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https://www.readbyqxmd.com/read/28808666/lipidomic-evaluation-of-feline-neurologic-disease-after-aav-gene-therapy
#1
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/28806616/parvovirus-b19-integration-into-human-cd36-erythroid-progenitor-cells
#2
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
#3
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
#4
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
#5
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/28803853/developmental-suppression-of-forebrain-trka-receptors-and-attentional-capacities-in-aging-rats-a-longitudinal-study
#6
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/28799250/extracellular-vesicles-nature-s-nanoparticles-for-improving-gene-transfer-with-adeno-associated-virus-vectors
#7
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/28793798/dual-aav-gene-therapy-for-duchenne-muscular-dystrophy-with-a-7-kb-mini-dystrophin-gene-in-the-canine-model
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28789965/application-of-polyploid-adeno-associated-virus-vectors-for-transduction-enhancement-and-neutralizing-antibody-evasion
#11
Zheng Chai, Junjiang Sun, Kelly Michelle Rigsbee, Mei Wang, R Jude Samulski, Chengwen Li
Adeno-associated virus (AAV) vectors have been used successfully in clinical trials for patients with hemophilia or blindness, but pre-existing neutralizing antibodies (Nab) are common in the general population and exclude many patients from clinical trials. Exploration of effective strategies to enhance AAV transduction and escape from Nab activity is still imperative. Previous studies have shown the compatibility of capsids from AAV serotypes and homology of recognition sites of AAV Nab located on different capsid subunits from one virion...
August 5, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28782832/aav-delivery-of-grp78-bip-promotes-adaptation-of-human-rpe-cell-to-er-stress
#12
Shima Ghaderi, Shahin Ahmadian, Zahra-Soheila Soheili, Hamid Ahmadieh, Shahram Samiei, Samira Kheitan, Ehsan Ranaei Pirmardan
Adeno associated virus (AAV)-mediated gene delivery of GRP78 (78kDa glucose-regulated protein) attenuates the condition of endoplasmic reticulum (ER) stress and prevents apoptotic loss of photoreceptors in retinitis pigmentosa (RP) rats. In the current study we overexpressed Grp78 with the help of AAV-2 in primary human retinal pigmented epithelium (hRPE) cell cultures and examined its effect on cell response to ER stress. The purpose of this work was studying potential stimulating effect of GRP78 on adaptation/pro-survival of hRPE cells under ER stress, as an in vitro model for RPE degeneration...
August 7, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28780079/antineutrophil-cytoplasmic-antibody-associated-vasculitides-and-igg4-related-disease-a-new-overlap-syndrome
#13
REVIEW
François-Xavier Danlos, Giovanni Maria Rossi, Daniel Blockmans, Giacomo Emmi, Andreas Kronbichler, Stéphane Durupt, Claire Maynard, Luminita Luca, Cyril Garrouste, Bertrand Lioger, Rachel Mourot-Cottet, Robin Dhote, Jean-Benoit Arlet, Thomas Hanslik, Philippe Rouvier, Mikael Ebbo, Xavier Puéchal, Dominique Nochy, Agnès Carlotti, Luc Mouthon, Loïc Guillevin, Augusto Vaglio, Benjamin Terrier
OBJECTIVE: Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. METHODS: We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria...
August 2, 2017: Autoimmunity Reviews
https://www.readbyqxmd.com/read/28776202/neurotrophin-gene-therapy-in-deafened-ears-with-cochlear-implants-long-term-effects-on-nerve-survival-and-functional-measures
#14
Bryan E Pfingst, Deborah J Colesa, Donald L Swiderski, Aaron P Hughes, Stefan B Strahl, Moaz Sinan, Yehoash Raphael
Because cochlear implants function by stimulating the auditory nerve, it is assumed that the condition of the nerve plays an important role in the efficacy of the prosthesis. Thus, considerable research has been devoted to methods of preserving the nerve following deafness. Neurotrophins have been identified as a potential contributor to neural health, but most of the research to date has been done in young animals and for short periods (less than 3 to 6 months) after the onset of treatment. The first objective of the current experiment was to examine the effects of a neurotrophin gene therapy delivery method on spiral ganglion neuron (SGN) preservation and function in the long term (5 to 14 months) in mature guinea pigs with cochlear implants...
August 3, 2017: Journal of the Association for Research in Otolaryngology: JARO
https://www.readbyqxmd.com/read/28774883/the-cardiac-microenvironment-uses-non-canonical-wnt-signaling-to-activate-monocytes-after-myocardial-infarction
#15
Ingmar Sören Meyer, Andreas Jungmann, Christoph Dieterich, Min Zhang, Felix Lasitschka, Susann Werkmeister, Jan Haas, Oliver J Müller, Michael Boutros, Matthias Nahrendorf, Hugo A Katus, Stefan E Hardt, Florian Leuschner
A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment-dependent changes in inflammatory monocytes after MI RNA sequencing analysis of murine Ly6C(high) monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade...
