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adeno-associated viral

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https://www.readbyqxmd.com/read/29349096/safety-and-efficacy-of-aav-retrograde-pancreatic-ductal-gene-delivery-in-normal-and-pancreatic-cancer-mice
#1
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/29344635/eradication-of-cervical-cancer-in-vivo-by-an-aav-vector-that-encodes-shrna-targeting-human-papillomavirus-type-16%C3%A2-e6-e7
#2
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
#3
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
#4
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/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
#5
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/29325457/synthetic-adeno-associated-viral-vector-efficiently-targets-mouse-and-non-human-primate-retina-in-vivo
#6
Livia S Carvalho, Ru Xiao, Sarah Wassmer, Aliete Langsdorf, Eric Zinn, Simon Pacouret, Samiksha Shah, Jason I Comander, Leo Kim, Laurence Lim, Luk H Vandenberghe
Gene therapy is a promising approach in the treatment of inherited and common complex disorders of the retina. Preclinical and clinical studies have validated the use of adeno-associated viral vectors (AAV) as a safe and efficient delivery vehicle for gene transfer. RPE and rods, and to a lesser extent, cone photoreceptors can be efficiently targeted with AAV. Other retinal cell types however are more challenging targets. The aim of this study was to characterize the transduction profile and efficiency of in silico designed, synthetic Anc80 AAVs for retinal gene transfer...
January 12, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29321310/therapeutic-efficacy-of-vectored-pgt121-gene-delivery-in-hiv-1-infected-humanized-mice
#7
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/29317724/rfx1-and-rfx3-transcription-factors-interact-with-the-d-sequence-of-adeno-associated-virus-inverted-terminal-repeat-and-regulate-aav-transduction
#8
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
#9
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/29304344/endogenous-reprogramming-of-alpha-cells-into-beta-cells-induced-by-viral-gene-therapy-reverses-autoimmune-diabetes
#10
Xiangwei Xiao, Ping Guo, Chiyo Shiota, Ting Zhang, Gina M Coudriet, Shane Fischbach, Krishna Prasadan, Joseph Fusco, Sabarinathan Ramachandran, Piotr Witkowski, Jon D Piganelli, George K Gittes
Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin+ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes...
January 4, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29289570/high-efficiency-transduction-of-spinal-cord-motor-neurons-by-intrauterine-delivery-of-integration-deficient-lentiviral-vectors
#11
S G Ahmed, S N Waddington, M G Boza-Morán, R J Yáñez-Muñoz
Integration-deficient lentiviral vectors (IDLVs) are promising gene delivery tools that retain the high transduction efficiency of standard lentiviral vectors, yet fail to integrate as proviruses and are instead converted into episomal circles. These episomes are metabolically stable and support long-term expression of transgenes in non-dividing cells, exhibiting a decreased risk of insertional mutagenesis. We have embarked on an extensive study to compare the transduction efficiency of IDLVs pseudotyped with different envelopes (vesicular stomatitis, Rabies, Mokola and Ross River viral envelopes) and self-complementary adeno-associated viral vectors, serotype-9 (scAAV-9) in spinal cord tissues after intraspinal injection of mouse embryos (E16)...
December 28, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29287910/ventral-tegmental-area-d2-receptor-knockdown-enhances-choice-impulsivity-in-a-delay-discounting-task-in-rats
#12
Kimberly A Bernosky-Smith, Yan-Yan Qiu, Malte Feja, Yun Beom Lee, Brian Loughlin, Jun-Xu Li, Caroline E Bass
Impulsivity associated with abnormal dopamine (DA) function has been observed in several disorders, including addiction. Choice impulsivity is the preference for small, immediate rewards over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discount rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with DA D2 receptor (D2R) availability in the midbrain and striatum, it is difficult to mechanistically link the two, due to the diverse neuroanatomical localization of D2Rs, which are found throughout the brain, in many types of neurons and neuronal subcompartments...
December 26, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29282655/a-novel-and-high-efficient-aav6-mutant
#13
Feifei Wang, Can Huang, Jinjing Cao, Xiaomei Liu, Dongxin Wang, Chun Zhang, Qin Chen
Adeno-associated virus has been gaining prominence in its use as a highly secure virus gene vector with low immunogenicity in the field of human gene therapy. However, wild-type adeno-associated virus sometimes has low transduction efficiency for certain tissues or cells both in vivo and in vitro. Thus, achieving the desired level of expression often requires a large dose. Large doses of viral injection in clinical applications will not only trigger the body's immune response but will come at a high production cost...
