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Human gene editing

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https://www.readbyqxmd.com/read/29150011/optimization-of-crispr-cas9-genome-editing-for-loss-of-function-in-the-early-chick-embryo
#1
Shashank Gandhi, Michael L Piacentino, Felipe M Vieceli, Marianne E Bronner
The advent of CRISPR/Cas9 has made genome editing possible in virtually any organism, including those not previously amenable to genetic manipulations. Here, we present an optimization of CRISPR/Cas9 for application to early avian embryos with improved efficiency via a three-fold strategy. First, we employed Cas9 protein flanked with two nuclear localization signal sequences for improved nuclear localization. Second, we used a modified guide RNA (gRNA) scaffold that obviates premature termination of transcription and unstable Cas9-gRNA interactions...
December 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/29150006/genome-engineering-using-haploid-embryonic-stem-cells
#2
Takuro Horii, Izuho Hatada
Haploidy is a useful feature for the study of gene function because disruption of one allele in haploid cells, which contain only a single set of chromosomes, can cause loss-of-function phenotypes. Recent success in generating haploid embryonic stem (ES) cells from several mammalian species, including human, provides a new platform for simple genetic manipulation of the mammalian genome. The genome-editing potential of the CRISPR/Cas system is enhanced by the use of haploid ES cells. For example, CRISPR/Cas has been used for high-efficiency generation of multiple knockouts and knockins in haploid ES cells, with potential application in genome-wide screening...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29150003/crispr-cas9-technology-applications-and-human-disease-modeling
#3
Marta Martinez-Lage, Raúl Torres-Ruiz, Sandra Rodriguez-Perales
The CRISPR/Cas9 system development has revolutionized the field of genome engineering through the efficient creation of targeted breaks in the DNA of almost any organism and cell type, opening an avenue for a wide range of applications in biomedical research and medicine. Apart from gene edition through knock-in or knock-out approaches, CRISPR/Cas9 technology has been used for many other purposes, including regulation of endogenous gene expression, epigenome editing, live-cell imaging of chromosomal loci, edition of RNA and high-throughput screening...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29149598/harnessing-bet-inhibitor-sensitivity-reveals-amigo2-as-a-melanoma-survival-gene
#4
Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A Davies, Christopher R Vakoc, Eva Hernando, Emily Bernstein
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29149056/characterization-of-ovine-a3z1-restriction-properties-against-small-ruminant-lentiviruses-srlvs
#5
Lorena de Pablo-Maiso, Idoia Glaria, Helena Crespo, Estanislao Nistal-Villán, Valgerdur Andrésdóttir, Damián de Andrés, Beatriz Amorena, Ramsés Reina
Intrinsic factors of the innate immune system include the apolipoprotein B editing enzyme catalytic polypeptide-like 3 (APOBEC3) protein family. APOBEC3 inhibits replication of different virus families by cytosine deamination of viral DNA and a not fully characterized cytosine deamination-independent mechanism. Sheep are susceptible to small ruminant lentivirus (SRLVs) infection and contain three APOBEC3 genes encoding four proteins (A3Z1, Z2, Z3 and Z2-Z3) with yet not deeply described antiviral properties...
November 17, 2017: Viruses
https://www.readbyqxmd.com/read/29145975/in-cancer-a-to-i-rna-editing-can-be-the-driver-the-passenger-or-the-mechanic
#6
Nabeel S Ganem, Noa Ben-Asher, Ayelet T Lamm
In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements...
May 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/29141958/dna-methylation-defines-regional-identity-of-human-intestinal-epithelial-organoids-and-undergoes-dynamic-changes-during-development
#7
Judith Kraiczy, Komal M Nayak, Kate J Howell, Alexander Ross, Jessica Forbester, Camilla Salvestrini, Roxana Mustata, Sally Perkins, Amanda Andersson-Rolf, Esther Leenen, Anke Liebert, Ludovic Vallier, Philip C Rosenstiel, Oliver Stegle, Gordon Dougan, Robert Heuschkel, Bon-Kyoung Koo, Matthias Zilbauer
OBJECTIVE: Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited. DESIGN: We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology...
