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Virus AND gene edit

Su Yang, Shihua Li, Xiao-Jiang Li
Virus-mediated expression of CRISPR/Cas9 is commonly used for genome editing in animal brains to model or treat neurological diseases, but the potential neurotoxicity of overexpressing bacterial Cas9 in the mammalian brain remains unknown. Through RNA sequencing (RNA-seq) analysis, we find that virus-mediated expression of Cas9 influences the expression of genes involved in neuronal functions. Reducing the half-life of Cas9 by tagging with geminin, whose expression is regulated by the cell cycle, maintains the genome editing capacity of Cas9 but significantly alleviates neurotoxicity...
December 4, 2018: Cell Reports
Zheng Hu, Ding Ma
Cervical cancer is a complex disease caused by both genetic susceptibility and environmental factors. Inherited genomic variance, high-risk human papilloma virus (HPV) infection/integration, genome methylation and somatic mutation could all constitute one machine learning model, laying the ground for molecular classification and the precision medicine of cervical cancer. Therefore, for cervical screening, next generation sequencing (NGS)-based HPV DNA and other molecular tests as well as dynamic machine learning models would accurately predict patients with potential to develop the cancer, thereby reducing the burden of repeated screening...
February 25, 2018: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Christian K Pfaller, Ryan C Donohue, Stepan Nersisyan, Leonid Brodsky, Roberto Cattaneo
The interferon (IFN)-mediated innate immune response is the first line of defense against viruses. However, an IFN-stimulated gene, the adenosine deaminase acting on RNA 1 (ADAR1), favors the replication of several viruses. ADAR1 binds double-stranded RNA and converts adenosine to inosine by deamination. This form of editing makes duplex RNA unstable, thereby preventing IFN induction. To better understand how ADAR1 works at the cellular level, we generated cell lines that express exclusively either the IFN-inducible, cytoplasmic isoform ADAR1p150, the constitutively expressed nuclear isoform ADAR1p110, or no isoform...
November 2018: PLoS Biology
David J Jiang, Christine L Xu, Stephen H Tsang
Recently, there have been revolutions in the development of both gene medicine therapy and genome surgical treatments for inherited disorders. Much of this progress has been centered on hereditary retinal dystrophies, because the eye is an immune-privileged and anatomically ideal target. Gene therapy treatments, already demonstrated to be safe and efficacious in numerous clinical trials, are benefitting from the development of new viral vectors, such as dual and triple adeno-associated virus (AAV) vectors. CRISPR/Cas9, which revolutionized the field of gene editing, is being adapted into more precise "high fidelity" and catalytically dead variants...
November 26, 2018: Genes
Vivian S Vigliotti, Isabel Martinez
Children under the age of five years old face significant mortality risks around the world. Public health innovations, particularly gene-editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) could help to reduce the risk of death in children under the age of five years old. For example, CRISPR-based strategies could reduce infectious disease morbidity by gene editing mosquitoes to prevent transmission of malaria. CRISPR gene editing technology could also help to screen for influenza virus and prevent it from replicating; influenza is a particularly difficult to treat and severe virus causing many deaths in children...
October 2, 2018: Seminars in Perinatology
Dong Hyun Jo, Taeyoung Koo, Chang Sik Cho, Jin Hyoung Kim, Jin-Soo Kim, Jeong Hun Kim
Genome editing with CRISPR systems provides an unprecedented opportunity to modulate cellular responses in pathological conditions by inactivating undruggable targets, such as transcription factors. Previously, we demonstrated that the smallest Cas9 ortholog characterized to date, from Campylobacter jejuni (CjCas9) targeted to Hif1a and delivered in an adeno-associated virus (AAV) vector, effectively suppressed pathological choroidal neovascularization in the mouse retina. Before implementation of CjCas9 as an in vivo therapeutic modality, it is essential to investigate the long-term effects of target gene disruption via AAV-mediated delivery of CjCas9 in vivo...
