7 results on '"Jan Van Der Schueren"'
Search Results
2. Identification and Characterization of Novel CFTR Potentiators
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Kathleen Sonck, Mia Jans, Katja Conrath, Ann Vandevelde, Andrew M. Swensen, Pieter F. W. Stouten, Oscar Mammoliti, Maarten Gees, Katleen Verdonck, Steven Emiel Van Der Plas, Anne Sophie Wesse, Jan Van Der Schueren, Luc Nelles, Martin James Inglis Andrews, Sara Musch, and Tzyh Chang Hwang
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Class iii ,Pharmacology ,Cystic fibrosis ,Unmet needs ,03 medical and health sciences ,medicine ,F508del cftr ,Pharmacology (medical) ,In patient ,CFTR ,bronchial epithelial cells ,Original Research ,biology ,Chemistry ,lcsh:RM1-950 ,CF ,potentiator ,Potentiator ,respiratory system ,medicine.disease ,electrophysiology ,Cystic fibrosis transmembrane conductance regulator ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,biology.protein - Abstract
There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients.
- Published
- 2018
3. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent
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Steven E, Van der Plas, Hans, Kelgtermans, Tom, De Munck, Sébastien L X, Martina, Sébastien, Dropsit, Evelyne, Quinton, Ann, De Blieck, Caroline, Joannesse, Linda, Tomaskovic, Mia, Jans, Thierry, Christophe, Ellen, van der Aar, Monica, Borgonovi, Luc, Nelles, Maarten, Gees, Pieter, Stouten, Jan, Van Der Schueren, Oscar, Mammoliti, Katja, Conrath, and Martin, Andrews
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Structure-Activity Relationship ,Cystic Fibrosis ,Drug Discovery ,Mutation ,Animals ,Cystic Fibrosis Transmembrane Conductance Regulator ,Humans ,Pyrazoles ,Mutant Proteins ,Quinolones ,Aminophenols ,Chloride Channel Agonists ,Rats - Abstract
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.
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- 2017
4. Adenoviral Vectors Expressing siRNAs for Discovery and Validation of Gene Function
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Mark Jacques Yvonne Lambrecht, Emir Mesic, Remko Johannes Clasen, Rudi Tissingh, Kim Thys, Peter Herwig Maria Tomme, Heidi Pavliska, Marcel Hoffmann, Libin Ma, Gert-Jan Arts, Kristina Dokic, Jan van der Schueren, Helmuth van Es, Sofie Herman, Frits Michiels, Richele Dooijes, Ellen Langemeijer, and Reginald Christophe Xavier Brys
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Adult ,Keratinocytes ,Umbilical Veins ,Small interfering RNA ,Genetic Vectors ,Computational biology ,Biology ,Transfection ,Adenoviridae ,Cell Line ,Arthritis, Rheumatoid ,Structure-Activity Relationship ,Transduction (genetics) ,Plasmid ,RNA interference ,Gene expression ,Methods ,Genetics ,Humans ,RNA, Small Interfering ,Gene ,Genetics (clinical) ,Regulation of gene expression ,Genome, Human ,Synovial Membrane ,Fibroblasts ,Epidermal Cells ,Gene Expression Regulation ,Genes ,DNA, Viral ,Nucleic Acid Conformation ,Endothelium, Vascular - Abstract
RNA interference is a powerful tool for studying gene function and for drug target discovery in diverse organisms and cell types. In mammalian systems, small interfering RNAs (siRNAs), or DNA plasmids expressing these siRNAs, have been used to down-modulate gene expression. However, inefficient transfection protocols, in particular, for primary cell types, have hampered the use of these tools in disease-relevant cellular assays. To be able to use this technology for genome-wide function screening, a more robust transduction protocol, resulting in a longer duration of the knock-down effect, is required. Here, we describe the validation of adenoviral vectors that express hairpin RNAs that are further processed to siRNAs. Infection of cell lines, or primary human cells, with these viruses leads to an efficient, sequence-specific, and prolonged reduction of the corresponding target mRNA, resulting in a reduction of the encoded protein level in the cell. For knock-down of one of the targets, GαS, we have measured inhibition of ligand-dependant, G-protein-coupled signaling. It is expected that this technology will prove to be of great value in target validation and target discovery efforts.
