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Crispr/cas9 hepatitis

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https://www.readbyqxmd.com/read/27860197/crispr-cas9-the-ultimate-weapon-to-battle-infectious-diseases
#1
REVIEW
M Doerflinger, W Forsyth, G Ebert, M Pellegrini, M J Herold
Infectious diseases are a leading cause of death worldwide. Novel therapeutics are urgently required to treat multi-drug resistant organisms such as Mycobacterium tuberculosis (Mtb) and to mitigate morbidity and mortality caused by acute infections such as malaria and dengue fever virus as well as chronic infections such as human immunodeficiency virus -1 (HIV-1) and hepatitis B virus (HBV). The CRISPR/Cas9 system, which has revolutionized biomedical research, holds great promise for the identification and validation of novel drug targets...
November 16, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27783675/dna-polymerase-%C3%AE%C2%BA-is-a-key-cellular-factor-for-the-formation-of-covalently-closed-circular-dna-of-hepatitis-b-virus
#2
Yonghe Qi, Zhenchao Gao, Guangwei Xu, Bo Peng, Chenxuan Liu, Huan Yan, Qiyan Yao, Guoliang Sun, Yang Liu, Dingbin Tang, Zilin Song, Wenhui He, Yinyan Sun, Ju-Tao Guo, Wenhui Li
Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27708159/insulin-resistance-and-diabetes-caused-by-genetic-or-diet-induced-kbtbd2-deficiency-in-mice
#3
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27659023/highly-multiplexed-crispr-cas9-nuclease-and-cas9-nickase-vectors-for-inactivation-of-hepatitis-b-virus
#4
Tetsushi Sakuma, Keiichi Masaki, Hiromi Abe-Chayama, Keiji Mochida, Takashi Yamamoto, Kazuaki Chayama
CRISPR-Cas9-mediated genome-editing technology contributes not only to basic genomic studies but also to clinical studies such as genetic correction and virus inactivation. Hepatitis B virus (HBV) is a major target for potential application of CRISPR-Cas9 in eliminating viral DNA from human cells. However, the high stability of covalently closed circular DNA (cccDNA) makes it difficult to completely clear HBV infection. Here, we report highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vector systems that simultaneously target three critical domains of the HBV genome...
November 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27614072/talen-crispr-mediated-engineering-of-a-promoterless-anti-viral-rnai-hairpin-into-an-endogenous-mirna-locus
#5
Elena Senís, Stefan Mockenhaupt, Daniel Rupp, Tobias Bauer, Nagarajan Paramasivam, Bettina Knapp, Jan Gronych, Stefanie Grosse, Marc P Windisch, Florian Schmidt, Fabian J Theis, Roland Eils, Peter Lichter, Matthias Schlesner, Ralf Bartenschlager, Dirk Grimm
Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infection...
September 9, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27585307/crispr-cas9-technology-targeting-fas-gene-protects-mice-from-concanavalin-a-induced-fulminant-hepatic-failure
#6
Wei-Cheng Liang, Pu-Ping Liang, Cheuk-Wa Wong, Tzi-Bun Ng, Jun-Jiu Huang, Jin-Fang Zhang, Mary Miu-Yee Waye, Wei-Ming Fu
Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively...
September 1, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27570484/an-effective-molecular-target-site-in-hepatitis-b-virus-s-gene-for-cas9-cleavage-and-mutational-inactivation
#7
Hao Li, Chunyu Sheng, Hongbo Liu, Guangze Liu, Xinying Du, Juan Du, Linsheng Zhan, Peng Li, Chaojie Yang, Lihua Qi, Jian Wang, Xiaoxia Yang, Leili Jia, Jing Xie, Ligui Wang, Rongzhang Hao, Dongping Xu, Yigang Tong, Yusen Zhou, Jianjun Zhou, Yansong Sun, Qiao Li, Shaofu Qiu, Hongbin Song
Chronic hepatitis B infection remains incurable because HBV cccDNA can persist indefinitely in patients recovering from acute HBV infection. Given the incidence of HBV infection and the shortcomings of current therapeutic options, a novel antiviral strategy is urgently needed. To inactivate HBV replication and destroy the HBV genome, we employed genome editing tool CRISPR/Cas9. Specifically, we found a CRISPR/Cas9 system (gRNA-S4) that effectively targeted the HBsAg region and could suppress efficiently viral replication with minimal off-target effects and impact on cell viability...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27383988/a-crispr-screen-defines-a-signal-peptide-processing-pathway-required-by-flaviviruses
#8
Rong Zhang, Jonathan J Miner, Matthew J Gorman, Keiko Rausch, Holly Ramage, James P White, Adam Zuiani, Ping Zhang, Estefania Fernandez, Qiang Zhang, Kimberly A Dowd, Theodore C Pierson, Sara Cherry, Michael S Diamond
Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles...