October 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Naoaki Mizuno, Eiji Mizutani, Hideyuki Sato, Mariko Kasai, Aki Ogawa, Fabian Suchy, Tomoyuki Yamaguchi, Hiromitsu Nakauchi
Intra-embryo genome editing by CRISPR/Cas9 enables easy generation of gene-modified animals by non-homologous end joining (NHEJ)-mediated frameshift mutations or homology-directed repair (HDR)-mediated point mutations. However, large modifications, such as gene replacement or gene fusions, are still difficult to introduce in embryos without costly micromanipulators. Moreover, micromanipulation techniques for intra-embryo genome editing have been established in only a small set of animals. To overcome these issues, we developed a method of large-fragment DNA knockin without micromanipulation...
November 2, 2018: iScience
Shin-Lin Tu, Jeannette P Staheli, Colum McClay, Kathleen McLeod, Timothy M Rose, Chris Upton
Base-By-Base is a comprehensive tool for the creation and editing of multiple sequence alignments that is coded in Java and runs on multiple platforms. It can be used with gene and protein sequences as well as with large viral genomes, which themselves can contain gene annotations. This report describes new features added to Base-By-Base over the last 7 years. The two most significant additions are: (1) The recoding and inclusion of "consensus-degenerate hybrid oligonucleotide primers" (CODEHOP), a popular tool for the design of degenerate primers from a multiple sequence alignment of proteins; and (2) the ability to perform fuzzy searches within the columns of sequence data in multiple sequence alignments to determine the distribution of sequence variants among the sequences...
November 15, 2018: Viruses
Richard Whitley, Joel Baines
Infection with herpes simplex virus (HSV) types 1 and 2 is ubiquitous in the human population. Most commonly, virus replication is limited to the epithelia and establishes latency in enervating sensory neurons, reactivating periodically to produce localized recurrent lesions. However, these viruses can also cause severe disease such as recurrent keratitis leading potentially to blindness, as well as encephalitis, and systemic disease in neonates and immunocompromised patients. Although antiviral therapy has allowed continual and substantial improvement in the management of both primary and recurrent infections, resistance to currently available drugs and long-term toxicity pose a current and future threat that should be addressed through the development of new antiviral compounds directed against new targets...
2018: F1000Research
Qin Liang, Claudio Monetti, Maria V Shutova, Eric J Neely, Sabiha Hacibekiroglu, Huijuan Yang, Christopher Kim, Puzheng Zhang, Chengjin Li, Kristina Nagy, Maria Mileikovsky, Istvan Gyongy, Hoon-Ki Sung, Andras Nagy
Human pluripotent cell lines hold enormous promise for the development of cell-based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes1 , but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system...
November 14, 2018: Nature
Jeffrey R Strich, Daniel S Chertow
Infectious diseases remain a global threat contributing to excess morbidity and mortality annually with persistent potential for destabilizing pandemics. Improved understanding of the pathogenesis of bacteria, viruses, fungi, and parasites, along with rapid diagnosis and treatment of human infections are essential to improving infectious diseases outcomes worldwide. Genomic loci in bacteria and archea, termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) proteins, function as an adaptive immune system for prokaryotes protecting against foreign invaders...
November 14, 2018: Journal of Clinical Microbiology
Marta Martinez-Lage, Pilar Puig-Serra, Pablo Menendez, Raul Torres-Ruiz, Sandra Rodriguez-Perales
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment...
November 12, 2018: Biomedicines
Oliver Manners, Belinda Baquero-Perez, Adrian Whitehouse
N6 -methyladenosine (m6 A) is a highly pervasive and dynamic modification found on eukaryotic RNA. Despite the failure to comprehend the true regulatory potential of this epitranscriptomic mark for decades, our knowledge of m6 A has rapidly expanded in recent years. The modification has now been functionally linked to all stages of mRNA metabolism and demonstrated to regulate a variety of biological processes. Furthermore, m6 A has been identified on transcripts encoded by a wide range of viruses. Studies to investigate m6 A function in viral-host interactions have highlighted distinct roles indicating widespread regulatory control over viral life cycles...
November 7, 2018: Biochimica et biophysica acta. Gene regulatory mechanisms
Xing Liu, Bin He
Oncolytic herpes simplex virus 1 (HSV-1), devoid of the γ1 34.5 gene, exerts antitumor activities. However, the oncolytic effect differs, ranging from pronounced to little responses. Although viral and host factors are involved, much remains to be deciphered. Here we report that engineered HSV-1 (ΔN146), bearing amino acids 147-263 of γ1 34.5, replicates competently in and lyses malignant cells refractory to the γ1 34.5 null mutant. Upon infection, ΔN146 precludes phosphorylation of translation initiation factor eIF2α, ensuring viral protein synthesis...
