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AAV OR Adeno-associated virus

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https://www.readbyqxmd.com/read/29677353/humoral-immune-response-after-intravitreal-but-not-after-subretinal-aav8-in-primates-and-patients
#1
Felix F Reichel, Tobias Peters, Barbara Wilhelm, Martin Biel, Marius Ueffing, Bernd Wissinger, Karl U Bartz-Schmidt, Reinhild Klein, Stylianos Michalakis, M Dominik Fischer
Purpose: To study longitudinal changes of anti-drug antibody (ADA) titers to recombinant adeno-associated virus serotype 8 (rAAV8) capsid epitopes in nonhuman primates (NHP) and patients. Methods: Three groups of six NHP each received subretinal injections (high dose: 1 × 1012 vector genomes [vg], low dose: 1 × 1011 vg, or vehicle only). Four additional animals received intravitreal injections of the high dose (1 × 1012 vg). Three patients received 1 × 1010 vg as subretinal injections...
April 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29671258/atrial-overexpression-of-microrna-27b-attenuates-angiotensin-ii-induced-atrial-fibrosis-and-fibrillation-by-targeting-alk5
#2
Yanshan Wang, Heng Cai, Hongmei Li, Zhisheng Gao, Kunqing Song
Atrial fibrosis influences atrial fibrillation (AF) development by transforming growth factor beta 1 (TGF-β1)/Smad pathway. Although microRNAs are implicated in the pathogenesis of various diseases, information regarding the functional role of microRNAs in atrial dysfunction is limited. In the present study, we found that microRNA-27b (miR-27b) was the dominant member of miR-27 family expressed in left atrium. Moreover, the expression of miR-27b was significantly reduced after angiotensin II (AngII) infusion...
April 18, 2018: Human Cell
https://www.readbyqxmd.com/read/29671068/intracellular-generation-of-single-strand-template-increases-the-knock-in-efficiency-by-combining-crispr-cas9-with-aav
#3
Qing Xiao, Taishan Min, Shuangping Ma, Lingna Hu, Hongyan Chen, Daru Lu
Targeted integration of transgenes facilitates functional genomic research and holds prospect for gene therapy. The established microhomology-mediated end-joining (MMEJ)-based strategy leads to the precise gene knock-in with easily constructed donor, yet the limited efficiency remains to be further improved. Here, we show that single-strand DNA (ssDNA) donor contributes to efficient increase of knock-in efficiency and establishes a method to achieve the intracellular linearization of long ssDNA donor. We identified that the CRISPR/Cas9 system is responsible for breaking double-strand DNA (dsDNA) of palindromic structure in inverted terminal repeats (ITRs) region of recombinant adeno-associated virus (AAV), leading to the inhibition of viral second-strand DNA synthesis...
April 18, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29670079/upregulation-of-neuronal-astrocyte-elevated-gene-1-protects-nigral-dopaminergic-neurons-in-vivo
#4
Eunju Leem, Hyung-Jun Kim, Minji Choi, Sehwan Kim, Yong-Seok Oh, Kea Joo Lee, Young-Shik Choe, Jae-Young Um, Won-Ho Shin, Jae Yeong Jeong, Byung Kwan Jin, Dong Woon Kim, Catriona McLean, Paul B Fisher, Nikolai Kholodilov, Kwang Seok Ahn, Jae Man Lee, Un Ju Jung, Seok-Geun Lee, Sang Ryong Kim
The role of astrocyte elevated gene-1 (AEG-1) in nigral dopaminergic (DA) neurons has not been studied. Here we report that the expression of AEG-1 was significantly lower in DA neurons in the postmortem substantia nigra of patients with Parkinson's disease (PD) compared to age-matched controls. Similarly, decreased AEG-1 levels were found in the 6-hydroxydopamine (6-OHDA) mouse model of PD. An adeno-associated virus-induced increase in the expression of AEG-1 attenuated the 6-OHDA-triggered apoptotic death of nigral DA neurons...
April 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29669786/rearrangement-of-the-protein-phosphatase-1-interactome-during-heart-failure-progression
#5
David Y Chiang, Katherina M Alsina, Eleonora Corradini, Martin Fitzpatrick, Li Ni, Satadru K Lahiri, Julia Reynolds, Xiaolu Pan, Larry Scott, Albert J R Heck, Xander H Wehrens
Background -Heart failure (HF) is a complex disease with a rising prevalence despite advances in treatment. Protein phosphatase 1 (PP1) has long been implicated in HF pathogenesis but its exact role is both unclear and controversial. Most previous studies measured only the PP1 catalytic subunit (PP1c) without investigating its diverse set of interactors, which confer localization and substrate specificity to the holoenzyme. In this study we define the PP1 interactome in cardiac tissue and test the hypothesis that this interactome becomes rearranged during HF progression at the level of specific PP1c interactors...
April 18, 2018: Circulation
https://www.readbyqxmd.com/read/29668376/recombinant-adeno-associated-virus-based-gene-therapy-for-disorders-detected-by-newborn-screening-inherent-limitations-of-this-approach
#6
Terence R Flotte
No abstract text is available yet for this article.
