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adeno-associated viral

Maurizio Battaglia Parodi, Alessandro Arrigo, Robert E MacLaren, Emanuela Aragona, Lisa Toto, Rodolfo Mastropasqua, Maria Pia Manitto, Francesco Bandello
PURPOSE: Choroideremia is a rare degenerative retinal disease that causes incurable blindness. It occurs as a result of the deficiency of the X-linked CHM gene, which encodes the Rab escort protein 1 (REP1). Gene therapy has been developed to treat CHM using adeno-associated viral vectors and is currently undergoing clinical trials. Expression of the CHM gene is ubiquitous throughout the retina, and it is therefore important to identify which retinal layers are affected in the disease process...
March 14, 2018: Retina
Hengchao Chen, Yazhi Xing, Li Xia, Zhengnong Chen, Shankai Yin, Jian Wang
The synapse between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) has been identified as a sensitive structure to noise-induced damage in the mammalian cochlea. Since this synapse provides the major information pathway from the cochlea to the auditory brain, it is important to maintain its integrity. Neurotrophin-3 (NT-3) has been known to play an important role in the development and the functional maintenance of this synapse. Application of exogenous NT-3, or overexpression of this gene in a transgenic animal model, have shown the value to protect this synapse from noise-induced damage...
March 13, 2018: Gene Therapy
Lei Liu, Wataru Ito, Alexei Morozov
Region and cell-type restricted expression of light-activated ion channels is the indispensable tool to study properties of synapses in specific circuits and to monitor synaptic alterations by various stimuli including neuromodulators and behaviors, both ex vivo and in vivo . These analyses require the light-activated proteins or viral vectors for their delivery that do not interfere with the phenomenon under study. Here, we report a case of such interference in which the high-level expression of channelrhodopsin-2 introduced in the somatostatin-positive GABAergic neurons of the dorsomedial prefrontal cortex by an adeno-associated virus vector weakens the presynaptic GABAb receptor-mediated suppression of GABA release...
April 2018: Neurophotonics
Peter J Hamilton, Carissa J Lim, Eric J Nestler, Elizabeth A Heller
Delivery of molecular tools for targeted epigenome editing in rodent brain can be facilitated by the use of viral vector-mediated gene transfer coupled with stereotaxic surgery techniques. Here, we describe the surgical protocol utilized by our group, which is optimized for herpes simplex virus (HSV)-mediated delivery into mouse brain. The protocol outlined herein could also be applied for delivery of adeno-associated viruses (AAV) or lentiviruses in both mice and rats. This method allows for efficient viral transgene expression and subsequent epigenome editing in rodent brain with excellent spatiotemporal control...
2018: Methods in Molecular Biology
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yang Yongji, Changhai Lei, Shi Hu
Post-ischemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischemic heart failure...
March 9, 2018: Journal of Drug Targeting
Jana Miniarikova, Melvin M Evers, Pavlina Konstantinova
The single mutation underlying the fatal neuropathology of Huntington's disease (HD) is a CAG triplet expansion in exon 1 of the huntingtin (HTT) gene, which gives rise to a toxic mutant HTT protein. There have been a number of not yet successful therapeutic advances in the treatment of HD. The current excitement in the HD field is due to the recent development of therapies targeting the culprit of HD either at the DNA or RNA level to reduce the overall mutant HTT protein. In this review, we briefly describe short-term and long-term HTT-lowering strategies targeting HTT transcripts...
February 8, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Hillel Adesnik
A pair of 2009 papers by Cardin et al. and Sohal et al. marked a watershed moment as optogenetics exploded onto the scene of systems neuroscience. This pair of back-to-back papers in the June issue of Nature leveraged a powerful combination of the Cre/lox system, adeno-associated viral gene vectors, and optogenetics to re-examine the circuit basis of neuronal synchronization.
March 2018: Trends in Neurosciences
Dhruva Katrekar, Ana M Moreno, Genghao Chen, Atharv Worlikar, Prashant Mali
Recombinant adeno-associated viruses (AAVs) are among the most commonly used vehicles for in vivo gene delivery. However, their tropism is limited, and additionally their efficacy can be negatively affected by prevalence of neutralizing antibodies in sera. Methodologies to systematically engineer AAV capsid properties would thus be of great relevance. In this regard, we develop here multi-functional AAVs by engineering precision tethering of oligonucleotides onto the AAV surface, and thereby enabling a spectrum of nucleic-acid programmable functionalities...
February 26, 2018: Scientific Reports
Andrew J Crowther, Szu-Aun Lim, Brent Asrican, Blake H Albright, Josh Wooten, Chia-Yu Yeh, Hechen Bao, Domenic H Cerri, Jessica Hu, Yen-Yu Ian Shih, Aravind Asokan, Juan Song
Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need...
