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Virus AND gene edit

Tiffany A Peterson, Andrew G MacLean
Macrophages, one of the most abundant populations of leukocytes in the body, function as the first line of defense against pathogen invaders. Human Immunodeficiency virus 1 (HIV-1) remains to date one of the most extensively studied viral infections. Naturally occurring lentiviruses in domestic and primate species serve as valuable models to investigate lentiviral pathogenesis and novel therapeutics. Better understanding of the role macrophages play in HIV pathogenesis will aid in the advancement towards a cure...
October 13, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Tong Liu, Wen-Qiang Yang, Yu-Gu Xie, Pei-Wen Liu, Li-Hua Xie, Feng Lin, Chen-Ying Li, Jin-Bao Gu, Kun Wu, Gui-Yun Yan, Xiao-Guang Chen
Aedes (Stegomyia) albopictus, also known as the Asian tiger mosquito, is a mosquito that originated in Asia. In recent years, it has become increasingly rampant throughout the world. This mosquito can transmit several arboviruses, including dengue, Zika and chikungunya viruses, and is considered a public health threat. Despite the urgent need of genome-engineering to analyse specific gene functions, progress in genetical manipulation of Ae. albopictus has been slow due a lack of efficient methods and genetic markers...
October 11, 2018: Insect Science
Lukas Villiger, Hiu Man Grisch-Chan, Helen Lindsay, Femke Ringnalda, Chiara B Pogliano, Gabriella Allegri, Ralph Fingerhut, Johannes Häberle, Joao Matos, Mark D Robinson, Beat Thöny, Gerald Schwank
CRISPR-Cas-based genome editing holds great promise for targeting genetic disorders, including inborn errors of hepatocyte metabolism. Precise correction of disease-causing mutations in adult tissues in vivo, however, is challenging. It requires repair of Cas9-induced double-stranded DNA (dsDNA) breaks by homology-directed mechanisms, which are highly inefficient in nondividing cells. Here we corrected the disease phenotype of adult phenylalanine hydroxylase (Pah)enu2 mice, a model for the human autosomal recessive liver disease phenylketonuria (PKU)1 , using recently developed CRISPR-Cas-associated base editors2-4 ...
October 2018: Nature Medicine
Emily A Rex, Dahee Seo, Don B Gammon
RNA interference- and genome editing-based screening platforms have been widely used to identify host cell factors that restrict virus replication. However, these screens are typically conducted in cells that are naturally permissive to the viral pathogen under study. Therefore, the robust replication of viruses in control conditions may limit the dynamic range of these screens. Furthermore, these screens may be unable to easily identify cellular defense pathways that restrict virus replication if the virus is well-adapted to the host and capable of countering antiviral defenses...
September 13, 2018: Journal of Visualized Experiments: JoVE
Pei-Shi Yen, Anthony James, Jian-Chiuan Li, Chun-Hong Chen, Anna-Bella Failloux
Mosquito-borne arboviruses are responsible for recent dengue, chikungunya, and Zika pandemics. The yellow-fever mosquito, Aedes aegypti , plays an important role in the transmission of all three viruses. We developed a miRNA-based approach that results in a dual resistance phenotype in mosquitoes to dengue serotype 3 (DENV-3) and chikungunya (CHIKV) viruses. The target viruses are from two distinct arboviral families and the antiviral mechanism is designed to function through the endogenous miRNA pathway in infected mosquitoes...
2018: Communications biology
Yanfei Mao, Xiaoxuan Yang, Yiting Zhou, Zhengjing Zhang, Jose Ramon Botella, Jian-Kang Zhu
BACKGROUND: The CRISPR/Cas9 system, composed of a single-guide RNA for target recognition and a Cas9 protein for DNA cleavage, has the potential to revolutionize agriculture as well as medicine. Even though extensive work has been done to improve the gene editing activity of CRISPR/Cas9, little is known about the regulation of this bacterial system in eukaryotic host cells, especially at the post-transcriptional level. RESULTS: Here, we evaluate the expression levels of the two CRISPR/Cas9 components and the gene editing efficiency in a set of Arabidopsis mutants involved in RNA silencing...
