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https://www.readbyqxmd.com/read/29140568/crispr-cas9-based-safe-harbor-gene-editing-in-rhesus-ipscs
#1
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/29130157/target-discovery-for-precision-medicine-using-high-throughput-genome-engineering
#2
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
#3
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
#4
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/29130076/crispr-correction-of-a-homozygous-low-density-lipoprotein-receptor-mutation-in-familial-hypercholesterolemia-induced-pluripotent-stem-cells
#5
Linda Omer, Elizabeth A Hudson, Shirong Zheng, James B Hoying, Yuan Shan, Nolan L Boyd
Familial hypercholesterolemia (FH) is a hereditary disease primarily due to mutations in the low-density lipoprotein receptor (LDLR) that lead to elevated cholesterol and premature development of cardiovascular disease. Homozygous FH patients (HoFH) with two dysfunctional LDLR alleles are not as successfully treated with standard hypercholesterol therapies, and more aggressive therapeutic approaches to control cholesterol levels must be considered. Liver transplant can resolve HoFH, and hepatocyte transplantation has shown promising results in animals and humans...
November 2017: Hepatol Commun
https://www.readbyqxmd.com/read/29122757/crispr-mediated-tcr-replacement-generates-superior-anticancer-transgenic-t-cells
#6
Mateusz Legut, Garry Dolton, Afsar Ali Mian, Oliver Ottmann, Andrew Sewell
Adoptive transfer of T-cells genetically modified to express a cancer-specific T-cell receptor (TCR) has shown significant therapeutic potential for both hematological and solid tumors. However, a major issue of transducing T-cells with a transgenic TCR is the pre-existing expression of TCRs in the recipient cells. These endogenous TCRs compete with the transgenic TCR for surface expression and allow mixed dimer formation. Mixed dimers, formed by mispairing between the endogenous and transgenic TCRs, may harbor autoreactive specificities...
November 9, 2017: Blood
https://www.readbyqxmd.com/read/29114029/rapid-selection-free-high-efficiency-genome-editing-in-protozoan-parasites-using-crispr-cas9-ribonucleoproteins
#7
Lia Carolina Soares Medeiros, Lilith South, Duo Peng, Juan M Bustamante, Wei Wang, Molly Bunkofske, Natasha Perumal, Fernando Sanchez-Valdez, Rick L Tarleton
Trypanosomatids (order Kinetoplastida), including the human pathogens Trypanosoma cruzi (agent of Chagas disease), Trypanosoma brucei, (African sleeping sickness), and Leishmania (leishmaniasis), affect millions of people and animals globally. T. cruzi is considered one of the least studied and most poorly understood tropical disease-causing parasites, in part because of the relative lack of facile genetic engineering tools. This situation has improved recently through the application of clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9) technology, but a number of limitations remain, including the toxicity of continuous Cas9 expression and the long drug marker selection times...
November 7, 2017: MBio
https://www.readbyqxmd.com/read/29113536/the-pigmented-epithelium-a-bright-partner-against-photoreceptor-degeneration
#8
Joaquín Letelier, Paola Bovolenta, Juan R Martínez-Morales
Sight depends on the intimate association between photoreceptors and pigment epithelial cells. The evolutionary origin of this cellular tandem can be traced back to the emergence of bilateral animals, at least 450 million years ago, as they define the minimal unit of the ancestral prototypic eye. Phototransduction is a demanding process from the energetic and homeostatic points of view, and not surprisingly photoreceptive cells are particularly susceptible to damage and degeneration. Here, we will examine the different ancillary roles that the pigmented cells play in the physiology and homeostasis of photoreceptors, linking each one of these processes to the most common hereditary retinal diseases...
November 7, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/29111217/ruxolitinib-partially-reverses-functional-nk-cell-deficiency-in-patients-with-stat1-gain-of-function-mutations
#9
Alexander Vargas-Hernandez, Emily M Mace, Ofer Zimmerman, Christa S Zerbe, Alexandra F Freeman, Sergio Rosenzweig, Jennifer W Leiding, Troy Torgerson, Matthew C Altman, Edith Schussler, Charlotte Cunningham-Rundles, Ivan K Chinn, Alexandre F Carisey, Imelda C Hanson, Nicholas L Rider, Steven M Holland, Jordan S Orange, Lisa R Forbes
BACKGROUND: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in STAT1 GOF patients. METHODS: NK cell phenotype and function were determined in 16 STAT1 GOF patients...