July 7, 2016: Nature
https://www.readbyqxmd.com/read/27291420/hyperlipidemia-and-hepatitis-in-liver-specific-creb3l3-knockout-mice-generated-using-a-one-step-crispr-cas9-system
#9
Yoshimi Nakagawa, Fusaka Oikawa, Seiya Mizuno, Hiroshi Ohno, Yuka Yagishita, Aoi Satoh, Yoshinori Osaki, Kenta Takei, Takuya Kikuchi, Song-Iee Han, Takashi Matsuzaka, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Naoya Yahagi, Masaaki Isaka, Hiroaki Suzuki, Hirohito Sone, Satoru Takahashi, Nobuhiro Yamada, Hitoshi Shimano
cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27203444/complete-spectrum-of-crispr-cas9-induced-mutations-on-hbv-cccdna
#10
Christoph Seeger, Ji A Sohn
Hepatitis B virus (HBV) causes chronic infections that cannot yet be cured. The virus persists in infected hepatocytes, because covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs, is stable in nondividing cells. Antiviral therapies with nucleoside analogues inhibit HBV DNA synthesis in capsids in the cytoplasm of infected hepatocytes, but do not destroy nuclear cccDNA. Because over 200 million people are still infected, a cure for chronic hepatitis B (CHB) has become one of the major challenges in antiviral therapy...
August 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27138846/efficient-and-controlled-generation-of-2d-and-3d-bile-duct-tissue-from-human-pluripotent-stem-cell-derived-spheroids
#11
Lipeng Tian, Abhijeet Deshmukh, Zhaohui Ye, Yoon-Young Jang
While in vitro liver tissue engineering has been increasingly studied during the last several years, presently engineered liver tissues lack the bile duct system. The lack of bile drainage not only hinders essential digestive functions of the liver, but also leads to accumulation of bile that is toxic to hepatocytes and known to cause liver cirrhosis. Clearly, generation of bile duct tissue is essential for engineering functional and healthy liver. Differentiation of human induced pluripotent stem cells (iPSCs) to bile duct tissue requires long and/or complex culture conditions, and has been inefficient so far...
August 2016: Stem Cell Reviews
https://www.readbyqxmd.com/read/27049051/crispr-cas9-produces-anti-hepatitis-b-virus-effect-in-hepatoma-cells-and-transgenic-mouse
#12
Wei Zhu, Kun Xie, Yuanjian Xu, Le Wang, Kaiming Chen, Longzhen Zhang, Jianmin Fang
Chronic infection of hepatitis B virus (HBV) is at risk of liver cirrhosis and hepatocellular carcinoma and remains one of the major public health problems worldwide. It is a major barrier of persistence HBV cccDNA under current antiviral therapy as novel strategies of disrupting HBV cccDNA is pressing. The (CRISPR)/Cas9 system is presently emerging in gene editing and we also apply it for targeting and deleting the conserved regions of HBV genome. Two homologous sequences of HBV S and X genes were carried with CRISPR/Cas9 endonuclease to build pCas9 constructs, which may mediate anti-HBV effects of in vitro and in vivo systems in this study...
June 2, 2016: Virus Research
https://www.readbyqxmd.com/read/26964564/crispr-cas9-mediated-somatic-correction-of-a-novel-coagulator-factor-ix-gene-mutation-ameliorates-hemophilia-in-mouse
#13
Yuting Guan, Yanlin Ma, Qi Li, Zhenliang Sun, Lie Ma, Lijuan Wu, Liren Wang, Li Zeng, Yanjiao Shao, Yuting Chen, Ning Ma, Wenqing Lu, Kewen Hu, Honghui Han, Yanhong Yu, Yuanhua Huang, Mingyao Liu, Dali Li
The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice...
2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/26774178/hepatic-transmembrane-6-superfamily-member-2-regulates-cholesterol-metabolism-in-mice
#14
Yanbo Fan, Haocheng Lu, Yanhong Guo, Tianqing Zhu, Minerva T Garcia-Barrio, Zhisheng Jiang, Cristen J Willer, Jifeng Zhang, Y Eugene Chen
BACKGROUND & AIMS: The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. METHODS: C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets...