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- 2003
5. Arrayed adenoviral expression libraries for functional screening
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Frits, Michiels, Helmuth, van Es, Luc, van Rompaey, Pascal, Merchiers, Bart, Francken, Karen, Pittois, Jan, van der Schueren, Reginald, Brys, Johan, Vandersmissen, Filip, Beirinckx, Sofie, Herman, Kristina, Dokic, Hugo, Klaassen, Evi, Narinx, Annick, Hagers, Wendy, Laenen, Ivo, Piest, Heidi, Pavliska, Yvonne, Rombout, Ellen, Langemeijer, Libin, Ma, Christel, Schipper, Marc De, Raeymaeker, Stephane, Schweicher, Mia, Jans, Kris, van Beeck, Ing-Ren, Tsang, Onno, van de Stolpe, Peter, Tomme, Gert-Jan, Arts, and Joost, Donker
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Gene Expression Regulation, Viral ,Placenta ,Biomedical Engineering ,Neovascularization, Physiologic ,Bioengineering ,Biology ,Kidney ,Applied Microbiology and Biotechnology ,Genome ,Epithelium ,Adenoviridae ,Cell Line ,Viral vector ,Transduction (genetics) ,Dogs ,Pregnancy ,Animals ,Humans ,Genomic library ,Gene ,Gene Library ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Genetics ,Osteoblasts ,Genome, Human ,Sequence Analysis, DNA ,Phenotype ,Feasibility Studies ,Molecular Medicine ,Female ,Human genome ,HeLa Cells ,Biotechnology - Abstract
With the publication of the sequence of the human genome, we are challenged to identify the functions of an estimated 70,000 human genes1,2 and the much larger number of proteins encoded by these genes. Of particular interest is the identification of gene products that play a role in human disease pathways, as these proteins include potential new targets that may lead to improved therapeutic strategies. This requires the direct measurement of gene function on a genomic scale in cell-based, functional assays. We have constructed and validated an individually arrayed, replication-defective adenoviral library harboring human cDNAs, termed PhenoSelect library. The adenoviral vector guarantees efficient transduction of diverse cell types, including primary cells. The arrayed format allows screening of this library in a variety of cellular assays in search for gene(s) that, by overexpression, induce a particular disease-related phenotype. The great majority of phenotypic assays, including morphological assays, can be screened with arrayed libraries. In contrast, pooled-library approaches often rely on phenotype-based isolation or selection of single cells by employing a flow cytometer or screening for cell survival. An arrayed placental PhenoSelect library was screened in cellular assays aimed at identifying regulators of osteogenesis, metastasis, and angiogenesis. This resulted in the identification of known regulators, as well as novel sequences that encode proteins hitherto not known to play a role in these pathways. These results establish the value of the PhenoSelect platform, in combination with cellular screens, for gene function discovery.
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- 2002
6. Disruption of 12 ORFs located on chromosomes IV, VII and XIV of Saccharomyces cerevisiae reveals two essential genes
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Jacqueline Vander Stappen, Guido Volckaert, Elisabeth Vanstreels, Maria-Helena Voet, Jan Van der Schueren, and Johan Robben
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Genetics ,biology ,Base Sequence ,Saccharomyces cerevisiae ,Genes, Fungal ,Molecular Sequence Data ,Chromosome Mapping ,Bioengineering ,Chromosomes, Bacterial ,biology.organism_classification ,Applied Microbiology and Biotechnology ,Biochemistry ,Genome ,Homology (biology) ,Complementation ,Open reading frame ,Open Reading Frames ,Plasmid ,ORFS ,Gene ,Biotechnology - Abstract
We describe the generation of null-mutants of 12 open reading frames (ORFs), discovered during the systematic sequencing of the Saccharomyces cerevisiae genome. These ORFs are located on chromosome IV (YDL183c), on chromosome VII (YGL139w, YGL140c, YGL141w, YGR280c and YGR284c) or on chromosome XIV (YNL006w, YNR004w, YNR007c, YNR008w, YNR009w and YNR013c). Disruptants were generated using the PCR-based short flanking homology (SFH) strategy in yeast strain FY1679. Tetrad analysis, following sporulation of the heterozygous disruptants, revealed that YGR280c and YNL006w are essential genes for vegetative yeast growth in rich medium. The lethality of the two genes was confirmed by gene complementation analysis. The protein encoded by YNL006w (LST8) is now known to be involved in transport of permeases from the Golgi to the plasma membrane. Basic phenotypic analyses were performed on haploid disruptants from both mating types of 10 non-essential genes. One disruptant (YNR004w) revealed a slow growth rate on glucose-minimal medium at 15° C. For each of the individual ORFs, a disruption cassette and the corresponding cognate gene were cloned into appropriate plasmids. Copyright © 2002 John Wiley & Sons, Ltd.
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- 2002
7. Erratum: Corrigendum: Arrayed adenoviral expression libraries for functional screening
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Ing-Ren Tsang, Karen Pittois, Peter Herwig Maria Tomme, Stephane Schweicher, Luc Van Rompaey, Libin Ma, Hugo Klaassen, Filip Beirinckx, Sofie Herman, Heidi Pavliska, Helmuth van Es, Bart Francken, Pascal Gerard Merchiers, Christel Schipper, Johan Vandersmissen, Marc De Raeymaeker, Wendy Laenen, Onno van de Stolpe, Annick Hagers, Mia Jans, Reginald Brys, Frits Michiels, Kris Van Beeck, Ivo Piest, Ellen Langemeijer, Yvonne Rombout, Kristina Dokic, Evi Narinx, and Jan van der Schueren
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Expression (architecture) ,Nat ,Biomedical Engineering ,Molecular Medicine ,Bioengineering ,Regret ,Computational biology ,Psychology ,Applied Microbiology and Biotechnology ,Biotechnology - Abstract
Nat. Biotechnol. 20, 1154–1157 (2002). Gert-Jan Arts and Joost Donker were inadvertently omitted from the list of authors when this report was submitted for publication. The authors regret the omission.
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- 2003
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