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adeno associated virus

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https://www.readbyqxmd.com/read/29350681/aav-9-mediated-phosphatase-1-inhibitor-1-overexpression-improves-cardiac-contractility-in-unchallenged-mice-but-is-deleterious-in-pressure-overload
#1
D M Schwab, L Tilemann, R Bauer, M Heckmann, A Jungmann, M Wagner, J Burgis, C Vettel, H A Katus, A El-Armouche, O J Müller
The downregulation of β-adrenergic receptors (β-AR) and decreased cAMP-dependent protein kinase activity in failing hearts results in decreased phosphorylation and inactivation of phosphatase-inhibitor-1 (I-1), a distal amplifier element of β-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to β-AR desensitization; therefore its modulation is a promising approach in heart failure treatment...
January 19, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29349097/universal-method-for-the-purification-of-recombinant-aav-vectors-of-differing-serotypes
#2
Shelley A Nass, Maryellen A Mattingly, Denise A Woodcock, Brenda L Burnham, Jeffrey A Ardinger, Shayla E Osmond, Amy M Frederick, Abraham Scaria, Seng H Cheng, Catherine R O'Riordan
The generation of clinical good manufacturing practices (GMP)-grade adeno-associated virus (AAV) vectors requires purification strategies that support the generation of vectors of high purity, and that exhibit a good safety and efficacy profile. To date, most reported purification schemas are serotype dependent, requiring method development for each AAV gene therapy product. Here, we describe a platform purification process that is compatible with the purification of multiple AAV serotypes. The method generates vector preparations of high purity that are enriched for capsids with full vector genomes, and that minimizes the fractional content of empty capsids...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29349096/safety-and-efficacy-of-aav-retrograde-pancreatic-ductal-gene-delivery-in-normal-and-pancreatic-cancer-mice
#3
Kayla A Quirin, Jason J Kwon, Arafat Alioufi, Tricia Factora, Constance J Temm, Max Jacobsen, George E Sandusky, Kim Shontz, Louis G Chicoine, K Reed Clark, Joshua T Mendell, Murray Korc, Janaiah Kota
Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg)...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29344663/adeno-associated-virus-type-2-mediated-gene-transfer-of-a-short-hairpin-rna-targeting-human-igfbp-2-suppresses-the-proliferation-and-invasion-of-mda-mb-468-cells
#4
Chao Gao, Ru-Song Zhang, Nan Zheng, Chen Wang
Adeno-associated virus 2 (AAV2) is prepotent in the biological treatment of breast tumor because of its low pathogenicity and immunogenicity. Our previous study demonstrated that insulin‑like growth factor‑binding protein 2 (IGFBP‑2) was highly expressed in patients with breast metastasis. In the present study, the effects of recombinant AAV2 on the growth and metastasis of breast cancer cells were determined in vitro, and in vivo. rAAV2-ZsGreen-shRNA-scramble and rAAV2‑ZsGreen‑shRNA‑hIGFBP‑2 were used to transfect MDA‑MB‑468, and MCF‑10A cells respectively, and observed that these virus could not penetrate the normal human breast epithelia MCF‑10A cell line...
January 16, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29344635/eradication-of-cervical-cancer-in-vivo-by-an-aav-vector-that-encodes-shrna-targeting-human-papillomavirus-type-16%C3%A2-e6-e7
#5
Naoto Sato, Yasushi Saga, Ryosuke Uchibori, Tomonori Tsukahara, Masashi Urabe, Akihiro Kume, Hiroyuki Fujiwara, Mitsuaki Suzuki, Keiya Ozawa, Hiroaki Mizukami
The major causative agent of cervical cancer is human papilloma virus (HPV); the viral proteins E6 and E7 induce carcinogenesis through the inactivation of the host tumor-suppressor gene. Therefore, the stable expression of specific inhibitors of E6 and E7 in cancer cells is expected to provide effective treatment for cervical cancer without affecting normal tissue. In this study, we propose a novel therapeutic approach using an adeno-associated virus (AAV) vector encoding short hairpin RNA (shRNA) against the oncoproteins E6 and E7 (shE6E7) of HPV type 16 (HPV‑16), termed AAV‑shE6E7...
