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https://www.readbyqxmd.com/read/28932756/non-clinical-safety-and-efficacy-of-an-aav2-8-vector-administered-intravenously-for-treatment-of-mucopolysaccharidosis-type-vi
#1
Rita Ferla, Marialuisa Alliegro, Jean-Brice Marteau, Margherita Dell'Anno, Edoardo Nusco, Severine Pouillot, Stefania Galimberti, Maria Grazia Valsecchi, Vincent Zuliani, Alberto Auricchio
In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28926997/effects-of-cellular-methylation-on-transgene-expression-and-site-specific-integration-of-adeno-associated-virus
#2
Diptiman Chanda, Jonathan A Hensel, Jerome T Higgs, Rajat Grover, Niroop Kaza, Selvarangan Ponnazhagan
DNA methylation is a major epigenetic event that affects not only cellular gene expression but that also has the potential to influence bacterial and viral DNA in their host-dependent functions. Adeno-associated virus (AAV) genome contains a high degree of CpG sequences capable of methylation in its terminal repeat sequences, which are the sole elements retained in AAV-based vectors used in gene therapy. The present study determined the influence of methylation status of the host cell on wild type (wt) AAV integration and recombinant (r) AAV transgene expression in HeLa cells...
September 18, 2017: Genes
https://www.readbyqxmd.com/read/28922951/a-retrospective-study-of-cytokine-profiles-changes-in-mice-with-fviii-inhibitor-development-after-aav-mediated-gene-therapy-in-hemophilia-a-mouse-model
#3
Junjiang Sun, Zhenhua Yuan, Yasmina L Abajas, Dorreen E Szollosi, Genlin Hu, Baolai Hua, Xiao Xiao, Chengwen Li
The development of inhibitory autoantibodies to the infused clotting factor VIII is a major complication for severe hemophilia A management. Novel therapy options for hemophilia have significantly progressed in the last decade and a gene therapy cure for hemophilia is translating into reality. However, mechanistic studies of FVIII autoantibodies (FVIII inhibitors) have lagged behind and remain a challenge for both protein replacement and gene therapy. FVIII inhibitor formation is assumed to be a classical T cell-dependent immune response in which cytokines/chemokines play an important role...
September 19, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28922945/aav-gene-therapy-in-a-sheep-model-of-tay-sachs-disease
#4
Heather Gray-Edwards, Ashley N Randle, Stacy Maitland, Hector Benatti, Spencer Hubbard, Peter Canning, Matthew Vogel, Brandon Brunson, Misako Hwang, Lauren Ellis, Allison M Bradbury, Atoska Gentry, Amanda Taylor, Anne Wooldridge, Dewey Wilhite, Randoplh Winter, Brain Whitlock, Jacob A Johnson, Merrilee Holland, Nouha Salibi, Ronald Beyers, James Sartin, Thomas Denney, Nancy R Cox, Miguel Sena-Esteves, Douglas R Martin
Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). Tay-Sachs disease also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 tesla MRI, echocardiograms, electrodiagnostics and cerebrospinal fluid (CSF) biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α+β) injected at high (1...
September 19, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28922943/differential-prevalence-of-antibodies-against-adeno-associated-virus-in-healthy-children-and-patients-with-mucopolysaccharidosis-iii-perspective-for-aav-mediated-gene-therapy
#5
Haiyan Fu, Aaron S Meadows, Ricardo J Pineda, Krista L Kunkler, Kristen V Truxal, Kim L McBride, Kevin Flanigan, Douglas M McCarty
Recombinant AAV vectors are promising gene therapy tools. However, pre-existing antibodies (Abs) to many useful AAV serotypes pose a critical challenge for the translation of gene therapies. As part of AAV gene therapy program for treating MPS III patients, we investigated the seroprevalence profiles of AAV1-9 and rh74 in MPS IIIA/IIIB patients and in healthy children. Using ELISA for αAAV-IgG, we observed significantly higher sero-prevalence for AAV1 and AAVrh74 in 2-7y-old MPS III patients than in healthy controls...
September 19, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28918161/clinical-and-pathological-significance-of-cutaneous-manifestations-in-anca-associated-vasculitides
#6
REVIEW
Laure Frumholtz, Sara Laurent-Roussel, Olivier Aumaître, François Maurier, Guillaume Le Guenno, Agnes Carlotti, Alexiane Dallot, Jean Louis Kemeny, Laurent Antunes, Nicolas Froment, Sylvie Fraitag, Jonathan London, Alice Berezne, Benoît Terris, Claire Le Jeunne, Luc Mouthon, Selim Aractingi, Loïc Guillevin, Nicolas Dupin, Benjamin Terrier
OBJECTIVES: Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking. METHODS: We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner. RESULTS: CM were more frequent in EGPA (53...
