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AAV expression,cells

Hugh C Welles, Madeleine F Jennewein, Rosemarie D Mason, Sandeep Narpala, Lingshu Wang, Cheng Cheng, Yi Zhang, John-Paul Todd, Jeffrey D Lifson, Alejandro B Balazs, Galit Alter, Adrian B McDermott, John R Mascola, Mario Roederer
Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections...
December 5, 2018: PLoS Pathogens
Diana Carranza, Sara Torres-Rusillo, Gloria Ceballos-Pérez, Eva Blanco-Jimenez, Martin Muñoz-López, José L García-Pérez, Ignacio J Molina
Ataxia-telangiectasia (A-T) is a complex disease arising from mutations in the ATM gene (Ataxia-Telangiectasia Mutated), which plays crucial roles in repairing double-strand DNA breaks (DSBs). Heterogeneous immunodeficiency, extreme radiosensitivity, frequent appearance of tumors and neurological degeneration are hallmarks of the disease, which carries high morbidity and mortality because only palliative treatments are currently available. Gene therapy was effective in animal models of the disease, but the large size of the ATM cDNA required the use of HSV-1 or HSV/AAV hybrid amplicon vectors, whose characteristics make them unlikely tools for treating A-T patients...
2018: Frontiers in Immunology
Wan Zhu, Daniel Saw, Miriam Weiss, Zhengda Sun, Meng Wei, Sonali Shaligram, Sen Wang, Hua Su
Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. The pathogenesis of bAVM has not been fully understood. Animal models are important tools for dissecting bAVM pathogenesis and testing new therapies. We have developed several mouse bAVM models using genetically modified mice. However, due to the body size, mouse bAVM models have some limitations. Recent studies identified somatic mutations in sporadic human bAVM. To develop a feasible tool to create sporadic bAVM in rodent and animals larger than rodent, we made tests using the CRISPR/Cas9 technique to induce somatic gene mutations in mouse brain in situ...
December 3, 2018: Translational Stroke Research
Sandra Lilliebladh, Åsa Johansson, Åsa Pettersson, Sophie Ohlsson, Thomas Hellmark
T cell-mediated immune responses are thought to play an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAV). CD4+ T cells can be divided into subsets depending on their expression of chemokine receptors. In this study, different CD4+ T cell populations in patients with AAV were analysed and compared to healthy blood donors as well as therapy controls. 18 patients with active AAV, 46 in remission, 21 healthy controls (HBD), and 15 therapy controls (TC) were enrolled...
2018: Journal of Immunology Research
Hanan Al-Moyed, Andreia P Cepeda, SangYong Jung, Tobias Moser, Sebastian Kügler, Ellen Reisinger
Normal hearing and synaptic transmission at afferent auditory inner hair cell (IHC) synapses require otoferlin. Deafness DFNB9, caused by mutations in the OTOF gene encoding otoferlin, might be treated by transferring wild-type otoferlin cDNA into IHCs, which is difficult due to the large size of this transgene. In this study, we generated two adeno-associated viruses (AAVs), each containing half of the otoferlin cDNA Co-injecting these dual-AAV2/6 half-vectors into the cochleae of 6- to 7-day-old otoferlin knock-out ( Otof -/- ) mice led to the expression of full-length otoferlin in up to 50% of IHCs...
December 3, 2018: EMBO Molecular Medicine
Dylan J Finneran, Dave Morgan, Marcia N Gordon, Kevin R Nash
Accumulating evidence increasingly implicates regulation of neuroinflammation as a potential therapeutic target in Alzheimer's disease and other neurodegenerative disorders. Fractalkine (FKN) is a unique chemokine that is expressed and secreted by neurons and reduces expression of pro-inflammatory genes. To further demonstrate the utility of agents that increase FKN signaling throughout the central nervous system as possible therapies for AD, we assessed the impact of soluble FKN (sFKN) over expression on cognition in tau depositing rTg450 mice after the onset of cognitive deficits...
November 29, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Alvise Berti, Roberto Caporali, Carlomaurizio Montecucco, Giuseppe Paolazzi, Sara Monti
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) usually affect adults and older populations. The well recognized clinical (i.e., granulomatosis with polyangiitis [GPA], microscopic polyangiitis, and eosinophilic GPA) and serological phenotypes (i.e., anti-MPO-ANCA, anti-PR3-ANCA and ANCA negative) within AAV differ substantially for clinical, demographic, and epidemiological features, including age at presentation. Whether and how aging could contribute to the clinical expression of these disease phenotypes is intriguing and still overlooked...
