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https://www.readbyqxmd.com/read/28822691/fatal-meningitis-in-swine-after-intrathecal-administration-of-adeno-associated-virus-expressing-syngeneic-interleukin-10
#1
Mark D Unger, Josef Pleticha, James E Collins, Anibal G Armien, Jennifer L Brazzell, Laura K Newman, Lukas F Heilmann, Jodi A Scholz, Timothy P Maus, Andreas S Beutler
Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia...
August 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28822689/cholesterol-lowering-gene-therapy-counteracts-the-development-of-non-ischemic-cardiomyopathy-in-mice
#2
Ilayaraja Muthuramu, Ruhul Amin, Andrey Postnov, Mudit Mishra, Joseph Pierre Aboumsallem, Tom Dresselaers, Uwe Himmelreich, Paul P Van Veldhoven, Olivier Gheysens, Frank Jacobs, Bart De Geest
A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.8% (p < 0.0001) reduction of plasma cholesterol compared with controls. Mortality rate was lower (p < 0.05) in AAV8-LDLr TAC mice compared with control TAC mice (hazard ratio for mortality 0...
August 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28820183/technique-of-retinal-gene-therapy-delivery-of-viral-vector-into-the-subretinal-space
#3
K Xue, M Groppe, A P Salvetti, R E MacLaren
PurposeSafe and reproducible delivery of gene therapy vector into the subretinal space is essential for successful targeting of the retinal pigment epithelium (RPE) and photoreceptors. The success of surgery is critical for the clinical efficacy of retinal gene therapy. Iatrogenic detachment of the degenerate (often adherent) retina in patients with hereditary retinal degenerations and small volume (eg, 0.1 ml) subretinal injections pose new surgical challenges.MethodsOur subretinal gene therapy technique involved pre-operative planning with optical coherence tomography (OCT) and autofluorescence (AF) imaging, 23 G pars plana vitrectomy, internal limiting membrane staining with Membrane Blue Dual (DORC BV, Zuidland, Netherlands), a two-step subretinal injection using a 41 G Teflon tipped cannula (DORC) first with normal saline to create a parafoveal bleb followed by slow infusion of viral vector via the same self-sealing retinotomy...
August 18, 2017: Eye
https://www.readbyqxmd.com/read/28811460/prevention-of-atrial-fibrillation-by-using-sarcoplasmic-reticulum-calcium-atpase-pump-overexpression-in-a-rabbit-model-of-rapid-atrial-pacing
#4
Hong Li Wang, Xian Hui Zhou, Zhi Qiang Li, Ping Fan, Qi Na Zhou, Yao Dong Li, Yue Mei Hou, Bao Peng Tang
BACKGROUND Recent research suggests that abnormal Ca2+ handling plays a role in the occurrence and maintenance of atrial fibrillation (AF). Therefore, Ca2+ release and ingestion depend on properties of the ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ATPase2a (SERCA2a). This study aimed to detect whether SERCA2a gene overexpression has a preventive effect on atrial fibrillation caused by rapid pacing right atrium. MATERIAL AND METHODS Forty-eight New Zealand white rabbits were randomly divided into a control group, AF group, AAV9/GFP group, and AAV9/SERCA2a group...
August 16, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28810808/advances-and-challenges-in-cardiovascular-gene-therapy
#5
Seppo Ylä-Herttuala, Johanna Lähteenvuo
25 years of gene therapy have not yet yielded standard therapeutic solutions for clinical use in cardiovascular medicine, but several therapeutic targets have been identified and foundations for future therapies have been set. The safety of viral gene therapy has been established with a wide variety of vectors and transgenes. Adenoviruses and adeno-associated viruses have established their role as vectors of choice for many cardiovascular applications and appropriate viral doses have been established for several tissues and applications...
August 16, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28809089/inverted-quasi-spherical-droplets-on-polydopamine-tio2-substrates-for-enhancing-gene-delivery
#6
Seung-Hyun Kim, Mihyun Lee, Mira Cho, Il-Sun Kim, Kook In Park, Haeshin Lee, Jae-Hyung Jang
Devising efficient gene delivery systems is crucial to enhancing the therapeutic efficacy of gene-cell therapy approaches. Herein, inverted quasi-spherical (iQS) droplet systems, which enhance gene delivery efficiencies by reducing the path lengths of gene vectors, mediating motions of vectors at early stages, and raising the contact frequencies of vectors with cells, are developed by adopting the principle of 3D hanging-drop cell culture. Micrometer-sized polydopamine (pDA) holes are created on superhydrophobic titanium isopropoxide (TiO2 )-coated substrates by physical scraping; droplets are loaded on the pDA holes, and inversion of the substrate generates iQS droplets with large contact angles...