August 3, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28771235/systemic-gene-delivery-transduces-the-enteric-nervous-system-of-guinea-pigs-and-cynomolgus-macaques
#16
S E Gombash, C J Cowley, J A Fitzgerald, C A Lepak, M G Neides, K Hook, L J Todd, G-D Wang, C Mueller, B K Kaspar, E C Bielefeld, A J Fischer, J D Wood, K D Foust
Characterization of adeno-associated viral vector (AAV) mediated gene delivery to the enteric nervous system (ENS) was recently described in mice and rats. In these proof-of-concept experiments, we show that intravenous injections of clinically relevant AAVs can transduce the ENS in guinea pigs and non-human primates. Neonatal guinea pigs were given intravenous injections of either AAV8 or AAV9 vectors that contained a green fluorescent protein (GFP) expression cassette or PBS. Piglets were euthanized three weeks post-injection and tissues were harvested for immunofluorescent analysis...
August 3, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28771234/aav5-mihtt-gene-therapy-demonstrates-suppression-of-mutant-huntingtin-aggregation-and-neuronal-dysfunction-in-a-rat-model-of-huntington-s-disease
#17
J Miniarikova, V Zimmer, R Martier, C C Brouwers, C Pythoud, K Richetin, M Rey, J Lubelski, M M Evers, S J van Deventer, H Petry, N Déglon, P Konstantinova
Huntington's disease (HD) is a fatal progressive neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. To date, there is no treatment to halt or reverse the course of HD. Lowering of either total or only the mutant HTT expression is expected to have therapeutic benefit. This can be achieved by engineered micro (mi)RNAs targeting HTT transcripts and delivered by an adeno-associated viral (AAV) vector. We have previously showed a miHTT construct to induce total HTT knock-down in Hu128/21 HD mice, while miSNP50T and miSNP67T constructs induced allele-selective HTT knock-down in vitro...
August 3, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28769791/optimized-aav-rh-10-vectors-that-partially-evade-neutralizing-antibodies-during-hepatic-gene-transfer
#18
Ruchita Selot, Sathyathithan Arumugam, Bertin Mary, Sabna Cheemadan, Giridhara R Jayandharan
Of the 12 common serotypes used for gene delivery applications, Adeno-associated virus (AAV)rh.10 serotype has shown sustained hepatic transduction and has the lowest seropositivity in humans. We have evaluated if further modifications to AAVrh.10 at its phosphodegron like regions or predicted immunogenic epitopes could improve its hepatic gene transfer and immune evasion potential. Mutant AAVrh.10 vectors were generated by site directed mutagenesis of the predicted targets. These mutant vectors were first tested for their transduction efficiency in HeLa and HEK293T cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28768875/relevance-of-assembly-activating-protein-for-adeno-associated-virus-vector-production-and-capsid-protein-stability-in-mammalian-and-insect-cells
#19
Stefanie Große, Magalie Penaud-Budloo, Anne-Kathrin Herrmann, Kathleen Börner, Julia Fakhiri, Vibor Laketa, Chiara Krämer, Ellen Wiedtke, Manuel Gunkel, Lucie Ménard, Eduard Ayuso, Dirk Grimm
The discovery that Adeno-associated virus 2 (AAV2) encodes an eighth protein, called assembly-activating protein (AAP), transformed our understanding of wild-type AAV biology. Concurrently, it raised questions about the role of AAP during production of recombinant vectors based on natural or molecularly engineered AAV capsids. Here, we show that AAP is indeed essential for generation of functional recombinant AAV2 vectors in both, mammalian and insect cell-based vector production systems. Surprisingly, we observed that AAV2 capsid proteins VP1-3 are unstable in the absence of AAP2, likely due to rapid proteasomal degradation...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28768190/bmp4-gene-therapy-in-mature-mice-reduces-bat-activation-but-protects-from-obesity-by-browning-subcutaneous-adipose-tissue
#20
Jenny M Hoffmann, John R Grünberg, Christopher Church, Ivet Elias, Vilborg Palsdottir, John-Olov Jansson, Fatima Bosch, Ann Hammarstedt, Shahram Hedjazifar, Ulf Smith
We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes in vitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from obesity on a high-fat diet and have increased whole-body energy expenditure, improved insulin sensitivity, reduced liver fat, and reduced adipose tissue inflammation...
August 1, 2017: Cell Reports
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