November 28, 2018: Drugs & Aging
Namrata Kumar, William Stanford, Christopher de Solis, Aradhana, Nigel D Abraham, Trieu-Mi J Dao, Sadiqa Thaseen, Anusha Sairavi, Cuauhtemoc Ulises Gonzalez, Jonathan E Ploski
The RNA-guided Cas9 nuclease, from the type II prokaryotic clustered regularly interspersed short palindromic repeats (CRISPR) adaptive immune system, has been adapted by scientists to enable site specific genome editing of eukaryotic cells both in vitro and in vivo . Previously, we reported the development of an adeno-associated virus (AAV)-mediated CRISPR Streptococcus pyogenes (Sp) Cas9 system, in which the genome editing function can be regulated by controlling the expression of the guide RNA (sgRNA) in a doxycycline (Dox)-dependent manner...
2018: Frontiers in Molecular Neuroscience
Peng Sun, Zheli Liu
Current clinical treatments for ocular neovascularization are characterized by high possibility of damaging healthy tissues and high recurrence rates. It is necessary to develop new treatment methods to control neovascularization with a stable and effective effect. Kringle1 domain of hepatocyte growth factor (HGFK1) has anti-angiogenesis activity. Here, we established oxygen-induced retinopathy (OIR) model to study if using adeno-associated virus (AAV) as a delivery system to overexpression HGFK1 in retinal cells could benefit retinal neovascularization...
November 22, 2018: Biochemical and Biophysical Research Communications
Dong Hyun Jo, Taeyoung Koo, Chang Sik Cho, Jin Hyoung Kim, Jin-Soo Kim, Jeong Hun Kim
Genome editing with CRISPR systems provides an unprecedented opportunity to modulate cellular responses in pathological conditions by inactivating undruggable targets, such as transcription factors. Previously, we demonstrated that the smallest Cas9 ortholog characterized to date, from Campylobacter jejuni (CjCas9) targeted to Hif1a and delivered in an adeno-associated virus (AAV) vector, effectively suppressed pathological choroidal neovascularization in the mouse retina. Before implementation of CjCas9 as an in vivo therapeutic modality, it is essential to investigate the long-term effects of target gene disruption via AAV-mediated delivery of CjCas9 in vivo...
October 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Steven Hyun Seung Lee, Hee Jong Kim, Oh Kyu Shin, Jun-Sub Choi, Jin Kim, Young-Hwa Cho, Joohun Ha, Tae Kwann Park, Joo Yong Lee, Keerang Park, Heuiran Lee
Purpose: With anti-VEGF-based treatments for wet AMD requiring frequent injections, it is often burdensome to both patients and healthcare providers. To explore its possibility as a desirable alternative, we investigated the therapeutic potential of a recombinant adeno-associated virus 2 expressing a soluble variant of VEGF receptor-1 (rAAV2-sVEGFRv-1) in a laser-induced choroidal neovascularization (CNV) model, as CNV is a defining feature of AMD progression. Methods: C57/B6 mice were intravitreally administered with rAAV2-sVEGFRv-1, rAAV2-GFP, or clinically used bevacizumab after CNV lesions were induced via laser photocoagulation...
November 1, 2018: Investigative Ophthalmology & Visual Science
Amos Markus, Astar Shamul, Yoav Chemla, Nairouz Farah, Lital Shaham, Ronald S Goldstein, Yossi Mandel
Cell replacement therapy is a promising approach for treatment of retinal degenerative diseases. Several protocols for the generation of photoreceptor precursors (PRP) from human embryonic stem cells (hESC) have been reported with variable efficiency. Herein, we show the advantages of use of size-controlled embryoid bodies in the ESC differentiation process using two differentiation protocols. We further explored cell-labeling methods for following the survival of PRP transplanted subretinally in rat eyes. Size-controlled embryoid bodies (EBs) generated using microwell dishes and non-size-controlled EBs generated using V-shaped 96-well plates were differentiated into PRP using two differentiation protocols...
November 14, 2018: Experimental Eye Research
Lionel Galibert, Adrien Savy, Yohann Dickx, Delphine Bonnin, Bérangère Bertin, Isidore Mushimiyimana, Monique M van Oers, Otto-Wilhelm Merten
The ability to produce large quantities of recombinant Adeno-Associated Virus (rAAV) vectors is an important factor for the development of gene therapy-based medicine. The baculovirus/insect cell expression system is one of the major systems for large scale rAAV production. So far, most technological developments concerned the optimization of the AAV rep and cap genes in order to be expressed correctly in a heterologous system. However, the effect of the baculovirus infection on the production of rAAV has not been examined in detail...