April 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29668327/assessment-of-humoral-innate-and-t-cell-immune-responses-to-adeno-associated-virus-vectors
#7
Roberto Calcedo, Jessica A Chichester, James M Wilson
Adeno-associated virus (AAV)-based gene therapy is being applied to treat a wide array of diseases. Preexisting host immune responses to AAV and immune responses elicited by AAV vector administration remain a problem that needs to be further studied. Here we present a series of protocols to assess immune responses before and after AAV vector administration that are applicable to multiple animal models and phase 1 clinical trials. More specifically, they may be use to evaluate (1) the humoral immune response, through levels of AAV-neutralizing and binding antibodies; (2) the innate immune response, through the acute induction of inflammatory cytokines; and (3) the T-cell immune response, through the activation of transgene- and vector-specific CD8+ and CD4+ T cells...
April 2018: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/29663270/molecular-biology-and-gene-therapy-for-glycogen-storage-disease-type-ib
#8
Janice Y Chou, Jun-Ho Cho, Goo-Young Kim, Brian C Mansfield
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose-6-phosphate (G6P) transporter (G6PT or SLC37A4). The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the endoplasmic reticulum (ER). Inside the ER, G6P is hydrolyzed to glucose and phosphate by either the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α) or the ubiquitously expressed G6Pase-β. A deficiency in G6Pase-α causes GSD type Ia (GSD-Ia) and a deficiency in G6Pase-β causes GSD-I-related syndrome (GSD-Irs)...
April 16, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29659121/glucagon-like-peptide-1-ameliorates-cardiac-lipotoxicity-in-diabetic-cardiomyopathy-via-the-ppar%C3%AE-pathway
#9
Lujin Wu, Ke Wang, Wei Wang, Zheng Wen, Peihua Wang, Lei Liu, Dao Wen Wang
Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks...
April 16, 2018: Aging Cell
https://www.readbyqxmd.com/read/29656365/characterization-of-aav-vector-particle-stability-at-the-single-capsid-level
#10
Julien Bernaud, Axel Rossi, Anny Fis, Lara Gardette, Ludovic Aillot, Hildegard Büning, Martin Castelnovo, Anna Salvetti, Cendrine Faivre-Moskalenko
Virus families have evolved different strategies for genome uncoating, which are also followed by recombinant vectors. Vectors derived from adeno-associated viruses (AAV) are considered as leading delivery tools for in vivo gene transfer, and in particular gene therapy. Using a combination of atomic force microscopy (AFM), biochemical experiments, and physical modeling, we investigated here the physical properties and stability of AAV vector particles. We first compared the morphological properties of AAV vectors derived from two different serotypes (AAV8 and AAV9)...
April 14, 2018: Journal of Biological Physics
https://www.readbyqxmd.com/read/29655638/attenuation-of-the-niemann-pick-type-c2-disease-phenotype-by-intracisternal-administration-of-an-aavrh-10-vector-expressing-npc2
#11
Sandra Markmann, Jasmine Reid, Jonathan B Rosenberg, Bishnu P De, Stephen M Kaminsky, Ronald G Crystal, Dolan Sondhi
Niemann-Pick type C2 (NPC2) disease is a rare, neurodegenerative disorder caused by mutations in the NPC2 gene, leading to lysosomal accumulation of unesterified cholesterol and other lipids. It is characterized by hepatosplenomegaly, liver dysfunction and severe neurological manifestations, resulting in early death. There is no effective therapy for NPC2 disease. Here, we evaluated the effectiveness of an adeno-associated virus (AAV), serotype rh.10 gene transfer vector expressing the mouse Npc2 gene (AAVrh...
April 12, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29643817/overexpression-of-%C3%A3-arrestin1-in-the-rostral-ventrolateral-medulla-downregulates-angiotensin-receptor-and-lowers-blood-pressure-in-hypertension
#12
Jia-Cen Sun, Bing Liu, Ru-Wen Zhang, Pei-Lei Jiao, Xing Tan, Yang-Kai Wang, Wei-Zhong Wang
Background: Hypertension is characterized by sympathetic overactivity, which is associated with an enhancement in angiotensin receptor type I (AT1R) in the rostral ventrolateral medulla (RVLM). β-arrestin1, a canonical scaffold protein, has been suggested to show a negative effect on G protein-coupled receptors via its internalization and desensitization and/or the biased signaling pathway. The major objectives of the present study were to observe the effect of β-arrestin1 overexpression in the RVLM on cardiovascular regulation in spontaneously hypertensive rats (SHR), and further determine the effect of β-arrestin1 on AT1R expression in the RVLM...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29628393/in-vivo-genetic-manipulation-of-spermatogonial-stem-cells-and-their-microenvironment-by-adeno-associated-viruses
#13
Satoshi Watanabe, Mito Kanatsu-Shinohara, Narumi Ogonuki, Shogo Matoba, Atsuo Ogura, Takashi Shinohara
Adeno-associated virus (AAV) penetrates the blood-brain barrier, but it is unknown whether AAV penetrates other tight junctions. Genetic manipulation of testis has been hampered by the basement membrane of seminiferous tubules and the blood-testis barrier (BTB), which forms between Sertoli cells and divides the tubules into basal and adluminal compartments. Here, we demonstrate in vivo genetic manipulation of spermatogonial stem cells (SSCs) and their microenvironment via AAV1/9. AAV1/9 microinjected into the seminiferous tubules penetrated both the basement membrane and BTB, thereby transducing not only Sertoli cells and SSCs but also peritubular cells and Leydig cells...
