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Genome Editing human

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https://www.readbyqxmd.com/read/29453277/editing-out-five-serpina1-paralogs-to-create-a-mouse-model-of-genetic-emphysema
#1
Florie Borel, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, Airiel Davis, Alisha Gruntman, Terence R Flotte, Michael H Brodsky, Andrew M Hoffman, Mai K Elmallah, Christian Mueller
Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase...
February 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29452156/establishment-of-a-prkag2-cardiac-syndrome-disease-model-and-mechanism-study-using-human-induced-pluripotent-stem-cells
#2
Yongkun Zhan, Xiaolei Sun, Bin Li, Huanhuan Cai, Chen Xu, Qianqian Liang, Chao Lu, Ruizhe Qian, Sifeng Chen, Lianhua Yin, Wei Sheng, Guoying Huang, Aijun Sun, Junbo Ge, Ning Sun
PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.905G>A (R302Q) in the PRKAG2 gene and further corrected the R302Q mutation with CRISPR-Cas9 mediated genome editing...
February 13, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29449511/crispr-cas12a-target-binding-unleashes-indiscriminate-single-stranded-dnase-activity
#3
Janice S Chen, Enbo Ma, Lucas B Harrington, Maria Da Costa, Xinran Tian, Joel M Palefsky, Jennifer A Doudna
CRISPR-Cas12a (Cpf1) proteins are RNA-guided enzymes that bind and cut DNA as components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a has been harnessed for genome editing based on its ability to generate targeted, double-stranded DNA (dsDNA) breaks. Here we show that RNA-guided DNA binding unleashes indiscriminate single-stranded DNA (ssDNA) cleavage activity by Cas12a that completely degrades ssDNA molecules. We find that target-activated, non-specific ssDNase cleavage is also a property of other type V CRISPR-Cas12 enzymes...
February 15, 2018: Science
https://www.readbyqxmd.com/read/29446996/recent-advances-in-therapeutic-genome-editing-in-china
#4
Yang Yang, Qingnan Wang, Qian Li, Ke Men, Zhiyao He, Hongxin Deng, Weizhi Ji, Yuquan Wei
Editing of the genome to correct disease-causing mutations is a promising approach for the treatment of human diseases. Recent advances in the development of programmable nuclease-based genome editing tools have substantially improved the ability to make precise changes in the human genome. Genome editing technologies are already being used to correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional gene therapies. Chinese scientists have made remarkable breakthroughs in the field of therapeutic genome editing, particularly with the first clinical trial involving the clustered regularly interspaced short palindromic repeats-caspase 9 system that began in China...
February 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29446747/crispr-cas9-genome-editing-a-promising-tool-for-therapeutic-applications-of-induced-pluripotent-stem-cells
#5
Yanli Zhang, Danuta Sastre, Feng Wang
Induced pluripotent stem cells hold tremendous potential for biological and therapeutic applications. The development of efficient technologies for the targeted genome alteration of stem cells in disease models is a prerequisite for utilizing stem cells to their full potential. The revolutionary technology for genome editing known as the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) system is recently recognized as a powerful tool for editing DNA at specific loci...
February 14, 2018: Current Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29445326/structure-function-studies-of-the-%C3%AE-4-subunit-reveal-evolutionary-loss-of-a-glyr-subtype-involved-in-startle-and-escape-responses
#6
Sophie Leacock, Parnayan Syed, Victoria M James, Anna Bode, Koichi Kawakami, Angelo Keramidas, Maximiliano Suster, Joseph W Lynch, Robert J Harvey
Inhibitory glycine receptors (GlyRs) are pentameric ligand-gated anion channels with major roles in startle disease/hyperekplexia (GlyR α1), cortical neuronal migration/autism spectrum disorder (GlyR α2), and inflammatory pain sensitization/rhythmic breathing (GlyR α3). However, the role of the GlyR α4 subunit has remained enigmatic, because the corresponding human gene ( GLRA4 ) is thought to be a pseudogene due to an in-frame stop codon at position 390 within the fourth membrane-spanning domain (M4). Despite this, a recent genetic study has implicated GLRA4 in intellectual disability, behavioral problems and craniofacial anomalies...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29445268/genome-editing-applications-of-crispr-cas9-to-promote-in-vitro-studies-of-alzheimer-s-disease
#7
REVIEW
Vo Van Giau, Hyon Lee, Kyu Hwan Shim, Eva Bagyinszky, Seong Soo A An
Genetic variations play an important role in the clinical presentation and progression of Alzheimer's disease (AD), especially early-onset Alzheimer's disease. Hundreds of mutations have been reported with the majority resulting from alterations in β-amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ) genes. The roles of these mutations in the pathogenesis of AD have been classically confirmed or refuted through functional studies, where the mutations are cloned, inserted into cell lines, and monitored for changes in various properties including cell survival, amyloid production, or Aβ42/40 ratio...
