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https://www.readbyqxmd.com/read/28346434/optimization-of-adeno-associated-virus-vector-mediated-gene-transfer-to-the-respiratory-tract
#1
F Kurosaki, R Uchibori, N Mato, Y Sehara, Y Saga, M Urabe, H Mizukami, Y Sugiyama, A Kume
An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters, and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter...
March 27, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28345428/induction-of-t-cell-infiltration-and-programmed-death-ligand-2-expression-by-adeno-associated-virus-in-rhesus-macaque-skeletal-muscle-and-modulation-by-prednisone
#2
Megan L Cramer, Guohong Shao, Louise R Rodino-Klapac, Louis G Chicoine, Paul T Martin
Use of adeno-associated virus (AAV) to transduce genes into skeletal muscles can be associated with T-cell responses to viral capsid and/or to transgenic protein. Intramuscular mononuclear cell infiltrates primarily consisting of CD8+ T cells and also containing FOXP3+ regulatory T cells were present in rhesus macaque skeletal muscle treated with rAAVrh74.MCK.GALGT2 by vascular delivery. Administration of oral prednisone prior to AAV gene delivery and throughout the study reduced such infiltrates by 60% at 24 weeks post-AAV delivery compared to AAV-treated animals not receiving prednisone, regardless of the presence of pre-existing AAV serum antibodies at the time of treatment...
March 27, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#3
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28345001/effective-depletion-of-pre-existing-anti-aav-antibodies-requires-broad-immune-targeting
#4
Victoria M Velazquez, Aaron S Meadows, Ricardo J Pineda, Marybeth Camboni, Douglas M McCarty, Haiyan Fu
Pre-existing antibodies (Abs) to AAV pose a critical challenge for the translation of gene therapies. No effective approach is available to overcome pre-existing Abs. Given the complexity of Ab production, overcoming pre-existing Abs will require broad immune targeting. We generated a mouse model of pre-existing AAV9 Abs to test multiple immunosuppressants, including bortezomib, rapamycin, and prednisolone, individually or in combination. We identified an effective approach combining rapamycin and prednisolone, reducing serum AAV9 Abs by 70%-80% at 4 weeks and 85%-93% at 8 weeks of treatment...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28345000/syngeneic-aav-pseudo-particles-potentiate-gene-transduction-of-aav-vectors
#5
Qizhao Wang, Biao Dong, Katie A Pokiniewski, Jenni Firrman, Zhongren Wu, Mario P S Chin, Xiongwen Chen, LinShu Liu, Ruian Xu, Yong Diao, Weidong Xiao
Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of "empty" AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo-vectors with no DNA inside the capsids...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344998/low-dose-liver-targeted-gene-therapy-for-pompe-disease-enhances-therapeutic-efficacy-of-ert-via-immune-tolerance-induction
#6
Sang-Oh Han, Giuseppe Ronzitti, Benjamin Arnson, Christian Leborgne, Songtao Li, Federico Mingozzi, Dwight Koeberl
Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 10(11) vector genomes [vg]/kg)...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28341564/systemic-aav-gene-therapy-close-to-clinical-trials-for-several-neuromuscular-diseases
#7
Dominic J Wells
No abstract text is available yet for this article.
March 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28339745/chronic-nasal-staphylococcus-aureus-carriage-identifies-a-subset-of-newly-diagnosed-granulomatosis-with-polyangiitis-patients-with-high-relapse-rate
#8
Anna Salmela, Niels Rasmussen, Jan Willem Cohen Tervaert, David R W Jayne, Agneta Ekstrand
Objective.: The aim of this study was to evaluate whether chronic nasal carriage of Staphylococcus aureus (SA) is related to relapses in patients with newly diagnosed ANCA-associated vasculitis (AAV). Methods.: In two clinical trials (n = 200), for early systemic (n = 83) and generalized (n = 117) AAV, nasal swabs were obtained monthly and at the time of a relapse. Chronic nasal SA carriage (CNSAC) was defined as ⩾ 75% of cultures being SA positive, with non-carriers being SA negative in all cultures and remaining patients being intermittent carriers...