January 15, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29343568/an-alternate-route-for-adeno-associated-virus-entry-independent-of-aavr
#6
Amanda M Dudek, Sirika Pillay, Andreas S Puschnik, Claude M Nagamine, Fang Cheng, Jianming Qiu, Jan E Carette, Luk H Vandenberghe
Determinants and mechanisms of cell attachment and entry steer the Adeno-Associated Virus (AAV) in its utility as a gene therapy vector. Thus far a systematic assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR (KIAA0319L) to establish transduction has been lacking, despite potential implications for cell and tissue tropism. Here, a large set of human and simian AAVs as well as in silico reconstructed ancestral AAV capsids were interrogated for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and AAVrh32...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29341898/induction-of-alpha-synuclein-pathology-in-the-enteric-nervous-system-of-the-rat-and-non-human-primate-results-in-gastrointestinal-dysmotility-and-transient-cns-pathology
#7
Fredric P Manfredsson, Kelvin C Luk, Matthew J Benskey, Aysegul Guezer, Joanna Garcia, Nathan C Kuhn, Ivette M Sandoval, Joseph R Patterson, Alana O'Mara, Reid Yonkers, Jeffrey H Kordower
Alpha-Synuclein (α-syn) is by far the most highly vetted pathogenic and therapeutic target in Parkinson's disease. Aggregated α-syn is present in sporadic Parkinson's disease, both in the central nervous system (CNS) and peripheral nervous system (PNS). The enteric division of the PNS is of particular interest because 1) gastric dysfunction is a key clinical manifestation of Parkinson's disease, and 2) Lewy pathology in myenteric and submucosal neurons of the enteric nervous system (ENS) has been referred to as stage zero in the Braak pathological staging of Parkinson's disease...
January 13, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29339053/upregulation-of-nlrp3-via-stat3-dependent-histone-acetylation-contributes-to-painful-neuropathy-induced-by-bortezomib
#8
Cui-Cui Liu, Zhu-Xi Huang, Xiao Li, Kai-Feng Shen, Meng Liu, Han-Dong Ouyang, Su-Bo Zhang, Yu-Ting Ruan, Xiao-Long Zhang, Shao-Ling Wu, Wen-Jun Xin, Chao Ma
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats...
January 12, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29335275/interplay-between-chrebp-and-srebp-1c-coordinates-postprandial-glycolysis-and-lipogenesis-in-livers-of-mice
#9
Albert G Linden, Shili Li, Hwa Y Choi, Fei Fang, Masashi Fukasawa, Kosaku Uyeda, Robert E Hammer, Jay D Horton, Luke J Engelking, Guosheng Liang
Lipogenesis in liver is highest in the postprandial state; insulin activates SREBP-1c, which transcriptionally activates genes involved in fatty acid (FA) synthesis, whereas glucose activates ChREBP, which activates both glycolysis and FA synthesis. Whether SREBP-1c and ChREBP act independently of one another is unknown. Here, we characterized mice with liver-specific deletion of ChREBP (L-Chrebp-/- mice). Hepatic ChREBP deficiency resulted in reduced mRNA levels of glycolytic and lipogenic enzymes, particularly in response to sucrose refeeding following fasting, a dietary regimen that elicits maximal lipogenesis...
January 15, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29335220/adeno-associated-virus-vector-mediated-expression-of-dj-1-attenuates-learning-and-memory-deficits-in-2-2%C3%A2-4-4%C3%A2-tetrabromodiphenyl-ether-bde-47-treated-mice
#10
Juan Zhuang, Shan Wang, Qun Shan, Zi-Feng Zhang, Meng-Qiu Li, Gui-Hong Zheng, Shao-Hua Fan, Dong-Mei Wu, Bin Hu, Jun Lu, Yuan-Lin Zheng
Evidence indicates that oxidative stress is the central pathological feature of 2, 2´, 4, 4´-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity. Protein kinase C delta (PKCδ), an oxidative stress-sensitive kinase, can be proteolytically cleaved to yield a catalytically active fragment (PKCδ-CF) that is involved in various neurodegenerative disorders. Here, we showed that BDE-47 treatment increased ROS, malondialdehyde, and protein carbonyl levels in the mouse hippocampus. In turn, excessive ROS induced caspase-3-dependent PKCδ activation and stimulated NF-κB p65 nuclear translocation, resulting in inflammation in the mouse hippocampus...