February 17, 2018: Stem Cell Reports
Dunjia Wang, Xiaodong Wang, Xiaofang Liu, Liping Jiang, Guang Yang, Xiaoxia Shi, Cong Zhang, Fengyuan Piao
Epidemiological investigations and experimental studies indicate that chronic arsenic exposure can reduce learning and memory function. However, the underlying mechanism of this effect remains largely unknown. Emerging evidence suggests that microRNA (miRNA) play an important role in toxicant exposure and a regulatory role in cognitive function. In this study, we observed that subchronic arsenic exposure induced impairment of learning and memory and significantly up-regulated miRNA-219 (miR-219) expression in the mouse hippocampus...
February 24, 2018: Neurochemical Research
Andrew Osborne, Aiden Xz Wang, Alessia Tassoni, Peter S Widdowson, Keith R Martin
Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signalling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated viral (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signalling is hypothesised to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a down-regulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time...
February 21, 2018: Human Gene Therapy
Peter Bannerman, Fuzheng Guo, Olga Chechneva, Travis Burns, Xiaoqing Zhu, Yan Wang, Bokyung Kim, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB ]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy...
January 10, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jenny A Greig, Jayme M L Nordin, Christine Draper, Peter Bell, James M Wilson
Adeno-associated viral (AAV) vectors can target the liver, making them an attractive platform for gene therapy approaches that require the correction of hepatocytes. Crigler-Najjar syndrome is an autosomal recessive disorder of bilirubin metabolism that occurs when the liver's uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) enzyme activity is partially or completely absent. This syndrome is characterized by elevated bilirubin levels in the blood. We developed an AAV8 vector expressing a codon-optimized human version of UGT1A1 from a liver-specific promoter...
February 16, 2018: Human Gene Therapy
Ga Ram Jeong, Eun-Hae Jang, Jae Ryul Bae, Soyoung Jun, Ho Chul Kang, Chi-Hu Park, Joo-Ho Shin, Yukio Yamamoto, Keiko Tanaka-Yamamoto, Valina L Dawson, Ted M Dawson, Eun-Mi Hur, Byoung Dae Lee
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo...
February 13, 2018: Molecular Neurodegeneration
Waijiao Cai, Danielle Feng, Michael A Schwarzschild, Pamela J McLean, Xiqun Chen
Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species...
January 31, 2018: EBioMedicine
Caroline Le Duigou, Etienne Savary, Mélanie Morin-Brureau, Daniel Gomez-Dominguez, André Sobczyk, Farah Chali, Giampaolo Milior, Larissa Kraus, Jochen C Meier, Dimitri M Kullmann, Bertrand Mathon, Liset Menendez de la Prida, Georg Dorfmuller, Johan Pallud, Emmanuel Eugène, Stéphane Clemenceau, Richard Miles
BACKGROUND: Insights into human brain diseases may emerge from tissue obtained after operations on patients. However techniques requiring transduction of transgenes carried by viral vectors cannot be applied to acute human tissue. NEW METHOD: We show that organotypic culture techniques can be used to maintain tissue from patients with three different neurological syndromes for several weeks in vitro. Optimized viral vector techniques and promoters for transgene expression are described...
February 7, 2018: Journal of Neuroscience Methods
Kim L Powell, Xavier Fitzgerald, Claire Shallue, Valentina Jovanovska, Matthias Klugmann, Georg Von Jonquieres, Terence J O'Brien, Margaret J Morris
Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures...
January 29, 2018: Neurobiology of Disease
Cinzia Pisani, Georgios Strimpakos, Francesca Gabanella, Maria Grazia Di Certo, Annalisa Onori, Cinzia Severini, Siro Luvisetto, Stefano Farioli-Vecchioli, Irene Carrozzo, Antonio Esposito, Tamara Canu, Elisabetta Mattei, Nicoletta Corbi, Claudio Passananti
Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin "A" promoter. We have previously shown that the ZF-ATF "Jazz", either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic "mdx" mice...
January 30, 2018: Biochimica et Biophysica Acta
Rachel E Kelemen, Sarah B Erickson, Abhishek Chatterjee
The ability to modify the capsid proteins of human viruses is desirable both for installing probes to study their structure and function, and to attach retargeting agents to engineer viral infectivity. However, the installation of such capsid modifications currently faces two major challenges: (1) The complex and delicate capsid proteins often do not tolerate large modifications, and (2) capsid proteins are composed of the 20 canonical amino acids, precluding site-specific chemical modification of the virus...
2018: Methods in Molecular Biology
Xuan Li, Maria B Carreria, Kailyn R Witonsky, Tamara Zeric, Olivia M Lofaro, Jennifer M Bossert, Jianjun Zhang, Felicia Surjono, Christopher T Richie, Brandon K Harvey, Hyeon Son, Christopher W Cowan, Eric J Nestler, Yavin Shaham
BACKGROUND: Methamphetamine (meth) seeking progressively increases after withdrawal (incubation of meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in the rat dorsal striatum and incubation of meth craving. Here we used viral constructs to study the causal role of dorsal striatum HDAC5 in this incubation. METHODS: In experiment 1 (overexpression), we injected an adeno-associated virus bilaterally into dorsal striatum to express either green fluorescent protein (control) or a mutant form of HDAC5, which strongly localized to the nucleus...
December 29, 2017: Biological Psychiatry
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