yanghua Fu, Ding Chen, Ren-He Xu, Ge Lin, Jia Qu, Junzhao Zhao, Feng Gu
Clustered interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome engineering technologies are sparking a new revolution in biological research. This technology efficiently induces DNA double strand breaks at the targeted genomic sequence and results in indel mutations by the error-prone process of nonhomologous end joining DNA repair or homologous recombination with a DNA repair template. The efficiency of genome editing with CRISPR/Cas9 alone in human embryonic stem cells is still low...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27898092/transposon-mediated-generation-of-cellular-and-mouse-models-of-splicing-mutations-to-assess-the-efficacy-of-snrna-based-therapeutics
#11
Elena Barbon, Mattia Ferrarese, Laetitia van Wittenberghe, Peggy Sanatine, Giuseppe Ronzitti, Fanny Collaud, Pasqualina Colella, Mirko Pinotti, Federico Mingozzi
Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs). However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X) to integrate human factor IX (hFIX) minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt) or mutated (SChFIXex5-2C)...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27897038/aav-gene-therapy-for-liver-disease
#12
Lisa M Kattenhorn, Christopher H Tipper, Lorelei Stoica, Deborah S Geraghty, Teresa L Wright, K Reed Clark, Samuel Wadsworth
The field of adeno-associated virus (AAV) gene therapy has progressed rapidly over the past decade, with the advent of novel capsid serotypes, organ-specific promoters and an increasing understanding of the immune response to AAV administration. Liver-directed therapy, in particular, has made remarkable strides with a number of clinical trials currently planned and on-going in hemophilia A and B, as well as other liver disorders. This review focuses on liver-directed AAV gene therapy, including historic context, current challenges, and future developments...
November 29, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27895015/protective-effects-of-human-and-mouse-soluble-scavenger-like-cd6-lymphocyte-receptor-in-a-lethal-model-of-polymicrobial-sepsis
#13
Mario Martínez-Florensa, Marta Consuegra-Fernández, Fernando Aranda, Noelia Armiger-Borràs, Marianna Di Scala, Esther Carrasco, Jerónimo Pachón, Jordi Vila, Gloria González-Aseguinolaza, Francisco Lozano
Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria, and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold-standard antibiotics, in a lethal model of polymicrobial sepsis...
November 28, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27893183/toxic-effects-of-human-and-rodent-variants-of-alpha-synuclein-in-vivo
#14
Natalie Landeck, Kerstin Buck, Deniz Kirik
In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions. To date, the precise mechanisms leading to aggregation of asyn in the brain is not well understood. Previous studies in yeast, drosophila and transgenic mice suggested that a non-A beta component depleted version of human asyn [h-asyn(D70-83)] or human beta-synuclein (h-bsyn), naturally lacking this centrally located hydrophobic region, are less prone to form aggregates in vitro and are expected to be less toxic compared to h-asyn in vivo, although not all experimental studies unequivocally support the latter view...
November 28, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27891076/recombinant-adeno-associated-virus-serotype-6-raav6-potently-and-preferentially-transduces-rat-astrocytes-in-vitro-and-in-vivo
#15
Alexandra L Schober, Dmitriy A Gagarkin, Ying Chen, Guangping Gao, Lauren Jacobson, Alexander A Mongin
Recombinant adeno-associated virus vectors are an increasingly popular tool for gene delivery to the CNS because of their non-pathological nature, low immunogenicity, and ability to stably transduce dividing and non-dividing cells. One of the limitations of rAAVs is their preferential tropism for neuronal cells. Glial cells, specifically astrocytes, appear to be infected at low rates. To overcome this limitation, previous studies utilized rAAVs with astrocyte-specific promoters or assorted rAAV serotypes and pseudotypes with purported selectivity for astrocytes...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27889607/leptin-ob-r-signaling-is-elevated-in-mice-with-sj%C3%A3-gren-s-syndrome-and-is-implicated-in-disease-pathogenesis
#16
Ting Xu, Wen Xie, Yingchun Ma, Shiliang Zhou, Lu Zhang, Jinyun Chen, Mingyuan Cai, Rurong Sun, Peirong Zhang, Shaobo Yu, Zheng Xu, Wanlan Jiang, Min Wu
Sjögren's syndrome (SjS) is a systemic autoimmune disease resulting in a severe dry mouth and dry eyes. Currently, care for patients with SjS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms are uncertain. Leptin activates B cells to induce the secretion of proinflammatory and anti-inflammatory cytokines and is elevated in several autoimmune diseases. In this study, we found the expression of leptin and its receptor OB-R in mouse models of SjS are elevated both locally and systemically during SjS progression...
November 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27882354/bcl-2-associated-athanogene-3-protects-the-heart-from-ischemia-reperfusion-injury
#17
Feifei Su, Valerie D Myers, Tijana Knezevic, JuFang Wang, Erhe Gao, Muniswamy Madesh, Farzaneh G Tahrir, Manish K Gupta, Jennifer Gordon, Joseph Rabinowitz, Frederick V Ramsey, Douglas G Tilley, Kamel Khalili, Joseph Y Cheung, Arthur M Feldman
Bcl-2-associated athanogene 3 (BAG3) is an evolutionarily conserved protein expressed at high levels in the heart and the vasculature and in many cancers. While altered BAG3 expression has been associated with cardiac dysfunction, its role in ischemia/reperfusion (I/R) is unknown. To test the hypothesis that BAG3 protects the heart from reperfusion injury, in vivo cardiac function was measured in hearts infected with either recombinant adeno-associated virus serotype 9-expressing (rAAV9-expressing) BAG3 or GFP and subjected to I/R...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27874090/a-novel-process-of-viral-vector-barcoding-and-library-preparation-enables-high-diversity-library-generation-and-recombination-free-paired-end-sequencing
#18
Marcus Davidsson, Paula Diaz-Fernandez, Oliver D Schwich, Marcos Torroba, Gang Wang, Tomas Björklund
Detailed characterization and mapping of oligonucleotide function in vivo is generally a very time consuming effort that only allows for hypothesis driven subsampling of the full sequence to be analysed. Recent advances in deep sequencing together with highly efficient parallel oligonucleotide synthesis and cloning techniques have, however, opened up for entirely new ways to map genetic function in vivo. Here we present a novel, optimized protocol for the generation of universally applicable, barcode labelled, plasmid libraries...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27872154/genetic-determinants-of-myocardial-dysfunction
#19
REVIEW
Xianchi Li, Peiying Zhang
Heart failure (HF) is a major killer with high morbidity and mortality and nearly 37.7 million people are affected by HF globally, making this a global epidemic. HF is a complex pathophysiological syndrome in which the mechanical function of heart for pumping blood is compromised. Cardiac structural and functional abnormalities culminate in decreased cardiac output along with increased intracardiac pressures under resting or stress conditions, leading to HF. Besides the acquired risk factors, the independent role of hereditary and genetic factors in the development, progression and prognosis of HF remains to be established...
November 21, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27870893/activin-receptor-type-iib-inhibition-improves-muscle-phenotype-and-function-in-a-mouse-model-of-spinal-muscular-atrophy
#20
Min Liu, David W Hammers, Elisabeth R Barton, H Lee Sweeney
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter...
2016: PloS One
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