November 7, 2018: Journal of Virology
Anna Koslová, Dana Kučerová, Markéta Reinišová, Josef Geryk, Pavel Trefil, Jiří Hejnar
Avian leukosis viruses (ALVs), which are pathogens of concern in domestic poultry, utilize specific receptor proteins for cell entry that are both necessary and sufficient for host susceptibility to a given ALV subgroup. This unequivocal relationship offers receptors as suitable targets of selection and biotechnological manipulation with the aim of obtaining virus-resistant poultry. This approach is further supported by the existence of natural knock-outs of receptor genes that segregate in inbred lines of chickens...
November 2, 2018: Viruses
Lena Al-Harti, Jeymohan Joseph, Avindra Nath
This a summary of a National Institute of Mental Health (NIMH) sponsored symposium that was focused on the role of astrocytes as a reservoir of the human immunodeficiency virus in the brain. The talks were grouped into four themes. The first theme reviewed the evidence for HIV infection of astrocytes and discussed the challenges in the use of traditional methods of immunostaining and in situ hybridization for detection of infected astrocytes. The second theme focused on mechanisms of HIV entry into astrocytes and discussed CD4 independent mechanisms, such as receptor-mediated endocytosis and transmission of HIV by cell-to-cell contact with infected lymphocytes...
November 5, 2018: Journal of Neurovirology
Lee A Campbell, Lamarque M Coke, Christopher T Richie, Lowella V Fortuno, Aaron Y Park, Brandon K Harvey
Investigators have utilized the CRISPR/Cas9 gene-editing system to specifically target well-conserved regions of HIV, leading to decreased infectivity and pathogenesis in vitro and ex vivo. We utilized a specialized extracellular vesicle termed a "gesicle" to efficiently, yet transiently, deliver Cas9 in a ribonucleoprotein form targeting the HIV long terminal repeat (LTR). Gesicles are produced through expression of vesicular stomatitis virus glycoprotein and package protein as their cargo, thus bypassing the need for transgene delivery, and allowing finer control of Cas9 expression...
October 11, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Tongtong Yu, David T W Tzeng, Ran Li, Jianye Chen, Silin Zhong, Daqi Fu, Benzhong Zhu, Yunbo Luo, Hongliang Zhu
Background and Aims: In recent years, increasing numbers of long non-coding RNAs (lncRNAs) have been identified in humans, animals and plants, and several of them have been shown to play important roles in diverse biological processes. However, little work has been performed on the regulation mechanism of lncRNA biogenesis and expression, especially in plants. Compared with studies of tomato MADS-box transcription factor RIPENING INHIBITOR (RIN) target coding genes, there are few reports on its relationship to non-coding RNAs...
October 29, 2018: Annals of Botany
Michael P Phelps, Heechang Yang, Shivani Patel, Masmudur M Rahman, Grant McFadden, Eleanor Chen
Aberrant activation of the receptor tyrosine kinase-mediated RAS signaling cascade is the primary driver of embryonal rhabdomyosarcoma (ERMS), a pediatric cancer characterized by a block in myogenic differentiation. To investigate the cellular function of activated RAS signaling in regulating the growth and differentiation of ERMS cells, we genetically ablated activated RAS oncogenes with high-efficiency genome-editing technology. Knockout of NRAS in CRISPR-inducible ERMS xenograft models resulted in near-complete tumor regression through a combination of cell death and myogenic differentiation...
December 21, 2018: Molecular Therapy Oncolytics
Saedeh Khadempar, Shokoufeh Familghadakchi, Roozbeh Akbari Motlagh, Najmeh Farahani, Maryam Dashtiahangar, Hamzeh Rezaei, Seyed Mohammad Gheibi Hayat
The targeted genome modification using RNA-guided nucleases is associated with several advantages such as a rapid, easy, and efficient method that not only provides the manipulation and alteration of genes and functional studies for researchers, but also increases their awareness of the molecular basis of the disease and development of new and targeted therapeutic approaches. Different techniques have been emerged so far as the molecular scissors mediating targeted genome editing including zinc finger nuclease, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)...
October 26, 2018: Journal of Cellular Physiology
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