2018: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/29445025/strong-conservation-of-inbred-mouse-strain-microrna-loci-but-broad-variation-in-brain-micrornas-due-to-rna-editing-and-isomir-expression
#8
Kalevi Trontti, Juho Väänänen, Tessa Sipilä, Dario Greco, Iiris Hovatta
Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by 1) identifying miRNA SNPs in whole genome sequence data from 36 strains, and 2) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of 6 strains, to facilitate the study of miRNAs in neurobehavioral phenotypes...
February 14, 2018: RNA
https://www.readbyqxmd.com/read/29440643/dissection-and-function-of-autoimmunity-associated-tnfaip3-a20-gene-enhancers-in-humanized-mouse-models
#9
Upneet K Sokhi, Mark P Liber, Laura Frye, Sungho Park, Kyuho Kang, Tania Pannellini, Baohong Zhao, Rada Norinsky, Lionel B Ivashkiv, Shiaoching Gong
Enhancers regulate gene expression and have been linked with disease pathogenesis. Little is known about enhancers that regulate human disease-associated genes in primary cells relevant for pathogenesis. Here we use BAC transgenics and genome editing to dissect, in vivo and in primary immune cells, enhancers that regulate human TNFAIP3, which encodes A20 and is linked with autoimmune diseases. A20 expression is dependent on a topologically associating subdomain (sub-TAD) that harbors four enhancers, while another >20 enhancers in the A20 locus are redundant...
February 13, 2018: Nature Communications
https://www.readbyqxmd.com/read/29440377/efficient-derivation-of-stable-primed-pluripotent-embryonic-stem-cells-from-bovine-blastocysts
#10
Yanina Soledad Bogliotti, Jun Wu, Marcela Vilarino, Daiji Okamura, Delia Alba Soto, Cuiqing Zhong, Masahiro Sakurai, Rafael Vilar Sampaio, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Pablo Juan Ross
Embryonic stem cells (ESCs) are derived from the inner cell mass of preimplantation blastocysts. From agricultural and biomedical perspectives, the derivation of stable ESCs from domestic ungulates is important for genomic testing and selection, genome engineering, and modeling human diseases. Cattle are one of the most important domestic ungulates that are commonly used for food and bioreactors. To date, however, it remains a challenge to produce stable pluripotent bovine ESC lines. Employing a culture system containing fibroblast growth factor 2 and an inhibitor of the canonical Wnt-signaling pathway, we derived pluripotent bovine ESCs (bESCs) with stable morphology, transcriptome, karyotype, population-doubling time, pluripotency marker gene expression, and epigenetic features...
February 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29438257/recent-insights-into-vascular-development-from-studies-in-zebrafish
#11
Ryota L Matsuoka, Didier Y R Stainier
PURPOSE OF REVIEW: Zebrafish has provided a powerful platform to study vascular biology over the past 25 years, owing to their distinct advantages for imaging and genetic manipulation. In this review, we summarize recent progress in vascular biology with particular emphasis on vascular development in zebrafish. RECENT FINDINGS: The advent of transcription activator-like effector nuclease and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 genome-editing technologies has dramatically facilitated reverse genetic approaches in zebrafish, as in other models...
February 12, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29434956/dynamics-of-crispr-cas9-mediated-genomic-editing-of-the-axl-locus-in-hepatocellular-carcinoma-cells
#12
Irene Scharf, Lisa Bierbaumer, Heidemarie Huber, Philipp Wittmann, Christine Haider, Christine Pirker, Walter Berger, Wolfgang Mikulits
Genomic editing using the CRISPR/Cas9 technology allows selective interference with gene expression. With this method, a multitude of haploid and diploid cells from different organisms have been employed to successfully generate knockouts of genes coding for proteins or small RNAs. Yet, cancer cells exhibiting an aberrant ploidy are considered to be less accessible to CRISPR/Cas9-mediated genomic editing, as amplifications of the targeted gene locus could hamper its effectiveness. Here we examined the suitability of CRISPR/Cas9 to knockout the receptor tyrosine kinase Axl in the human hepatoma cell lines HLF and SNU449...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434619/from-bioengineering-to-crispr-cas9-a-personal-retrospective-of-20-years-of-research-in-programmable-genome-targeting
#13
Albert Jeltsch
Genome targeting of restriction enzymes and DNA methyltransferases has many important applications including genome and epigenome editing. 15-20 years ago, my group was involved in the development of approaches for programmable genome targeting, aiming to connect enzymes with an oligodeoxynucleotide (ODN), which could form a sequence-specific triple helix at the genomic target site. Importantly, the target site of such enzyme-ODN conjugate could be varied simply by altering the ODN sequence promising great applicative values...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29428910/a-review-of-crispr-based-genome-editing-survival-evolution-and-challenges
#14
Hafiz Ishfaq Ahmad, Muhammad Jamil Ahmad, Akhtar Rasool Asif, Muhammad Adnan, Muhammad Kashif Iqbal, Khalid Mehmood, Sayyed Aun Muhammad, Ali Akbar Bhuiyan, Abdelmotaleb Elokil, Xiaoyong Du, Changzhi Zhao, Xiangdong Liu, Shengsong Xie
Precise nucleic acid editing technologies have facilitated the research of cellular function and the development of novel therapeutics, especially the current programmable nucleases-based editing tools, such as the prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)-associated nucleases (Cas). As CRISPR-based therapies are advancing toward human clinical trials, it is important to understand how natural genetic variation in the human population may affect the results of these trials and even patient safety...
