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Sleeping beauty transposon

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https://www.readbyqxmd.com/read/28920716/transposons-moving-forward-from-preclinical-studies-to-clinical-trials
#1
Jaitip Tipanee, Thierry VandenDriessche, Marinee K Chuah
Transposons have emerged as promising vectors for gene therapy that can potentially overcome some of the limitations of commonly used viral vectors. Transposons stably integrate into the target cell genome, enabling persistent expression of therapeutic genes. Transposons have evolved from being used as basic tools in biomedical research to bona fide therapeutics. Currently, the most promising transposons for gene therapy applications are derived from Sleeping Beauty (SB) or piggyBac (PB). Stable transposition requires co-delivery of the transposon DNA with the corresponding transposase gene, mRNA, or protein...
August 22, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28888423/transposons-as-tools-for-functional-genomics-in-vertebrate-models
#2
REVIEW
Koichi Kawakami, David A Largaespada, Zoltán Ivics
Genetic tools and mutagenesis strategies based on transposable elements are currently under development with a vision to link primary DNA sequence information to gene functions in vertebrate models. By virtue of their inherent capacity to insert into DNA, transposons can be developed into powerful tools for chromosomal manipulations. Transposon-based forward mutagenesis screens have numerous advantages including high throughput, easy identification of mutated alleles, and providing insight into genetic networks and pathways based on phenotypes...
September 6, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28870121/wide-awake-and-ready-to-move-20-years-of-non-viral-therapeutic-genome-engineering-with-the-sleeping-beauty-transposon-system
#3
Russ Hodge, Suneel Narayanavari, Zsuzsanna Izsvák, Zoltán Ivics
Gene therapies will only become a widespread tool in the clinical treatment of human diseases with the advent of gene transfer vectors that integrate genetic information stably, safely, effectively, and economically. Two decades after the discovery of the Sleeping Beauty (SB) transposon, it has been transformed into a vector system that is fulfilling these requirements. SB may well overcome some of the limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are being used in the majority of ongoing clinical trials...
September 4, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28855524/rnai-combining-sleeping-beauty-transposon-system-inhibits-ex-vivo-expression-of-foot-and-mouth-disease-virus-vp1-in-transgenic-sheep-cells
#4
Shoulong Deng, Guangdong Li, Kun Yu, Xiuzhi Tian, Feng Wang, Wenting Li, Wuqi Jiang, Pengyun Ji, Hongbing Han, Juncai Fu, Xiaosheng Zhang, Jinlong Zhang, Yixun Liu, Zhengxing Lian, Guoshi Liu
Foot and mouth disease, which is induced by the foot and mouth disease virus (FMDV), takes its toll on the cloven-hoofed domestic animals. The VP1 gene in FMDV genome encodes the viral capsid, a vital element for FMDV replication. Sleeping Beauty (SB) is an active DNA-transposon system responsible for genetic transformation and insertional mutagenesis in vertebrates. In this study, a conserved VP1-shRNA which specifically targets the ovine FMDV-VP1 gene was constructed and combined with SB transposase and transposon...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28852016/the-histidine-rich-peptide-lah4-l1-strongly-promotes-pamam-mediated-transfection-at-low-nitrogen-to-phosphorus-ratios-in-the-presence-of-serum
#5
Nan Liu, Burkhard Bechinger, Regine Süss
Non-viral vectors are widely used and investigated for the delivery of genetic material into cells. However, gene delivery barriers like lysosomal degradation, serum inhibition and transient gene expression so far still limit their clinical applications. Aiming to overcome these limitations, a pH-sensitive hybrid gene vector (PSL complex) was designed by self-assembly of poly(amidoamine) (PAMAM) dendrimers, the histidine-rich peptide LAH4-L1 and the sleeping beauty transposon system (SB transposon system, a plasmid system capable of efficient and precise genomic insertion)...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807594/thyroid-hormone-receptor-beta-agonist-gc-1-inhibits-met-%C3%AE-catenin-driven-hepatocellular-cancer
#6
Elisabetta Puliga, Qian Min, Junyan Tao, Rong Zhang, Tirthadipa Pradhan-Sundd, Minakshi Poddar, Sucha Singh, Amedeo Columbano, Jinming Yu, Satdarshan P Monga
The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promoting regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation particularly due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it will be critical to address any effect of GC-1 on HCC growth and development, before its use can be advocated to stimulate regeneration in chronic liver diseases. In the current study, we first examine the effect of GC-1 on β-catenin-TCF4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1...
August 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28724549/identification-of-new-tumor-suppressor-genes-in-triple-negative-breast-cancer
#7
Roberto Rangel, Liliana Guzman-Rojas, Takahiro Kodama, Michiko Kodama, Justin Y Newberg, Neal G Copeland, Nancy A Jenkins
Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines...