January 8, 2018: Journal of Hazardous Materials
https://www.readbyqxmd.com/read/29326962/emerging-issues-in-aav-mediated-in%C3%A2-vivo-gene-therapy
#11
REVIEW
Pasqualina Colella, Giuseppe Ronzitti, Federico Mingozzi
In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29326299/targeting-mutant-kras-with-crispr-cas9-controls-tumor-growth
#12
Hyongbum Henry Kim, Wonjoo Kim, Sangeun Lee, Han Sang Kim, Minjung Song, Yong Hoon Cha, Young-Hoon Kim, Jeonghong Shin, Eun-Seo Lee, Yeonsoo Joo, Jae J Song, Eun Ju Choi, Jae W Choi, Jinu Lee, Moonkyung Kang, Jong In Yook, Min Goo Lee, Yeon-Soo Kim, Soonmyung Paik
KRAS is the most frequently mutated oncogene in human tumors and its activating mutations represents important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA...
January 11, 2018: Genome Research
https://www.readbyqxmd.com/read/29325933/sestrin2-prevents-age-related-intolerance-to-post-myocardial-infarction-via-ampk-pgc-1%C3%AE-pathway
#13
Nanhu Quan, Lin Wang, Xu Chen, Chelsea Luckett, Courtney Cates, Thomas Rousselle, Yang Zheng, Ji Li
We have revealed that a novel stress-inducible protein, Sestrin2, declines in the heart with aging. Moreover, there is an interaction between Sestrin2 and energy sensor AMPK in the heart in response to ischemic stress. The objective of this study is to determine whether Sestrin2-AMPK complex modulates PGC-1α in the heart and protects the heart from ischemic insults. In order to characterize the role of cardiac Sestrin2-AMPK signaling cascade in aging, C57BL/6 wild type young mice (3-4months), aged mice (24-26months) and young Sestrin2 KO mice were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia...
January 8, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29325092/intravenous-administration-of-scaav9-hexb-normalizes-lifespan-and-prevents-pathology-in-sandhoff-disease-mice
#14
Natalia Niemir, Laura Rouvière, Aurore Besse, Marie T Vanier, Jasmin Dmytrus, Thibaut Marais, Stéphanie Astord, Jean-Philippe Puech, Ganna Panasyuk, Jonathan D Cooper, Martine Barkats, Catherine Caillaud
Sandhoff disease (SD) is a rare inherited disorder caused by a deficiency of β-hexosaminidase activity which is fatal because no effective treatment is available. A mouse model of Hexb deficiency reproduces the key pathognomonic features of SD patients with severe ubiquitous lysosomal dysfunction, GM2 accumulation, neuroinflammation and neurodegeneration, culminating in death at 4 months. Here, we show that a single intravenous neonatal administration of a self-complementary adeno-associated virus 9 vector (scAAV9) expressing the Hexb cDNA in SD mice is safe and sufficient to prevent disease development...