February 11, 2018: Current Issues in Molecular Biology
https://www.readbyqxmd.com/read/29428902/recent-advance-on-genome-editing-for-therapy-of-%C3%AE-hemoglobinopathies
#15
Jia-Wei Liu, Tao Hong, Xin Qin, Ying-Min Liang, Ping Zhang
β-hemoglobinopathies are one of six groups of common illnesses affecting human health. Although the genetic mechanisms have been elucidated for several decades, curable treatment options, other than allogeneic bone marrow transplantation, are still lacking. In recent years, rapid development in genome editing technologies and their clinical applications have opened up new directions for treatment of β-hemoglobinopathies. Genome editing technologies, as applied in autologous CD34 + hematopoietic stem and progenitor cells, represents a promising remedial means for the β-globin disorders...
February 20, 2018: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/29426832/genome-wide-tracking-of-dcas9-methyltransferase-footprints
#16
Christina Galonska, Jocelyn Charlton, Alexandra L Mattei, Julie Donaghey, Kendell Clement, Hongcang Gu, Arman W Mohammad, Elena K Stamenova, Davide Cacchiarelli, Sven Klages, Bernd Timmermann, Tobias Cantz, Hans R Schöler, Andreas Gnirke, Michael J Ziller, Alexander Meissner
In normal mammalian development cytosine methylation is essential and is directed to specific regions of the genome. Despite notable advances through mapping its genome-wide distribution, studying the direct contribution of DNA methylation to gene and genome regulation has been limited by the lack of tools for its precise manipulation. Thus, combining the targeting capability of the CRISPR-Cas9 system with an epigenetic modifier has attracted interest in the scientific community. In contrast to profiling the genome-wide cleavage of a nuclease competent Cas9, tracing the global activity of a dead Cas9 (dCas9) methyltransferase fusion protein is challenging within a highly methylated genome...
February 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29425498/hybridization-kinetics-explains-crispr-cas-off-targeting-rules
#17
Misha Klein, Behrouz Eslami-Mossallam, Dylan Gonzalez Arroyo, Martin Depken
Due to their specificity, efficiency, and ease of programming, CRISPR-associated nucleases are popular tools for genome editing. On the genomic scale, these nucleases still show considerable off-target activity though, posing a serious obstacle to the development of therapies. Off targeting is often minimized by choosing especially high-specificity guide sequences, based on algorithms that codify empirically determined off-targeting rules. A lack of mechanistic understanding of these rules has so far necessitated their ad hoc implementation, likely contributing to the limited precision of present algorithms...
February 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29423804/primary-airway-epithelial-cell-gene-editing-using-crispr-cas9
#18
Jamie L Everman, Cydney Rios, Max A Seibold
The adaptation of the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated endonuclease 9 (CRISPR-Cas9) machinery from prokaryotic organisms has resulted in a gene editing system that is highly versatile, easily constructed, and can be leveraged to generate human cells knocked out (KO) for a specific gene. While standard transfection techniques can be used for the introduction of CRISPR-Cas9 expression cassettes to many cell types, delivery by this method is not efficient in many primary cell types, including primary human airway epithelial cells (AECs)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29423217/primordial-germ-cell-mediated-transgenesis-and-genome-editing-in-birds
#19
REVIEW
Jae Yong Han, Young Hyun Park
Transgenesis and genome editing in birds are based on a unique germline transmission system using primordial germ cells (PGCs), which is quite different from the mammalian transgenic and genome editing system. PGCs are progenitor cells of gametes that can deliver genetic information to the next generation. Since avian PGCs were first discovered in nineteenth century, there have been numerous efforts to reveal their origin, specification, and unique migration pattern, and to improve germline transmission efficiency...
2018: Journal of Animal Science and Biotechnology
https://www.readbyqxmd.com/read/29423214/use-of-gene-editing-technology-to-introduce-targeted-modifications-in-pigs
#20
REVIEW
Junghyun Ryu, Randall S Prather, Kiho Lee
Pigs are an important resource in agriculture and serve as a model for human diseases. Due to their physiological and anatomical similarities with humans, pigs can recapitulate symptoms of human diseases, making them a useful model in biomedicine. However, in the past pig models have not been widely used partially because of the difficulty in genetic modification. The lack of true embryonic stem cells in pigs forced researchers to utilize genetic modification in somatic cells and somatic cell nuclear transfer (SCNT) to generate genetically engineered (GE) pigs carrying site-specific modifications...
2018: Journal of Animal Science and Biotechnology
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