July 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/28650484/insertional-mutagenesis-identifies-drivers-of-a-novel-oncogenic-pathway-in-invasive-lobular-breast-carcinoma
#8
Sjors M Kas, Julian R de Ruiter, Koen Schipper, Stefano Annunziato, Eva Schut, Sjoerd Klarenbeek, Anne Paulien Drenth, Eline van der Burg, Christiaan Klijn, Jelle J Ten Hoeve, David J Adams, Marco J Koudijs, Jelle Wesseling, Micha Nethe, Lodewyk F A Wessels, Jos Jonkers
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1...
August 2017: Nature Genetics
https://www.readbyqxmd.com/read/28584132/transposon-mutagenesis-identifies-chromatin-modifiers-cooperating-with-ras-in-thyroid-tumorigenesis-and-detects-atxn7-as-a-cancer-gene
#9
Cristina Montero-Conde, Luis J Leandro-Garcia, Xu Chen, Gisele Oler, Sergio Ruiz-Llorente, Mabel Ryder, Iñigo Landa, Francisco Sanchez-Vega, Konnor La, Ronald A Ghossein, Dean F Bajorin, Jeffrey A Knauf, Jesse D Riordan, Adam J Dupuy, James A Fagin
Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with Hras(G12V) in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-Hras(G12V) mice...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28530135/prolonged-expression-of-secreted-enzymes-in-dogs-after-liver-directed-delivery-of-sleeping-beauty-transposons-implications-for-non-viral-gene-therapy-of-systemic-disease
#10
Elena L Aronovich, Kendra A Hyland, Bryan C Hall, Jason B Bell, Erik R Olson, Myra Urness Rusten, David W Hunter, N Matthew Ellinwood, R Scott McIvor, Perry B Hackett
The non-viral, integrating Sleeping Beauty (SB) transposon system is efficient in treating systemic monogenic disease in mice, including hemophilia A and B caused by deficiency of blood clotting factors and mucopolysaccharidosis types I and VII caused by α-L-iduronidase (IDUA) and β-glucuronidase (GUSB) deficiency, respectively. Modified approaches of the hydrodynamics-based procedure to deliver transposons to the liver in dogs were recently reported. Using the transgenic canine reporter secreted alkaline phosphatase (cSEAP), transgenic protein in the plasma was demonstrated for up to 6 weeks post infusion...
July 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28521544/correction-to-hudecek-izsv%C3%A3-k-johnen-renner-thumann-and-ivics-going-non-viral-the-sleeping-beauty-transposon-system-breaks-on-through-to-the-clinical-side
#11
(no author information available yet)
No abstract text is available yet for this article.
May 18, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28513320/crispr-cas9-based-pten-knock-out-and-sleeping-beauty-transposon-mediated-nras-knock-in-induces-hepatocellular-carcinoma-and-hepatic-lipid-accumulation-in-mice
#12
Mingming Gao, Dexi Liu
Both Pten and Nras are downstream mediators of receptor tyrosine kinase activation that plays important roles in controlling cell survival and proliferation. Here, we investigated whether and how Pten loss cross-talks with Nras activation in driving liver cancer development in mice. Somatic disruption of hepatic Pten and overexpression of Nras were achieved in out-bred immunocompetent CD-1 mice through a hydrodynamic delivery of plasmids carrying Sleeping Beauty transposon-based integration of Nras and the CRISPR/Cas9-mediated Pten knock-out system...
May 17, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28447859/transgene-expression-in-dogs-after-liver-directed-hydrodynamic-delivery-of-sleeping-beauty-transposons-using-balloon-catheters
#13
Kendra A Hyland, Elena L Aronovich, Erik R Olson, Jason B Bell, Myra Urness Rusten, Roland Gunther, David W Hunter, Perry B Hackett, R Scott McIvor
The Sleeping Beauty transposon system has been extensively tested for integration of reporter and therapeutic genes in vitro and in vivo in mice. Dogs were used as a large animal model for human therapy and minimally invasive infusion of DNA solutions. DNA solutions were delivered into the entire liver or the left side of the liver using balloon catheters for temporary occlusion of venous outflow. A peak intravascular pressure between 80 and 140 mmHg supported sufficient DNA delivery in dog liver for detection of secretable reporter proteins...
July 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28445233/preclinical-models-for-translational-sarcoma-research
#14
Rainer Hamacher, Sebastian Bauer
PURPOSE OF REVIEW: Sarcoma is a basket term for mesenchymal tumors for which more than 75 genetically and histologically distinct subtypes are recognized. Therapeutic progress has largely been achieved with classical chemotherapeutic drugs that were tested in empirical clinical trials. However, outcome in metastatic patients remains poor and with few exceptions numerous trials have failed or only provided limited improvement in recent years. RECENT FINDINGS: Given the genomic heterogeneity, preclinical model systems will be indispensable to identify new molecular targets and to prioritize drugs and drug combinations...