October 27, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29107808/genetic-therapies-for-cystic-fibrosis-lung-disease
#10
REVIEW
Stephen L Hart, Patrick T Harrison
Gene therapy for cystic fibrosis (CF) has been the subject of intense research over the last twenty-five years or more, using both viral and liposomal delivery methods, but so far without the emergence of a clinical therapy. New approaches to CF gene therapy involving recent improvements to vector systems, both viral and non-viral, as well as new nucleic acid technologies have led to renewed interest in the field. The field of therapeutic gene editing is rapidly developing with the emergence of CRISPR/Cas9 as well as chemically modified mRNA therapeutics...
November 3, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29103804/fibrinogen-activates-bmp-signaling-in-oligodendrocyte-progenitor-cells-and-inhibits-remyelination-after-vascular-damage
#11
Mark A Petersen, Jae Kyu Ryu, Kae-Jiun Chang, Ainhoa Etxeberria, Sophia Bardehle, Andrew S Mendiola, Wanjiru Kamau-Devers, Stephen P J Fancy, Andrea Thor, Eric A Bushong, Bernat Baeza-Raja, Catriona A Syme, Michael D Wu, Pamela E Rios Coronado, Anke Meyer-Franke, Stephanie Yahn, Lauriane Pous, Jae K Lee, Christian Schachtrup, Hans Lassmann, Eric J Huang, May H Han, Martina Absinta, Daniel S Reich, Mark H Ellisman, David H Rowitch, Jonah R Chan, Katerina Akassoglou
Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro...
October 19, 2017: Neuron
https://www.readbyqxmd.com/read/29095988/changes-in-extracellular-matrix-cause-rpe-cells-to-make-basal-deposits-and-activate-the-alternative-complement-pathway
#12
Rosario Fernandez-Godino, Kinga M Bujakowska, Eric A Pierce
The design of efficient therapies for age-related macular degeneration (AMD) is limited by our understanding of the pathogenesis of basal deposits, which form between retinal pigment epithelium (RPE) and Bruch's membrane (BrM) early in disease, and involve activation of the complement system. To investigate the roles of BrM, RPE and complement in AMD, we generated abnormal extracellular matrix (ECM) using CRISPR-edited ARPE-19 cells. We introduced to these cells the p.R345W mutation in EFEMP1, which causes early-onset macular degeneration...
October 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29091160/gene-therapy-advances-challenges-and-perspectives
#13
Giulliana Augusta Rangel Gonçalves, Raquel de Melo Alves Paiva
The ability to make site-specific modifications to the human genome has been an objective in medicine since the recognition of the gene as the basic unit of heredity. Thus, gene therapy is understood as the ability of genetic improvement through the correction of altered (mutated) genes or site-specific modifications that target therapeutic treatment. This therapy became possible through the advances of genetics and bioengineering that enabled manipulating vectors for delivery of extrachromosomal material to target cells...
July 2017: Einstein
https://www.readbyqxmd.com/read/29090592/genome-editing-technologies-to-fight-infectious-diseases
#14
Marta Trevisan, Giorgio Palù, Luisa Barzon
Genome editing by programmable nucleases represents a promising tool that could be exploited to develop new therapeutic strategies to fight infectious diseases. These nucleases, such as zinc-finger nucleases, transcription activator-like effector nucleases, clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) and homing endonucleases, are molecular scissors that can be targeted at predetermined loci in order to modify the genome sequence of an organism. Areas covered: By perturbing genomic DNA at predetermined loci, programmable nucleases can be used as antiviral and antimicrobial treatment...