September 14, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28918073/a-directed-evolution-approach-to-select-for-novel-adeno-associated-virus-capsids-on-an-hiv-1-producer-t-cell-line
#7
Dawn P Wooley, Priyanka Sharma, John R Weinstein, Poornima Kotha Lakshmi Narayan, David V Schaffer, Katherine J D A Excoffon
A directed evolution approach was used to select for Adeno-associated virus (AAV) capsids that would exhibit more tropism toward an HIV-1 producer T cell line with the long-term goal of developing improved gene transfer vectors. A library of AAV variants was used to infect H9T cells previously infected or uninfected by HIV-1 followed by AAV amplification with wild-type adenovirus. Six rounds of biological selection were performed, including negative selection and diversification after round three. The H9T cells were successfully infected with all three wild-type viruses (AAV, adenovirus, and HIV-1)...
September 13, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28918020/rationally-engineered-aav-capsids-improve-transduction-and-volumetric-spread-in-the-cns
#8
Nicholas M Kanaan, Rhyomi C Sellnow, Sanford L Boye, Ben Coberly, Antonette Bennett, Mavis Agbandje-McKenna, Caryl E Sortwell, William W Hauswirth, Shannon E Boye, Fredric P Manfredsson
Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited spread and transduction efficacy in large regions of the human brain. Using rationally designed modifications of the capsid, novel AAV capsids have been generated that improve intracellular processing and result in increased transgene expression...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28918015/a-microrna124-target-sequence-restores-astrocyte-specificity-of-gfaabc1d-driven-transgene-expression-in-aav-mediated-gene-transfer
#9
Grit Taschenberger, Julia Tereshchenko, Sebastian Kügler
Experimentally restricting transgene expression exclusively to astrocytes has proven difficult. Using adeno-associated-virus-mediated gene transfer, we assessed two commonly used glial fibrillary acidic protein promoters: the full-length version gfa2 (2,210-bp human glial fibrillary acidic protein [GFAP] promoter) and the truncated variant gfaABC1D (681-bp GFAP promoter). The capacity to drive efficient, but also cell-type specific, expression of the EGFP in astrocytes was tested both in vitro in rat primary cortical cultures as well as in vivo in the rat striatum...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28917713/the-bvas-is-an-independent-predictor-of-cardiovascular-events-and-cardiovascular-disease-related-mortality-in-patients-with-anca-associated-vasculitis-a-study-of-504-cases-in-a-single-chinese-center
#10
Yi-Hua Bai, Zhi-Ying Li, Dong-Yuan Chang, Min Chen, Cees G M Kallenberg, Ming-Hui Zhao
BACKGROUND: Cardiovascular diseases (CVD) are the major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during long-term follow-up. This study investigated risk factors for cardiovascular events (CVE) and CVD-related mortality in Chinese AAV patients. METHODS: Five hundred and four AAV patients in our center were retrospectively included. The predictive value of variables associated with CVE and CVD-related mortality were analyzed...
August 31, 2017: Seminars in Arthritis and Rheumatism
https://www.readbyqxmd.com/read/28916770/changes-in-cd73-cd39-and-cd26-expression-on-t-lymphocytes-of-anca-associated-vasculitis-patients-suggest-impairment-in-adenosine-generation-and-turn-over
#11
Lovis Kling, Urs Benck, Annette Breedijk, Lisa Leikeim, Marianne Heitzmann, Stefan Porubsky, Bernhard K Krämer, Benito A Yard, Anna-Isabelle Kälsch
Extracellular adenosine, generated via the concerted action of CD39 and CD73, contributes to T-cell differentiation and function. Adenosine concentrations are furthermore influenced by adenosine deaminase binding protein CD26. Because aberrant T-cell phenotypes had been reported in anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitis (AAV) patients, an impaired expression of these molecules on T-cells of AAV patients was hypothesized in the present study. While in AAV patients (n = 29) CD26 was increased on CD4(+) lymphocytes, CD39 and CD73 were generally reduced on patients' T-cells...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28912572/follistatin-n-terminus-differentially-regulates-muscle-size-and-fat-in-vivo
#12
Hui Zheng, Chunping Qiao, Ruhang Tang, Jianbin Li, Karen Bulaklak, Zhenhua Huang, Chunxia Zhao, Yi Dai, Juan Li, Xiao Xiao
Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno-associated viral vector (AAV)...
September 15, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28911202/pathogenicity-of-a-novel-missense-variant-associated-with-choroideremia-and-its-impact-on-gene-replacement-therapy
#13
Simona Torriano, Nejla Erkilic, Valérie Faugère, Krishna Damodar, Christian P Hamel, Anne-Francoise Roux, Vasiliki Kalatzis
Choroideremia (CHM) is an inherited retinal dystrophy characterised by progressive degeneration of photoreceptors, retinal pigment epithelium (RPE) and underlying choroid. It is caused by loss-of-function mutations in CHM, which has an X-linked inheritance, and is thus an ideal candidate for gene replacement strategies. CHM encodes REP1, which plays a key role in the prenylation of Rab GTPases. We recently showed that an induced pluripotent stem cell (iPSc)-derived RPE model for CHM is fully functional and reproduces the underlying prenylation defect...