July 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28402189/going-non-viral-the-sleeping-beauty-transposon-system-breaks-on-through-to-the-clinical-side
#15
REVIEW
Michael Hudecek, Zsuzsanna Izsvák, Sandra Johnen, Matthias Renner, Gabriele Thumann, Zoltán Ivics
Molecular medicine has entered a high-tech age that provides curative treatments of complex genetic diseases through genetically engineered cellular medicinal products. Their clinical implementation requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective and economically viable manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are prevalent in ongoing pre-clinical and translational research...
August 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28345263/nmr-solution-structure-of-the-red-subdomain-of-the-sleeping-beauty-transposase
#16
Tatiana A Konnova, Christopher M Singer, Irina V Nesmelova
DNA transposons can be employed for stable gene transfer in vertebrates. The Sleeping Beauty (SB) DNA transposon has been recently adapted for human application and is being evaluated in clinical trials, however its molecular mechanism is not clear. SB transposition is catalyzed by the transposase enzyme, which is a multi-domain protein containing the catalytic and the DNA-binding domains. The DNA-binding domain of the SB transposase contains two structurally independent subdomains, PAI and RED. Recently, the structures of the catalytic domain and the PAI subdomain have been determined, however no structural information on the RED subdomain and its interactions with DNA has been available...
June 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28325297/engineering-of-pedf-expressing-primary-pigment-epithelial-cells-by-the-sb-transposon-system-delivered-by-pfar4-plasmids
#17
Gabriele Thumann, Nina Harmening, Cécile Prat-Souteyrand, Corinne Marie, Marie Pastor, Attila Sebe, Csaba Miskey, Laurence D Hurst, Sabine Diarra, Martina Kropp, Peter Walter, Daniel Scherman, Zoltán Ivics, Zsuzsanna Izsvák, Sandra Johnen
Neovascular age-related macular degeneration (nvAMD) is characterized by choroidal blood vessels growing into the subretinal space, leading to retinal pigment epithelial (RPE) cell degeneration and vision loss. Vessel growth results from an imbalance of pro-angiogenic (e.g., vascular endothelial growth factor [VEGF]) and anti-angiogenic factors (e.g., pigment epithelium-derived factor [PEDF]). Current treatment using intravitreal injections of anti-VEGF antibodies improves vision in about 30% of patients but may be accompanied by side effects and non-compliance...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28319090/a-single-copy-sleeping-beauty-transposon-mutagenesis-screen-identifies-new-pten-cooperating-tumor-suppressor-genes
#18
Jorge de la Rosa, Julia Weber, Mathias Josef Friedrich, Yilong Li, Lena Rad, Hannes Ponstingl, Qi Liang, Sandra Bernaldo de Quirós, Imran Noorani, Emmanouil Metzakopian, Alexander Strong, Meng Amy Li, Aurora Astudillo, María Teresa Fernández-García, María Soledad Fernández-García, Gary J Hoffman, Rocío Fuente, George S Vassiliou, Roland Rad, Carlos López-Otín, Allan Bradley, Juan Cadiñanos
The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer...
May 2017: Nature Genetics
https://www.readbyqxmd.com/read/28301581/assessing-tn5-and-sleeping-beauty-for-transpositional-transgenesis-by-cytoplasmic-injection-into-bovine-and-ovine-zygotes
#19
R J Bevacqua, R Fernandez-Martin, N G Canel, A Gibbons, D Texeira, F Lange, G Vans Landschoot, V Savy, O Briski, M I Hiriart, E Grueso, Z Ivics, O Taboga, W A Kues, S Ferraris, D F Salamone
Transgenic domestic animals represent an alternative to bioreactors for large-scale production of biopharmaceuticals and could also provide more accurate biomedical models than rodents. However, their generation remains inefficient. Recently, DNA transposons allowed improved transgenesis efficiencies in mice and pigs. In this work, Tn5 and Sleeping Beauty (SB) transposon systems were evaluated for transgenesis by simple cytoplasmic injection in livestock zygotes. In the case of Tn5, the transposome complex of transposon nucleic acid and Tn5 protein was injected...
2017: PloS One
https://www.readbyqxmd.com/read/28284560/computational-discovery-of-niclosamide-ethanolamine-a-repurposed-drug-candidate-that-reduces-growth-of-hepatocellular-carcinoma-cells-in%C3%A2-vitro-and-in-mice-by-inhibiting-cell-division-cycle-37-signaling
#20
Bin Chen, Wei Wei, Li Ma, Bin Yang, Ryan M Gill, Mei-Sze Chua, Atul J Butte, Samuel So
BACKGROUND & AIMS: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). METHODS: We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic...
June 2017: Gastroenterology
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