April 2, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29626093/restoring-mitochondrial-calcium-uniporter-expression-in-diabetic-mouse-heart-improves-mitochondrial-calcium-handling-and-cardiac-function
#14
Jorge Suarez, Federico Cividini, Brian T Scott, Kim Lehmann, Julieta Diaz-Juarez, Tanja Diemer, Anzhi Dai, Jorge A Suarez, Mohit Jain, Wolfgang H Dillmann
Diabetes mellitus is a growing health care problem, resulting in significant cardiovascular morbidity and mortality. Diabetes also increases the risk for heart failure (HF) and decreased cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium level ([Ca2+]m) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate pyruvate dehydrogenase complex (PDC) activity. The mitochondrial calcium uniporter (MCU) complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore have a marked impact on cardiac myocyte metabolism and function...
April 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29624790/gene-therapy-for-glut1-deficient-mouse-using-an-adeno-associated-virus-vector-with-the-human-intrinsic-glut1-promoter
#15
Sachie Nakamura, Shin-Ichi Muramatsu, Naomi Takino, Mika Ito, Eriko F Jimbo, Kuniko Shimazaki, Tatsushi Onaka, Sumio Ohtsuki, Tetsuya Terasaki, Takanori Yamagata, Hitoshi Osaka
BACKGROUND: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. METHODS: We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1)...
April 6, 2018: Journal of Gene Medicine
https://www.readbyqxmd.com/read/29624465/practical-implications-of-factor-ix-gene-transfer-for-individuals-with-hemophilia-b-a-clinical-perspective
#16
Wolfgang Miesbach, Eileen K Sawyer
Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement...
April 6, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29624457/low-seroprevalence-of-neutralizing-antibodies-targeting-two-clade-f-aav-in-humans
#17
Jeff L Ellsworth, Michael O'Callaghan, Hillard Rubin, Albert Seymour
To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses (AAVs), the seroprevalence of neutralizing antibodies (NAbs) to these AAVs was assessed in a representative human population and compared to that of AAV9. NAb levels were measured in 100 unique human sera of different races (34, Black, 33 Caucasian, and 33 Hispanic) and sex (49% female, 51% male) collected within the United States. Fifty-six sera were tested in Huh7 cells and 44 sera were tested in 2V6...
March 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29621273/ultrafiltered-recombinant-aav8-vector-can-be-safely-administered-in-vivo-and-efficiently-transduces-liver
#18
Mark D Kleven, Michelle M Gomes, Aaron M Wortham, Caroline A Enns, Christoph A Kahl
Viral vectors are extensively purified for use in biomedical research, in order to separate biologically active virus particles and to eliminate production related impurities that are assumed to be detrimental to the host. For recombinant adeno-associated virus (rAAV) vectors this is typically accomplished using density gradient-based methods, which are tedious and require specialized ultracentrifugation equipment. In order to streamline the preparation of rAAV vectors for pilot and small animal studies, we recently devised a simple ultrafiltration approach that permits rapid virus concentration and partial removal of production-related impurities...
2018: PloS One
https://www.readbyqxmd.com/read/29618655/il-27-gene-therapy-induces-depletion-of-tregs-and-enhances-the-efficacy-of-cancer-immunotherapy
#19
Jianmin Zhu, Jin-Qing Liu, Min Shi, Xinhua Cheng, Miao Ding, Jianchao C Zhang, Jonathan P Davis, Sanjay Varikuti, Abhay R Satoskar, Lanchun Lu, Xueliang Pan, Pan Zheng, Yang Liu, Xue-Feng Bai
Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment...
April 5, 2018: JCI Insight
https://www.readbyqxmd.com/read/29617629/effects-of-interleukin-6-on-posterior-capsular-opacification
#20
Bo Ma, Lan Yang, Ruihua Jing, Jie Liu, Yumeng Quan, Qiaoyan Hui, Jingming Li, Li Qin, Cheng Pei
The purpose of this work was to determine the effects of interleukin-6 (IL-6) on the development of posterior capsular opacification (PCO) in vitro and in vivo. Western blot and real-time PCR were used to test the IL-6-induced epithelial-mesenchymal transition (EMT) marker α-smooth muscle actin (α-SMA), the extracellular matrix (ECM) markers fibronectin (Fn) and type I collagen (COL-1), transforming growth factor β2 (TGF-β2 ), and the activation and role of the JAK/STAT3 signaling pathway in human lens epithelial cells (HLECs)...
April 1, 2018: Experimental Eye Research
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