August 15, 2017: Macromolecular Bioscience
https://www.readbyqxmd.com/read/28808666/lipidomic-evaluation-of-feline-neurologic-disease-after-aav-gene-therapy
#7
Heather L Gray-Edwards, Xuntian Jiang, Ashley N Randle, Amanda R Taylor, Taylor L Voss, Aime K Johnson, Victoria J McCurdy, Miguel Sena-Esteves, Daniel S Ory, Douglas R Martin
GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at >5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28807567/a-new-promoter-allows-optogenetic-vision-restoration-with-enhanced-sensitivity-in-macaque-retina
#8
Antoine Chaffiol, Romain Caplette, Céline Jaillard, Elena Brazhnikova, Mélissa Desrosiers, Elisabeth Dubus, Laëtitia Duhamel, Emilie Macé, Olivier Marre, Patrick Benoit, Philippe Hantraye, Alexis-Pierre Bemelmans, Ernst Bamberg, Jens Duebel, José-Alain Sahel, Serge Picaud, Deniz Dalkara
The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second- and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca(2+)-permeable channelrhodopsin (CatCh) at safe light intensities...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28806616/parvovirus-b19-integration-into-human-cd36-erythroid-progenitor-cells
#9
Tyler Janovitz, Susan Wong, Neal S Young, Thiago Oliveira, Erik Falck-Pedersen
The pathogenic autonomous human parvovirus B19 (B19V) productively infects erythroid progenitor cells (EPCs). Functional similarities between B19V nonstructural protein (NS1), a DNA binding endonuclease, and the Rep proteins of Adeno-Associated Virus (AAV) led us to hypothesize that NS1 may facilitate targeted nicking of the human genome and B19 vDNA integration. We adapted an integration capture sequencing protocol (IC-Seq) to screen B19V infected human CD36+ EPCs for viral integrants, and discovered 40,000 unique B19V integration events distributed throughout the human genome...
August 11, 2017: Virology
https://www.readbyqxmd.com/read/28805815/aav-mediated-direct-in-vivo-crispr-screen-identifies-functional-suppressors-in-glioblastoma
#10
Ryan D Chow, Christopher D Guzman, Guangchuan Wang, Florian Schmidt, Mark W Youngblood, Lupeng Ye, Youssef Errami, Matthew B Dong, Michael A Martinez, Sensen Zhang, Paul Renauer, Kaya Bilguvar, Murat Gunel, Phillip A Sharp, Feng Zhang, Randall J Platt, Sidi Chen
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts...
August 14, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28805798/repeated-aav-mediated-gene-transfer-by-serotype-switching-enables-long-lasting-therapeutic-levels-of-hugt1a1-enzyme-in-a-mouse-model-of-crigler-najjar-syndrome-type-i
#11
L Bočkor, G Bortolussi, A Iaconcig, G Chiaruttini, C Tiribelli, M Giacca, F Benvenuti, L Zentilin, A F Muro
Adeno-associated virus (AAV)-mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I (CNSI) is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain...
August 14, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28804553/sirt3-attenuates-doxorubicin-induced-cardiac-hypertrophy-and-mitochondrial-dysfunction-via-suppression-of-bnip3
#12
Qiong Du, Bin Zhu, Qing Zhai, Bo Yu
Doxorubicin (Dox) is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by development of cardiotoxicity. Sirtuin-3 (Sirt3) is the major deacetylase within the mitochondrial matrix that plays an important role in regulation of cardiac function. This study was performed to identify the regulatory role of Sirt3 on Dox-induced cardiac hypertrophy and mitochondrial dysfunction in rats in vivo and in vitro...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28804450/whole-brain-mapping-of-the-inputs-and-outputs-of-the-medial-part-of-the-olfactory-tubercle
#13
Zhijian Zhang, Hongruo Zhang, Pengjie Wen, Xutao Zhu, Li Wang, Qing Liu, Jie Wang, Xiaobin He, Huadong Wang, Fuqiang Xu
The medial part of the olfactory tubercle (OT) is a brain structure located at the interface of the reward and olfactory system. It is closely related to pheromone-rewards, natural reinforcement, addiction and many other behaviors. However, the structure of the anatomic circuitry of the medial part of the OT is still unclear. In the present study, the medial part of the OT was found to be highly connected with a wide range of brain areas with the help of the pseudorabies virus tracing tool. In order to further investigate the detailed connections for specific neurons, another tracing tool - rabies virus was utilized for D1R-cre and D2R-cre mice...