September 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28900506/combination-of-aav-trail-with-mir-221-zip-therapeutic-strategy-overcomes-the-resistance-to-trail-induced-apoptosis-in-liver-cancer
#14
Sisi Ma, Jiazeng Sun, Yabin Guo, Peng Zhang, Yanxin Liu, Dexian Zheng, Juan Shi
TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells. However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy. Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy. In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells. Specific inhibitors of miR-221 and/or miR-222, called sponge, TuD and miR-Zip were constructed, and their ability to overcome TRAIL resistance was compared...
2017: Theranostics
https://www.readbyqxmd.com/read/28900002/modeling-parkinson-s-disease-pathology-by-combination-of-fibril-seeds-and-%C3%AE-synuclein-overexpression-in-the-rat-brain
#15
Poonam Thakur, Ludivine S Breger, Martin Lundblad, Oi Wan Wan, Bengt Mattsson, Kelvin C Luk, Virginia M Y Lee, John Q Trojanowski, Anders Björklund
Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28899799/neutrophil-extracellular-traps-nets-in-autoimmune-diseases-a-comprehensive-review
#16
REVIEW
Keum Hwa Lee, Andreas Kronbichler, David Duck-Young Park, YoungMin Park, Hanwool Moon, Hyungdo Kim, Jun Hyug Choi, YoungSeo Choi, Songjoo Shim, Il Suk Lyu, Byung Hwan Yun, Yeonseung Han, Donghee Lee, Sang Yoon Lee, Byung Hun Yoo, Kyung Hwan Lee, Tai Lim Kim, Heonki Kim, Joo Sung Shim, Wonseok Nam, Heesung So, SooYeon Choi, Sangmok Lee, Jae Il Shin
The structures named neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membrane of activated neutrophils. NETs are found in a variety of conditions, such as infection, malignancy, atherosclerosis, and autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. The impact of NETs on the development mechanisms of autoimmune diseases are proposed to arise from an imbalance between "NETosis" which is a process of NET formation and NET degradation...
September 9, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28890324/direct-head-to-head-evaluation-of-recombinant-adeno-associated-viral-vectors-manufactured-in-human-versus-insect-cells
#17
Oleksandr Kondratov, Damien Marsic, Sean M Crosson, Hector R Mendez-Gomez, Oleksandr Moskalenko, Mario Mietzsch, Regine Heilbronn, Jonathan R Allison, Kari B Green, Mavis Agbandje-McKenna, Sergei Zolotukhin
The major drawback of the Baculovirus/Sf9 system for recombinant adeno-associated viral (rAAV) manufacturing is that most of the Bac-derived rAAV vector serotypes, with few exceptions, demonstrate altered capsid compositions and lower biological potencies. Here, we describe a new insect cell-based production platform utilizing attenuated Kozak sequence and a leaky ribosome scanning to achieve a serotype-specific modulation of AAV capsid proteins stoichiometry. By way of example, rAAV5 and rAAV9 were produced and comprehensively characterized side by side with HEK293-derived vectors...
August 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28888664/regulatory-t-cells-and-tlr9-activation-shape-antibody-formation-to-a-secreted-transgene-product-in-aav-muscle-gene-transfer
#18
Roland W Herzog, Mario Cooper, George Q Perrin, Moanaro Biswas, Ashley T Martino, Laurence Morel, Cox Terhorst, Brad E Hoffman
Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response...
August 1, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28885482/comparison-of-localized-and-systemic-otitis-media-with-anca-associated-vasculitis
#19
Masahiro Okada, Koichiro Suemori, Daiki Takagi, Masato Teraoka, Hiroyuki Yamada, Naohito Hato
OBJECTIVE: To investigate differences in immune activity based on the presence of multiple organ involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and whether hearing outcomes are different between patients with AAV localized to the ear and patients with systemic AAV. STUDY DESIGN: Retrospective case review. SETTING: University hospital. PATIENTS: Twenty patients with otitis media with AAV (OMAAV) who met the criteria proposed by the OMAAV study group in Japan...
September 6, 2017: Otology & Neurotology
https://www.readbyqxmd.com/read/28884027/aav-klf7-promotes-descending-propriospinal-neuron-axonal-plasticity-after-spinal-cord-injury
#20
Wen-Yuan Li, Ying Wang, Feng-Guo Zhai, Ping Sun, Yong-Xia Cheng, Ling-Xiao Deng, Zhen-Yu Wang
DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced...
2017: Neural Plasticity
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