November 15, 2017: Gut
https://www.readbyqxmd.com/read/29141633/genome-modification-of-cxcr4-by-staphylococcus-aureus-cas9-renders-cells-resistance-to-hiv-1-infection
#8
Qiankun Wang, Shuliang Chen, Qiaoqiao Xiao, Zhepeng Liu, Shuai Liu, Panpan Hou, Li Zhou, Wei Hou, Wenzhe Ho, Chunmei Li, Li Wu, Deyin Guo
BACKGROUND: The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4)-tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4(+) T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question...
November 15, 2017: Retrovirology
https://www.readbyqxmd.com/read/29140568/crispr-cas9-based-safe-harbor-gene-editing-in-rhesus-ipscs
#9
Ravi Chandra Yada, John W Ostrominski, Ilker Tunc, So Gun Hong, Jizhong Zou, Cynthia E Dunbar
NHP iPSCs provide a unique opportunity to test safety and efficacy of iPSC-derived therapies in clinically relevant NHP models. To monitor these cells in vivo, there is a need for safe and efficient labeling methods. Gene insertion into genomic safe harbors (GSHs) supports reliable transgene expression while minimizing the risk the modification poses to the host genome or target cell. Specifically, this protocol demonstrates targeting of the adeno-associated virus site 1 (AAVS1), one of the most widely used GSH loci in the human genome, with CRISPR/Cas9, allowing targeted marker or therapeutic gene insertion in rhesus macaque induced pluripotent stem cells (RhiPSCs)...
November 15, 2017: Current Protocols in Stem Cell Biology
https://www.readbyqxmd.com/read/29136157/depletion-of-recombination-specific-co-factors-by-the-c-terminal-mutant-of-the-activation-induced-cytidine-deaminase-causes-the-dominant-negative-effect-on-class-switch-recombination
#10
Azza Al Ismail, Afzal Husain, Maki Kobayashi, Tasuku Honjo, Nasim A Begum
Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with Hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild type WT AID whereas its mechanism remains unknown...
November 10, 2017: International Immunology
https://www.readbyqxmd.com/read/29133799/hit-and-run-epigenetic-editing-prevents-senescence-entry-in-primary-breast-cells-from-healthy-donors
#11
Emily A Saunderson, Peter Stepper, Jennifer J Gomm, Lily Hoa, Adrienne Morgan, Michael D Allen, J Louise Jones, John G Gribben, Tomasz P Jurkowski, Gabriella Ficz
Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29130947/application-of-digital-pcr-in-detecting-human-diseases-associated-gene-mutation
#12
Yu Tong, Shizhen Shen, Hui Jiang, Zhi Chen
Gene mutation has been considered a research hotspot, and the rapid development of biomedicine has enabled significant advances in the evaluation of gene mutations. The advent of digital polymerase chain reaction (dPCR) elevates the detection of gene mutations to unprecedented levels of precision, especially in cancer-associated genes. dPCR has been utilized in the detection of tumor markers in cell-free DNA (cfDNA) samples from patients with different types of cancer in samples such as plasma, cerebrospinal fluid, urine and sputum, which confers significant value for dPCR in both clinical applications and basic research...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29130157/target-discovery-for-precision-medicine-using-high-throughput-genome-engineering
#13
Xinyi Guo, Poonam Chitale, Neville E Sanjana
Over the past few years, programmable RNA-guided nucleases such as the CRISPR/Cas9 system have ushered in a new era of precision genome editing in diverse model systems and in human cells. Functional screens using large libraries of RNA guides can interrogate a large hypothesis space to pinpoint particular genes and genetic elements involved in fundamental biological processes and disease-relevant phenotypes. Here, we review recent high-throughput CRISPR screens (e.g. loss-of-function, gain-of-function, and targeting noncoding elements) and highlight their potential for uncovering novel therapeutic targets, such as those involved in cancer resistance to small molecular drugs and immunotherapies, tumor evolution, infectious disease, inborn genetic disorders, and other therapeutic challenges...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29130152/combining-engineered-nucleases-with-adeno-associated-viral-vectors-for-therapeutic-gene-editing
#14
Benjamin E Epstein, David V Schaffer
With the recent advent of several generations of targeted DNA nucleases, most recently CRISPR/Cas9, genome editing has become broadly accessible across the biomedical community. Importantly, the capacity of these nucleases to modify specific genomic loci associated with human disease could render new classes of genetic disease, including autosomal dominant or even idiopathic disease, accessible to gene therapy. In parallel, the emergence of adeno-associated virus (AAV) as a clinically important vector raises the possibility of integrating these two technologies towards the development of gene editing therapies...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29130151/viral-vectors-engineered-cells-and-the-crispr-revolution