November 8, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/29089503/designing-broad-spectrum-anti-hiv-1-grnas-to-target-patient-derived-variants
#15
Will Dampier, Neil T Sullivan, Cheng-Han Chung, Joshua Chang Mell, Michael R Nonnemacher, Brian Wigdahl
Clustered regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated protein 9 (Cas9), including specific guide RNAs (gRNAs), can excise integrated human immunodeficiency virus type 1 (HIV-1) provirus from host chromosomes. To date, anti-HIV-1 gRNAs have been designed to account for off-target activity, however, they seldom account for genetic variation in the HIV-1 genome within and between patients, which will be crucial for therapeutic application of this technology. This analysis tests the ability of published anti-HIV-1 gRNAs to cleave publicly available patient-derived HIV-1 sequences to inform gRNA design and provides basic computational tools to researchers in the field...
October 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29083112/immunity-to-crispr-cas9-and-cas12a-therapeutics
#16
REVIEW
Wei Leong Chew
Genome-editing therapeutics are poised to treat human diseases. As we enter clinical trials with the most promising CRISPR-Cas9 and CRISPR-Cas12a (Cpf1) modalities, the risks associated with administering these foreign biomolecules into human patients become increasingly salient. Preclinical discovery with CRISPR-Cas9 and CRISPR-Cas12a systems and foundational gene therapy studies indicate that the host immune system can mount undesired responses against the administered proteins and nucleic acids, the gene-edited cells, and the host itself...
October 30, 2017: Wiley Interdisciplinary Reviews. Systems Biology and Medicine
https://www.readbyqxmd.com/read/29082723/-genome-editing-focus-on-the-off-target-effects
#17
Xiubin He, Feng Gu
Breakthroughs of genome-editing in recent years have paved the way to develop new therapeutic strategies. These genome-editing tools mainly include Zinc-finger nucleases (ZFNs), Transcription activator-like effector nucleases (TALENs), and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas-based RNA-guided DNA endonucleases. However, off-target effects are still the major issue in genome editing, and limit the application in gene therapy. Here, we summarized the cause and compared different detection methods of off-targets...
October 25, 2017: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
https://www.readbyqxmd.com/read/29082490/high-content-screening-approaches-that-minimize-confounding-factors-in-rnai-crispr-and-small-molecule-screening
#18
Steven A Haney
Screening arrayed libraries of reagents, particularly small molecules began as a vehicle for drug discovery, but the in last few years it has become a cornerstone of biological investigation, joining RNAi and CRISPR as methods for elucidating functional relationships that could not be anticipated, and illustrating the mechanisms behind basic and disease biology, and therapeutic resistance. However, these approaches share some common challenges, especially with respect to specificity or selectivity of the reagents as they are scaled to large protein families or the genome...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29079036/apela-promotes-tumour-growth-and-cell-migration-in-ovarian-cancer-in-a-p53-dependent-manner
#19
Yuyin Yi, Shu-Huei Tsai, Jung-Chien Cheng, Evan Y Wang, Michael S Anglesio, Dawn R Cochrane, Megan Fuller, Ewan A Gibb, Wei Wei, David G Huntsman, Aly Karsan, Pamela A Hoodless
OBJECTIVE: APELA is a small, secreted peptide that can function as a ligand for the G-protein coupled receptor, Apelin Receptor (APLNR, APJ). APELA plays an essential role in endoderm differentiation and cardiac development during embryogenesis. We investigated whether APELA exerts any functions in cancer progression. METHODS: The Cancer Genome Atlas (TCGA) RNA sequencing datasets, microarray from an OCCC mouse model, and RNA isolated from fresh frozen and FFPE patient tissue were used to assess APELA expression...
October 24, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29078326/crispr-cas9-mediated-saturated-mutagenesis-screen-predicts-clinical-drug-resistance-with-improved-accuracy
#20
Leyuan Ma, Jeffrey I Boucher, Janet Paulsen, Sebastian Matuszewski, Christopher A Eide, Jianhong Ou, Garrett Eickelberg, Richard D Press, Lihua Julie Zhu, Brian J Druker, Susan Branford, Scot A Wolfe, Jeffrey D Jensen, Celia A Schiffer, Michael R Green, Daniel N Bolon
Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof of concept, we mutagenized a selected region within the leukemic oncogene BCR-ABL1 Using bulk competitions with a deep-sequencing readout, we analyzed hundreds of mutations under multiple drug conditions and found that the effects of mutations on growth in the presence or absence of drug were critical for predicting clinically relevant resistant mutations, many of which were cancer adaptive in the absence of drug pressure...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
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