February 20, 2017: Rheumatology
https://www.readbyqxmd.com/read/28339364/clinical-and-prognostic-features-of-korean-patients-with-mpo-anca-pr3-anca-and-anca-negative-vasculitis
#9
Juyoung Yoo, Ho Jae Kim, Sung Soo Ahn, Seung Min Jung, Jason Jungsik Song, Yong-Beom Park, Sang-Won Lee
OBJECTIVES: We reclassified Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) into 3 categories of AAV including MPO-ANCA, PR3-ANCA and ANCA negative vasculitis, and investigated clinical and prognostic features. METHODS: We reviewed the medical records of 133 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), who had having either myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA or no ANCA, and who had ever achieved the first remission...
March 23, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28336343/viral-delivered-gene-therapy-to-treat-catecholamine-dependent-polymorphic-ventricular-tachycardia-cpvt2-in-mouse-models
#10
Efrat Kurtzwald-Josefson, Dor Yadin, Shiraz Harun-Khun, Maayan Waldman, Dan Aravot, Asher Shainberg, Michael Eldar, Edith Hochhauser, Michael Arad
BACKGROUND: The recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein defficiency. OBJECTIVE: To develop a viral-delivered gene therapy for CPVT2 and determine the relationship between CASQ2 expression and the antiarrhythmic efficacy in a murine model. METHODS: We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2(D307H)) or CASQ2 knock-out (CASQ2(Δ/Δ))...
March 20, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28335619/over-expression-of-the-x-linked-inhibitor-of-apoptosis-protects-against-retinal-degeneration-in-a-feline-model-of-retinal-detachment
#11
Sarah Wassmer, Brian Leonard, Stuart Coupland, Adam Baker, John Hamilton, William W Hauswirth, Catherine Tsilfidis
Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. We tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into 2 experimental groups...
March 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28335618/aav-an-overview-of-unanswered-questions
#12
Kenneth I Berns, Nicholas Muzyczka
Today AAV is one of the most promising and successful gene therapy vectors. AAV vectors have been successful in the treatment of several monogenic diseases in early clinical trials1. Although work in the past has focused primarily on gene replacement, many investigators are now adapting the vector system to new clinical modalities including RNAi and gene modifying strategies such as Crisper/cas91. Moreover, Glybera2 has been licensed for clinical use in the European Union for treatment of a lysosomal storage disease...
March 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28334834/aav-mediated-transfer-of-fkrp-shows-therapeutic-efficacy-in-a-murine-model-but-requires-control-of-gene-expression
#13
Evelyne Gicquel, Natacha Maizonnier, Steven J Foltz, William J Martin, Nathalie Bourg, Fedor Svinartchouk, Karine Charton, Aaron M Beedle, Isabelle Richard
Limb Girdle Muscular Dystrophies type 2I (LGMD2I), a recessive autosomal muscular dystrophy, is caused by mutations in the Fukutin Related Protein (FKRP) gene. It has been proposed that FKRP, a ribitol-5-phosphate transferase, is a participant in α-dystroglycan (αDG) glycosylation, which is important to ensure the cell/matrix anchor of muscle fibers. A LGMD2I knock-in mouse model was generated to express the most frequent mutation (L276I) encountered in patients. The expression of FKRP was not altered neither at transcriptional nor at translational levels, but its function was impacted since abnormal glycosylation of αDG was observed...
March 3, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334808/downregulation-of-pathways-implicated-in-liver-inflammation-and-tumorigenesis-of-glycogen-storage-disease-type-ia-mice-receiving-gene-therapy
#14
Goo-Young Kim, Joon Hyun Kwon, Jun-Ho Cho, Lisa Zhang, Brian C Mansfield, Janice Y Chou
Glycogen storage disease type Ia (GSD-Ia) is characterized by impaired glucose homeostasis and long-term risks of hepatocellular adenoma (HCA) and carcinoma (HCC). We have shown that the non-tumor-bearing (NT), recombinant adeno-associated virus (rAAV) vector-treated GSD-Ia mice (AAV-NT mice) expressing a wide range (0.9-63%) of normal hepatic glucose-6-phosphatase-α activity maintain glucose homeostasis and display physiologic features mimicking animals living under calorie restriction (CR). We now show that in AAV-NT mice, the signaling pathways of the CR mediators, AMP-activated protein kinase (AMPK) and sirtuin-1 are activated...