September 28, 2018: Genome Biology
Raed Ibraheim, Chun-Qing Song, Aamir Mir, Nadia Amrani, Wen Xue, Erik J Sontheimer
BACKGROUND: Clustered, regularly interspaced, short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) have recently opened a new avenue for gene therapy. Cas9 nuclease guided by a single-guide RNA (sgRNA) has been extensively used for genome editing. Currently, three Cas9 orthologs have been adapted for in vivo genome engineering applications: Streptococcus pyogenes Cas9 (SpyCas9), Staphylococcus aureus Cas9 (SauCas9), and Campylobacter jejuni (CjeCas9). However, additional in vivo editing platforms are needed, in part to enable a greater range of sequences to be accessed via viral vectors, especially those in which Cas9 and sgRNA are combined into a single vector genome...
September 19, 2018: Genome Biology
J Schlegel, J Hoffmann, D Röll, B Müller, S Günther, W Zhang, A Janise, C Vössing, B Fühler, J Neidhardt, H Khanna, B Lorenz, K Stieger
Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI...
August 24, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Uma Sundram
Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma...
September 7, 2018: Advances in Anatomic Pathology
Scott J Dooley, Devin S McDougald, Krishna J Fisher, Jeanette L Bennicelli, Lloyd G Mitchell, Jean Bennett
Ocular gene therapy with recombinant adeno-associated virus (AAV) has shown vector-mediated gene augmentation to be safe and efficacious in the retina in one set of diseases (retinitis pigmentosa and Leber congenital amaurosis (LCA) caused by RPE65 deficiency), with excellent safety profiles to date and potential for efficacy in several additional diseases. However, size constraints imposed by the packaging capacity of the AAV genome restrict application to diseases with coding sequence lengths that are less than 5,000 nt...
September 7, 2018: Molecular Therapy. Nucleic Acids
Ning Yuan, Krishan Mohan Rai, Vimal Kumar Balasubramanian, Santosh Kumar Upadhyay, Hong Luo, Venugopal Mendu
BACKGROUND: As one of the largest subfamilies of the receptor-like protein kinases (RLKs) in plants, Leucine Rich Repeats-RLKs (LRR-RLKs) are involved in many critical biological processes including growth, development and stress responses in addition to various physiological roles. Arabidopsis contains 234 LRR-RLKs, and four members of Stress Induced Factor (SIF) subfamily (AtSIF1-AtSIF4) which are involved in abiotic and biotic stress responses. Herein, we aimed at identification and functional characterization of SIF subfamily in cultivated tetraploid cotton Gossypium hirsutum...
September 6, 2018: BMC Plant Biology
Yin-Hsiu Chien, Ni-Chung Lee, Sheng-Hong Tseng, Chun-Hwei Tai, Shin-Ichi Muramatsu, Barry J Byrne, Wuh-Liang Hwu
BACKGROUND: Aromatic l-amino acid decarboxylase (AADC) deficiency is an inherited disease that causes depletion of neurotransmitters and severe motor dysfunction in infants and children. We previously reported compassionate use of an adeno-associated virus (AAV) vector containing the human AADC gene (AAV2-hAADC) in four children with AADC deficiency (aged 4-6 years). In this study, we aimed to establish the efficacy and safety of this treatment. METHODS: We did an open-label, phase 1/2 trial at the National Taiwan University Hospital (Taipei, Taiwan)...
December 2017: Lancet Child & Adolescent Health
Leonela Amoasii, John C W Hildyard, Hui Li, Efrain Sanchez-Ortiz, Alex Mireault, Daniel Caballero, Rachel Harron, Thaleia-Rengina Stathopoulou, Claire Massey, John M Shelton, Rhonda Bassel-Duby, Richard J Piercy, Eric N Olson
Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational "hotspot" in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery ( n = 2) or 8 weeks after systemic delivery ( n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type...
October 5, 2018: Science
Zhanqi Dong, Liang Huang, Feifan Dong, Zhigang Hu, Qi Qin, Jiangqiong Long, Mingya Cao, Peng Chen, Cheng Lu, Min-Hui Pan
The CRISPR/Cas9 system is a powerful genetic engineering technique that has been widely used in gene therapy, as well as in the development of novel antimicrobials and transgenic insects. However, several challenges, including the lack of effective host target genes and the off-target effects, limit the application of CRISPR/Cas9 in insects. To mitigate these difficulties, we established a highly efficient virus-inducible CRISPR/Cas9 system in transgenic silkworms. This system includes the baculovirus-inducible promoter 39K, which directs transcription of the gene encoding, the Cas9 protein, and the U6 promoter which targets the sgATAD3A site of the ATPase family AAA domain-containing protein 3 (ATAD3A) gene...