#15
James E DiCarlo, Anurag Deeconda, Stephen H Tsang
Over the past few decades the ability to edit human cells has revolutionized modern biology and medicine. With advances in genome editing methodologies, gene delivery and cell-based therapeutics targeted at treatment of genetic disease have become a reality that will become more and more essential in clinical practice. Modifying specific mutations in eukaryotic cells using CRISPR-Cas systems derived from prokaryotic immune systems has allowed for precision in correcting various disease mutations. Furthermore, delivery of genetic payloads by employing viral tropism has become a crucial and effective mechanism for delivering genes and gene editing systems into cells...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29128367/nemo-links-nuclear-factor-%C3%AE%C2%BAb-to-human-diseases
#16
REVIEW
Gunter Maubach, Michael Naumann
The nuclear factor (NF)-κB essential modulator (NEMO) is a key regulator in NF-κB-mediated signaling. By transmitting extracellular or intracellular signals, NEMO can control NF-κB-regulated genes. NEMO dysfunction is associated with inherited diseases such as incontinentia pigmenti (IP), ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), and some cancers. We focus on molecular studies, human case reports, and mouse models emphasizing the significance of NEMO molecular interactions and modifications in health and diseases...
November 8, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29125958/investigation-of-brain-science-and-neurological-psychiatric-disorders-using-genetically-modified-non-human-primates
#17
REVIEW
Hideyuki Okano, Noriyuki Kishi
Although mice have been the most frequently used experimental animals in many research fields due to well-established gene manipulation techniques, recent evidence has revealed that rodent models do not always recapitulate pathophysiology of human neurological and psychiatric diseases due to the differences between humans and rodents. The recent developments in gene manipulation of non-human primate have been attracting much attention in the biomedical research field, because non-human primates have more applicable brain structure and function than rodents...
November 7, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/29124278/targeted-gene-editing-in-human-pluripotent-stem-cells-using-site-specific-nucleases
#18
Sylvia Merkert, Ulrich Martin
Introduction of induced pluripotent stem cell (iPSC) technology and site-directed nucleases brought a major breakthrough in the development of regenerative therapies and biomedical research. With the advancement of ZFNs, TALENs, and the CRISPR/Cas9 technology, straightforward and precise manipulation of the genome of human pluripotent stem cells (PSC) became possible, allowing relatively easy and fast generation of gene knockouts, integration of transgenes, or even introduction of single nucleotide changes for correction or introduction of disease-specific mutations...
November 10, 2017: Advances in Biochemical Engineering/biotechnology
https://www.readbyqxmd.com/read/29123113/talen-mediated-functional-correction-of-human-ipsc-derived-macrophages-in-context-of-hereditary-pulmonary-alveolar-proteinosis
#19
Alexandra Kuhn, Mania Ackermann, Claudio Mussolino, Toni Cathomen, Nico Lachmann, Thomas Moritz
Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs)...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29122734/gene-editing-of-mps-i-human-fibroblasts-by-co-delivery-of-a-crispr-cas9-plasmid-and-a-donor-oligonucleotide-using-nanoemulsions-as-nonviral-carriers
#20
Roselena Silvestri Schuh, Talita Giacomet de Carvalho, Roberto Giugliani, Ursula Matte, Guilherme Baldo, Helder Ferreira Teixeira
Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by the deficiency of alpha-L-iduronidase (IDUA). This study shows the use of nanoemulsions co-complexed with the plasmid of CRISPR/Cas9 system and a donor oligonucleotide aiming at MPS I gene editing in vitro. Nanoemulsions composed of MCT, DOPE, DOTAP, DSPE-PEG, and water were prepared by high-pressure homogenization. The DNA was complexed by adsorption or encapsulation of preformed DNA/DOTAP complexes with nanoemulsions at +4/ -1 charge ratio...
November 6, 2017: European Journal of Pharmaceutics and Biopharmaceutics
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