March 13, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334779/targeted-gene-knock-in-by-homology-directed-genome-editing-using-cas9-ribonucleoprotein-and-aav-donor-delivery
#15
Thomas Gaj, Brett T Staahl, Gonçalo M C Rodrigues, Prajit Limsirichai, Freja K Ekman, Jennifer A Doudna, David V Schaffer
Realizing the full potential of genome editing requires the development of efficient and broadly applicable methods for delivering programmable nucleases and donor templates for homology-directed repair (HDR). The RNA-guided Cas9 endonuclease can be introduced into cells as a purified protein in complex with a single guide RNA (sgRNA). Such ribonucleoproteins (RNPs) can facilitate the high-fidelity introduction of single-base substitutions via HDR following co-delivery with a single-stranded DNA oligonucleotide...
March 2, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334745/disease-correction-by-aav-mediated-gene-therapy-in-a-new-mouse-model-of-mucopolysaccharidosis-type-iiid
#16
Carles Roca, Sandra Motas, Sara Marcó, Albert Ribera, Víctor Sánchez, Xavier Sánchez, Joan Bertolin, Xavier León, Jennifer Pérez, Miguel Garcia, Pilar Villacampa, Jesús Ruberte, Anna Pujol, Virginia Haurigot, Fatima Bosch
Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D...
February 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334541/-autoantibodies-in-systemic-connective-tissue-disease-and-anca-associated-vasculitis-their-relationship-to-interstitial-lung-diseases-and-prognosis
#17
Martina Doubková, Jana Pokorná
Lung disease, including interstitial lung disease (ILD), is a frequent complication of systemic connective tissue disorders (CTD) and ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis (AAV). Pulmonary manifestations are prognostic factor of CTDs and vasculitis. Autoantibodies assessment is a part of differential diagnosis algorithm of lung diseases. Autoantibodies importance is mainly clinical-diagnostic. Using detection of some autoantibodies it is possible to determine prognosis of lung involvement, especially in CTDs...
2017: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/28325846/soluble-flt1-gene-therapy-alleviates-brain-arteriovenous-malformation-severity
#18
Wan Zhu, Fanxia Shen, Lei Mao, Lei Zhan, Shuai Kang, Zhengda Sun, Jeffrey Nelson, Rui Zhang, Dingquan Zou, Cameron M McDougall, Michael T Lawton, Thiennu H Vu, Zhijian Wu, Abraham Scaria, Peter Colosi, John Forsayeth, Hua Su
BACKGROUND AND PURPOSE: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. Excessive vascular endothelial growth factor has been implicated in bAVM pathophysiology. Because soluble FLT1 binds to vascular endothelial growth factor with high affinity, we tested intravenous delivery of an adeno-associated viral vector serotype-9 expressing soluble FLT1 (AAV9-sFLT1) to alleviate the bAVM phenotype...
March 21, 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/28325790/dopamine-terminals-from-the-ventral-tegmental-area-gate-intrinsic-inhibition-in-the-prefrontal-cortex
#19
William C Buchta, Stephen V Mahler, Benjamin Harlan, Gary S Aston-Jones, Arthur C Riegel
Spike frequency adaptation (SFA or accommodation) and calcium-activated potassium channels that underlie after-hyperpolarization potentials (AHP) regulate repetitive firing of neurons. Precisely how neuromodulators such as dopamine from the ventral tegmental area (VTA) regulate SFA and AHP (together referred to as intrinsic inhibition) in the prefrontal cortex (PFC) remains unclear. Using whole cell electrophysiology, we measured intrinsic inhibition in prelimbic (PL) layer 5 pyramidal cells of male adult rats...
March 2017: Physiological Reports
https://www.readbyqxmd.com/read/28325286/inclusion-of-the-woodchuck-hepatitis-virus-posttranscriptional-regulatory-element-enhances-aav2-driven-transduction-of-mouse-and-human-retina
#20
Maria I Patrício, Alun R Barnard, Harry O Orlans, Michelle E McClements, Robert E MacLaren
The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) has been included in the transgene cassette of adeno-associated virus (AAV) in several gene therapy clinical trials, including those for inherited retinal diseases. However, the extent to which WPRE increases transgene expression in the retina is still unclear. To address this question, AAV2 vectors containing a reporter gene with and without WPRE were initially compared in vitro and subsequently in vivo by subretinal delivery in mice...
March 17, 2017: Molecular Therapy. Nucleic Acids
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