August 28, 2018: Applied Microbiology and Biotechnology
Xi Liu, Yulan Cheng, John M Abraham, Zhixiong Wang, Zhe Wang, Xiquan Ke, Rong Yan, Eun Ji Shin, Saowanee Ngamruengphong, Mouen A Khashab, Guanjun Zhang, George McNamara, Andrew J Ewald, DeChen Lin, Zhengwen Liu, Stephen J Meltzer
Primary organoid cultures generated from patient biopsies comprise a novel improved platform for disease modeling, being genetically stable and closely recapitulating in vivo scenarios. Barrett esophagus (BE) is the major risk factor for esophageal adenocarcinoma. There has been a dearth of long-term in vitro expansion models of BE neoplastic transformation. We generated a long-term virus-free organoid expansion model of BE neoplasia from patient biopsies. Both wild-type and paired APC-knockout (APCKO ) BE organoids genome-edited by CRISPR-Cas9 showed characteristic goblet cell differentiation...
November 1, 2018: Cancer Letters
Li Xu, Yandi Gao, Yeh Siang Lau, Renzhi Han
The clustered, regularly interspaced, short, palindromic repeat (CRISPR) system has greatly facilitated genome engineering in both cultured cells and living organisms from a wide variety of species. The CRISPR technology has also been explored as novel therapeutics for a number of human diseases. Proof-of-concept data are highly encouraging as exemplified by recent studies that demonstrate the feasibility and efficacy of gene editing-based therapeutic approach for Duchenne muscular dystrophy (DMD) using a murine model...
August 2, 2018: Journal of Visualized Experiments: JoVE
Qi-Chao Dong, Hui-Min Chen, Xin Jin
Duchenne muscular dystrophy (DMD) is an X-linked recessive hereditary disease caused by mutations in the DMD gene that encodes dystrophin. It is characterized by progressive muscle weakness and degeneration of skeletal muscle and myocardium due to the absence of dystrophin. The disease often occurs at the age of 2-5 years, and most children may die of heart failure or respiratory insufficiency at the age of around 20 years. At present, supportive therapy is often used in clinical practice to improve symptoms, but this cannot improve the outcome of this disease...
August 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Sara Artusi, Yoshitaka Miyagawa, William F Goins, Justus B Cohen, Joseph C Glorioso
Neurodegenerative diseases (NDs) have a profound impact on human health worldwide and their incidence is predicted to increase as the population ages. ND severely limits the quality of life and leads to early death. Aside from treatments that may reduce symptoms, NDs are almost completely without means of therapeutic intervention. The genetic and biochemical basis of many NDs is beginning to emerge although most have complex etiologies for which common themes remain poorly resolved. Largely relying on progress in vector design, gene therapy is gaining increasing support as a strategy for genetic treatment of diseases...
August 14, 2018: Diseases (Basel)
Melvys Valledor, Richard S Myers, Paul C Schiller
Recombineering has transformed functional genomic analysis. Genome modification by recombineering using the phage lambda Red homologous recombination protein Beta in Escherichia coli has approached 100% efficiency. While highly efficient in E. coli, recombineering using the Red Synaptase/Exonuclease pair (SynExo) in other organisms declines in efficiency roughly correlating with phylogenetic distance from E. coli. SynExo recombinases are common to double-stranded DNA viruses infecting a variety of organisms, including humans...
2018: PloS One
Martina Donadoni, Rahsan Sariyer, Hassen Wollebo, Anna Bellizzi, Ilker Kudret Sariyer
The human neurotropic polyomavirus JC, JC virus (JCV), infects the majority of human population during early childhood and establishes a latent/persistent infection for the rest of the life. JCV is the etiologic agent of the fatal demyelinating disease of the central nervous system, progressive multifocal leukoencephalopathy (PML) that is seen primarily in immunocompromised individuals. In addition to the PML, JCV has also been shown to transform cells in culture systems and cause a variety of tumors in experimental animals...
March 2018: Genes & Cancer
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