May 2016: Gastroenterology
https://www.readbyqxmd.com/read/26540039/application-of-crispr-cas9-technology-to-hbv
#15
REVIEW
Guigao Lin, Kuo Zhang, Jinming Li
More than 240 million people around the world are chronically infected with hepatitis B virus (HBV). Nucleos(t)ide analogs and interferon are the only two families of drugs to treat HBV currently. However, none of these anti-virals directly target the stable nuclear covalently closed circular DNA (cccDNA), which acts as a transcription template for viral mRNA and pre-genomic RNA synthesis and secures virus persistence. Thus, the fact that only a small number of patients treated achieve sustained viral response (SVR) or cure, highlights the need for new therapies against HBV...
2015: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/26537785/preliminary-characterization-of-a-leptin-receptor-knockout-rat-created-by-crispr-cas9-system
#16
Dan Bao, Yuanwu Ma, Xu Zhang, Feifei Guan, Wei Chen, Kai Gao, Chuan Qin, Lianfeng Zhang
Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26511989/crispr-cas9-based-tools-for-targeted-genome-editing-and-replication-control-of-hbv
#17
Cheng Peng, Mengji Lu, Dongliang Yang
Hepatitis B virus (HBV) infection remains a major global health problem because current therapies rarely eliminate HBV infections to achieve a complete cure. A different treatment paradigm to effectively clear HBV infection and eradicate latent viral reservoirs is urgently required. In recent years, the development of a new RNA-guided gene-editing tool, the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system, has greatly facilitated site-specific mutagenesis and represents a very promising potential therapeutic tool for diseases, including for eradication of invasive pathogens such as HBV...
October 2015: Virologica Sinica
https://www.readbyqxmd.com/read/26508638/crispr-cas9-somatic-multiplex-mutagenesis-for-high-throughput-functional-cancer-genomics-in-mice
#18
Julia Weber, Rupert Öllinger, Mathias Friedrich, Ursula Ehmer, Maxim Barenboim, Katja Steiger, Irina Heid, Sebastian Mueller, Roman Maresch, Thomas Engleitner, Nina Gross, Ulf Geumann, Beiyuan Fu, Angela Segler, Detian Yuan, Sebastian Lange, Alexander Strong, Jorge de la Rosa, Irene Esposito, Pentao Liu, Juan Cadiñanos, George S Vassiliou, Roland M Schmid, Günter Schneider, Kristian Unger, Fengtang Yang, Rickmer Braren, Mathias Heikenwälder, Ignacio Varela, Dieter Saur, Allan Bradley, Roland Rad
Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed Darwinian selection of target genes, which suppress tumorigenesis in the respective cellular/tissue context, such as Pten or Cdkn2a, and conversely found low frequency of Brca1/2 alterations, explaining mutational spectra in human ICC/HCC...
November 10, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26476375/targeting-hepatitis-b-virus-cccdna-using-crispr-cas9
#19
REVIEW
Edward M Kennedy, Anand V R Kornepati, Bryan R Cullen
Despite the existence of an excellent prophylactic vaccine and the development of highly effective inhibitors of the viral polymerase, chronic hepatitis B virus (HBV) infection remains a major source of morbidity and mortality, especially in Africa and Asia. A significant problem is that, while polymerase inhibitors can effectively prevent the production of viral genomic DNA from pre-genomic RNA transcripts, they do not prevent the transcription and translation of viral mRNAs from the covalently closed circular DNA (cccDNA) templates present in the nuclei of infected cells...
November 2015: Antiviral Research
https://www.readbyqxmd.com/read/26375504/the-fate-of-human-platelets-exposed-to-porcine-renal-endothelium-a-single-pass-model-of-platelet-uptake-in-domestic-and-genetically-modified-porcine-organs
#20
James R Butler, Gregory R Martens, Ping Li, Zheng-Yu Wang, Jose L Estrada, Joseph M Ladowski, Matt Tector, A Joseph Tector
BACKGROUND: Thrombocytopenia may represent a significant challenge to the clinical application of solid-organ xenotransplantation. When studied in a pig-to-primate model, consumptive coagulopathy has challenged renal xenografts. New strategies of genetic manipulation have altered porcine carbohydrate profiles to significantly reduce human antibody binding to pig cells. As this process continues to eliminate immunologic barriers to clinical xenotransplantation, the relationship between human platelets and pig organs must be considered...
February 2016: Journal of Surgical Research
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