December 27, 2017: Virus Genes
https://www.readbyqxmd.com/read/29281894/adeno-associated-virus-2-aav2-mediated-reintroduction-of-microrna-19b-attenuates-hepatic-fibrosis
#14
Elizabeth Brandon-Warner, Jennifer H Benbow, Jacob H Swet, Nicole A Feilen, Catherine R Culberson, Iain H McKillop, Andrew S deLemos, Mark W Russo, Laura W Schrum
Fibrotic liver injury is a significant healthcare burden in the United States that represents a major cause of morbidity and mortality for which there are no effective FDA approved treatment strategies. Fibrosis is considered a disruption of normal wound healing responses mediated by fibroblastic cells which are triggered and sustained by pro-fibrotic cytokines such as transforming growth factor-beta1 (TGFβ1). TGFβ1-mediated transdifferentiation of hepatic stellate cells (HSCs) from quiescent to activated myofibroblast is a pivotal event in the development of fibrosis...
December 27, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29278489/reprogramming-the-activatable-peptide-display-function-of-adeno-associated-virus-nanoparticles
#15
Nicole N Thadani, Christopher Dempsey, Julia Zhao, Sonya M Vasquez, Junghae Suh
We harnessed an intrinsic activatable peptide display behavior shared by several parvoviruses, including the adeno-associated virus (AAV), in order to design protein-based nanodevices that can carry out an exogenous functional output in response to stimulus detection. Specifically, we generated truncated viral capsid subunits that, when combined with native capsid components into mosaic capsids, can perform robust activatable peptide display. By modulating the ratio of subunits in the mosaic capsid, properties of the activatable peptide display function can be optimized...
December 26, 2017: ACS Nano
https://www.readbyqxmd.com/read/29259525/%C3%A2-adeno-associated-virus-aav-dual-vector-strategies-for-gene-therapy-encoding-large-transgenes
#16
REVIEW
Michelle E McClements, Robert E MacLaren
The use of adeno-associated viral (AAV) vectors for gene therapy treatments of inherited disorders has accelerated over the past decade with multiple clinical trials ongoing in varying tissue types and new ones initiating every year. These vectors are exhibiting low-immunogenicity across the clinical trials in addition to showing evidence of efficacy, making it clear they are the current standard vector for any potential gene therapy treatment. However, AAV vectors do have a limitation in their packaging capacity, being capable of holding no more than ~5kb of DNA and in a therapeutic transgene scenario, this length of DNA would need to include genetic control elements in addition to the gene coding sequence (CDS) of interest...
December 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/29251729/virus-stamping-for-targeted-single-cell-infection-in-vitro-and-in-vivo
#17
Rajib Schubert, Stuart Trenholm, Kamill Balint, Georg Kosche, Cameron S Cowan, Manuel A Mohr, Martin Munz, David Martinez-Martin, Gotthold Fläschner, Richard Newton, Jacek Krol, Brigitte Gross Scherf, Keisuke Yonehara, Adrian Wertz, Aaron Ponti, Alexander Ghanem, Daniel Hillier, Karl-Klaus Conzelmann, Daniel J Müller, Botond Roska
Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle-a functionalized glass pipette tip or magnetic nanoparticles in a pipette-that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses...
December 18, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29249183/aav-gene-delivery-to-the-spinal-cord-serotypes-methods-candidate-diseases-and-clinical-trials
#18
Nathan Hardcastle, Nicholas M Boulis, Thais Federici
Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway. Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed...
December 18, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29244806/cellular-selectivity-of-aav-serotypes-for-gene-delivery-in-neurons-and-astrocytes-by-neonatal-intracerebroventricular-injection
#19
Sean L Hammond, Ashley N Leek, Evan H Richman, Ronald B Tjalkens
The non-pathogenic parvovirus, adeno-associated virus (AAV), is an efficient vector for transgene expression in vivo and shows promise for treatment of brain disorders in clinical trials. Currently, there are more than 100 AAV serotypes identified that differ in the binding capacity of capsid proteins to specific cell surface receptors that can transduce different cell types and brain regions in the CNS. In the current study, multiple AAV serotypes expressing a GFP reporter (AAV1, AAV2/1, AAVDJ, AAV8, AAVDJ8, AAV9, AAVDJ9) were screened for their infectivity in both primary murine astrocyte and neuronal cell cultures...
2017: PloS One
https://www.readbyqxmd.com/read/29236688/evolution-of-a-designed-protein-assembly-encapsulating-its-own-rna-genome
#20
Gabriel L Butterfield, Marc J Lajoie, Heather H Gustafson, Drew L Sellers, Una Nattermann, Daniel Ellis, Jacob B Bale, Sharon Ke, Garreck H Lenz, Angelica Yehdego, Rashmi Ravichandran, Suzie H Pun, Neil P King, David Baker
The challenges of evolution in a complex biochemical environment, coupling genotype to phenotype and protecting the genetic material, are solved elegantly in biological systems by the encapsulation of nucleic acids. In the simplest examples, viruses use capsids to surround their genomes. Although these naturally occurring systems have been modified to change their tropism and to display proteins or peptides, billions of years of evolution have favoured efficiency at the expense of modularity, making viral capsids difficult to engineer...
December 13, 2017: Nature
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