2017: Frontiers in Neural Circuits
https://www.readbyqxmd.com/read/28803853/developmental-suppression-of-forebrain-trka-receptors-and-attentional-capacities-in-aging-rats-a-longitudinal-study
#14
Brittney Yegla, Vinay Parikh
Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer's disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability...
August 10, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28803727/elimination-of-toxic-microsatellite-repeat-expansion-rna-by-rna-targeting-cas9
#15
Ranjan Batra, David A Nelles, Elaine Pirie, Steven M Blue, Ryan J Marina, Harrison Wang, Isaac A Chaim, James D Thomas, Nigel Zhang, Vu Nguyen, Stefan Aigner, Sebastian Markmiller, Guangbin Xia, Kevin D Corbett, Maurice S Swanson, Gene W Yeo
Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells...
August 8, 2017: Cell
https://www.readbyqxmd.com/read/28799250/extracellular-vesicles-nature-s-nanoparticles-for-improving-gene-transfer-with-adeno-associated-virus-vectors
#16
REVIEW
Bence György, Casey A Maguire
Gene therapy, the ability to treat a disease at the level of nucleic acid, has journeyed from science fiction, to hard lessons learned from early clinical trials, to improved technologies with efficacy in patients for several diseases. Adeno-associated virus (AAV) vectors are currently a leader for direct in vivo gene therapy. To date, AAV is safe in patients, with clinical benefit in trials to treat blindness, hemophilia, and a lipid disorder, with many more trials underway. Despite this remarkable progress, barriers exist for AAV vectors to be effective gene transfer vehicles in all organ/cell targets, as well as patient subpopulations...
August 11, 2017: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
https://www.readbyqxmd.com/read/28796554/adeno-associated-virus-human-bocavirus-1-chimeric-vectors-ferreting-out-their-role-in-airway-gene-therapy
#17
Terence R Flotte
No abstract text is available yet for this article.
August 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28793798/dual-aav-gene-therapy-for-duchenne-muscular-dystrophy-with-a-7-kb-mini-dystrophin-gene-in-the-canine-model
#18
Kasun Kodippili, Chady Hakim, Xiufang Pan, Hsiao T Yang, Yongping YUe, Yadong Zhang, Jin-Hong Shin, Nora N Yang, Dongsheng Duan
Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof-of-principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ∆H2-R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ∆H2-R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy...
August 10, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28793786/hemophilia-gene-therapy-ready-for-prime-time
#19
Thierry VandenDriessche, Marinee K L Chuah
Hemophilia A and B are congenital X-linked bleeding disorders caused by mutations in the genes encoding for the blood clotting factor VIII (FVIII) or factor IX (FIX), respectively. Since the beginning of gene therapy, hemophilia has been considered an attractive disease target that served as a trailblazer for the field at large. Different technologies have been explored to efficiently and safely deliver the therapeutic FVIII and FIX genes into the patients' cells. Currently, the most promising vectors for hemophilia gene therapy are adeno-associated viral vectors (AAV) and lentiviral vectors...
August 10, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28790199/in-vivo-genome-editing-restores-dystrophin-expression-and-cardiac-function-in-dystrophic-mice
#20
Mona El Refaey, Li Xu, Yandi Gao, Benjamin D Canan, Tm A Adesanya, Sarah C Warner, Keiko Akagi, David E Symer, Peter J Mohler, Jianjie Ma, Paul M Janssen, Renzhi Han
Rationale: Duchenne muscular dystrophy (DMD) is a severe inherited form of muscular dystrophy caused by mutations in the reading frame of the dystrophin gene disrupting its protein expression. Dystrophic cardiomyopathy is a leading cause of death in DMD patients and currently no effective treatment exists to halt its progression. Recent advancement in genome editing technologies offers a promising therapeutic approach in restoring dystrophin protein expression. However, the impact of this approach on DMD cardiac function has yet to be evaluated...
August 8, 2017: Circulation Research
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