2018: PloS One
Carlee R Giesige, Lindsay M Wallace, Kristin N Heller, Jocelyn O Eidahl, Nizar Y Saad, Allison M Fowler, Nettie K Pyne, Mustafa Al-Kharsan, Afrooz Rashnonejad, Gholamhossein Amini Chermahini, Jacqueline S Domire, Diana Mukweyi, Sara E Garwick-Coppens, Susan M Guckes, K John McLaughlin, Kathrin Meyer, Louise R Rodino-Klapac, Scott Q Harper
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There is currently no pharmacological treatment. The emergence of DUX4 enabled development of cell and animal models that could be used for basic and translational research. Since DUX4 is toxic, animal model development has been challenging, but progress has been made, revealing that tight regulation of DUX4 expression is critical for creating viable animals that develop myopathy...
November 15, 2018: JCI Insight
Ayako Yamaguchi, Diana J Woller, Paulo Rodrigues
The central vocal pathway of the African clawed frog, Xenopus laevis , is a powerful vertebrate model to understand mechanisms underlying central pattern generation. However, fast and efficient methods of introducing exogenous genes into the neurons of adult X. laevis are currently not available. Here, we systematically tested methods of transgene delivery into adult X. laevis neurons. Although successfully used for tadpole neurons for over a decade, electroporation was not efficient in transfecting adult neurons...
2018: Frontiers in Neural Circuits
Ming Yu, Li Guo, Nan Li, Kristin S Henzel, Huating Gu, Xiufang Ran, Wei Sun, Shuai Liu, Yingchang Lu, Dan Ehninger, Yu Zhou
BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2 , which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating...
2018: Frontiers in Cellular Neuroscience
Niels L Mulder, Rick Havinga, Joost L Kluiver, Albert K Groen, Janine K Kruit
MicroRNAs have emerged as essential regulators of beta-cell function and beta-cell proliferation. One of these microRNAs, miR-132, is highly induced in several obesity models and increased expression of miR-132 in vitro modulates glucose-stimulated insulin secretion. The aim of this study was to investigate the therapeutic benefits of miR-132 overexpression on beta-cell function in vivo. To overexpress miR-132 specifically in beta-cells, we employed adeno-associated virus (AAV8) mediated gene transfer using the rat insulin promoter in a double-stranded, self-complementary AAV vector to overexpress miR-132...
October 1, 2018: Journal of Endocrinology
Zekun Wang, Fang Cheng, John F Engelhardt, Ziying Yan, Jianming Qiu
Human bocavirus 1 (HBoV1), an autonomous parvovirus, is a helper virus supporting replication of wild-type adeno-associated virus 2 (AAV2). In this study, we compared the helper functions from HBoV1 with those from adenovirus (Ad) for the production of recombinant AAV (rAAV) vector in HEK293 cells. We demonstrated that triple plasmids transfection of (1) a cloned HBoV1 helper minigenome (pBocaHelper) that expresses HBoV1 genes NP1 , NS2 , and BocaSR, (2) pAAV transfer plasmid, and (3) pAAVRepCap supports rAAV production in HEK293 cells...
December 14, 2018: Molecular Therapy. Methods & Clinical Development
Daniel Keppeler, Ricardo Martins Merino, David Lopez de la Morena, Burak Bali, Antoine Tarquin Huet, Anna Gehrt, Christian Wrobel, Swati Subramanian, Tobias Dombrowski, Fred Wolf, Vladan Rankovic, Andreas Neef, Tobias Moser
Optogenetic tools, providing non-invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light-off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature...
November 5, 2018: EMBO Journal
Yanlin Tan, Xingwang Yao, Zhehao Dai, Yunhua Wang, Guohua Lv
The present study aimed to explore the underlying mechanisms of bone morphogenetic protein 2 (BMP2) in alleviating intervertebral disc degeneration (IDD). A rat puncture IDD model was constructed, and the rats were randomly divided into six groups: Control; IDD (model); IDD+PBS [containing 1010 adeno‑associated virus serotype 2 (AAV)]; and IDD + AAV2‑BMP2 (106, 108 and 1010). IL‑1β was used to treat primary nucleus pulposus (NP) cells to mimic IDD in vitro. The effects of BMP2 in IDD were determined by magnetic resonance imaging (MRI), hematoxylin and eosin staining and Alcian Blue staining in vivo...
November 2, 2018: International Journal of Molecular Medicine
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