January 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29321310/therapeutic-efficacy-of-vectored-pgt121-gene-delivery-in-hiv-1-infected-humanized-mice
#15
Alexander Badamchi-Zadeh, Lawrence J Tartaglia, Peter Abbink, Christine A Bricault, Po-Ting Liu, Michael Boyd, Marinela Kirilova, Noe B Mercado, Ovini S Nanayakkara, Vladimir D Vrbanac, Andrew M Tager, Rafael A Larocca, Michael S Seaman, Dan H Barouch
Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource poor settings, where the HIV-1 disease burden is greatest. In vivo vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1 specific bNAb PGT121 in wildtype and immunocompromised C57Bl/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29318471/aav-mediated-gene-delivery-of-the-calreticulin-anti-angiogenic-domain-inhibits-ocular-neovascularization
#16
Leilei Tu, Jiang-Hui Wang, Veluchamy A Barathi, Selwyn M Prea, Zheng He, Jia Hui Lee, James Bender, Anna E King, Grant J Logan, Ian E Alexander, Youn-Shen Bee, Ming-Hong Tai, Gregory J Dusting, Bang V Bui, Jingxiang Zhong, Guei-Sheung Liu
Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization...
January 9, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29317724/rfx1-and-rfx3-transcription-factors-interact-with-the-d-sequence-of-adeno-associated-virus-inverted-terminal-repeat-and-regulate-aav-transduction
#17
Laura Julien, Julie Chassagne, Cécile Peccate, Stéphanie Lorain, France Piétri-Rouxel, Olivier Danos, Sofia Benkhelifa-Ziyyat
Adeno-associated virus (AAV) transduction efficiency depends on the way in which cellular proteins process viral genomes in the nucleus. In this study, we have investigated the binding of nuclear proteins to the double stranded D (dsD) sequence of the AAV inverted terminal repeat (ITRs) by electromobility shift assay. We present here several lines of evidence that transcription factors belonging to the RFX protein family bind specifically and selectively to AAV2 and AAV1 dsD sequences. Using supershift experiments, we characterize complexes containing RFX1 homodimers and RFX1/RFX3 heterodimers...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29316814/biology-of-the-adrenal-gland-cortex-obviates-effective-use-of-adeno-associated-virus-vectors-to-treat-hereditary-adrenal-disorders
#18
Sandra Markmann, Bishnu P De, Jasmine Reid, Clarisse Jose, Jonathan B Rosenberg, Philip Leopold, Stephen M Kaminsky, Dolan Sondhi, Odelya E Pagovich, Ronald G Crystal
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder occurring in 1:10,000-1:20,000 live births. In >95% of the cases, CAH results from mutations in the CYP21A2 gene, encoding the adrenal steroid enzyme 21-hydroxylase (21OH). Cardinal phenotypic features of CAH include genital ambiguity and sexual precocity, and in severe cases, neonatal salt loss and death. Current standard of care consists of life-long oral steroid replacement to reverse the cortisol deficiency. Although significant advances in the treatment of CAH have been made, the burden of a life-long therapeutic intervention is not ideal for quality of life...
January 9, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29316812/aavrh10-gene-therapy-ameliorates-central-and-peripheral-nervous-system-disease-in-canine-globoid-cell-leukodystrophy-krabbe-disease
#19
Allison M Bradbury, Mohammad A Rafi, Jessica Bagel, Becky K Brisson, Michael S Marshall, Jill Pesayco Salvador, Xuntian Jiang, Gary P Swain, Maria L Prociuk, Patricia O'Donnell, Caitlin Fitzgerald, Daniel S Ory, Ernesto R Bongarzone, G Diane Shelton, David A Wenger, Charles Vite
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase (GALC). Most commonly, deficits of GALC result in widespread central and peripheral nervous system (CNS, PNS) demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem cell transplantation is the current standard of care in children diagnosed prior to symptom onset; however, disease correction is incomplete. Herein we present the first adeno-associated virus (AAV) gene therapy experiments in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients...
January 9, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29314192/parvalbumin-producing-striatal-interneurons-receive-excitatory-inputs-onto-proximal-dendrites-from-the-motor-thalamus-in-male-mice
#20
Yasutake Nakano, Fuyuki Karube, Yasuharu Hirai, Kenta Kobayashi, Hiroyuki Hioki, Shinichiro Okamoto, Hiroshi Kameda, Fumino Fujiyama
In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor-related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)-producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor-related cortical and thalamic inputs to striatal PV interneurons...
January 4, 2018: Journal of Neuroscience Research
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