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A Small-Molecule-Responsive Riboswitch Enables Conditional Induction of Viral Vector-Mediated Gene Expression in Mice

A Small-Molecule-Responsive Riboswitch Enables Conditional Induction of Viral Vector-Mediated Gene Expression in Mice

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STROBEL, Benjamin, Matthias J. DÜCHS, Dragica BLAZEVIC, Philipp RECHTSTEINER, Clemens BRAUN, Katja S. BAUM-KROKER, Bernhard SCHMID, Thomas CIOSSEK, Dirk GOTTSCHLING, Jörg S. HARTIG, Sebastian KREUZ, 2020. A Small-Molecule-Responsive Riboswitch Enables Conditional Induction of Viral Vector-Mediated Gene Expression in Mice. In: ACS Synthetic Biology. American Chemical Society (ACS). 9(6), pp. 1292-1305. eISSN 2161-5063. Available under: doi: 10.1021/acssynbio.9b00410

@article{Strobel2020Small-50392, title={A Small-Molecule-Responsive Riboswitch Enables Conditional Induction of Viral Vector-Mediated Gene Expression in Mice}, year={2020}, doi={10.1021/acssynbio.9b00410}, number={6}, volume={9}, journal={ACS Synthetic Biology}, pages={1292--1305}, author={Strobel, Benjamin and Düchs, Matthias J. and Blazevic, Dragica and Rechtsteiner, Philipp and Braun, Clemens and Baum-Kroker, Katja S. and Schmid, Bernhard and Ciossek, Thomas and Gottschling, Dirk and Hartig, Jörg S. and Kreuz, Sebastian} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/50392"> <dc:contributor>Ciossek, Thomas</dc:contributor> <dc:contributor>Strobel, Benjamin</dc:contributor> <dc:language>eng</dc:language> <dc:creator>Schmid, Bernhard</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2020-07-29T12:56:26Z</dc:date> <dc:creator>Ciossek, Thomas</dc:creator> <dc:creator>Düchs, Matthias J.</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2020-07-29T12:56:26Z</dcterms:available> <dc:contributor>Blazevic, Dragica</dc:contributor> <dc:creator>Baum-Kroker, Katja S.</dc:creator> <dc:creator>Strobel, Benjamin</dc:creator> <dc:creator>Hartig, Jörg S.</dc:creator> <dc:contributor>Baum-Kroker, Katja S.</dc:contributor> <dcterms:title>A Small-Molecule-Responsive Riboswitch Enables Conditional Induction of Viral Vector-Mediated Gene Expression in Mice</dcterms:title> <dc:creator>Braun, Clemens</dc:creator> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/50392"/> <dc:creator>Blazevic, Dragica</dc:creator> <dc:contributor>Düchs, Matthias J.</dc:contributor> <dc:creator>Rechtsteiner, Philipp</dc:creator> <dcterms:issued>2020</dcterms:issued> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/29"/> <dc:creator>Kreuz, Sebastian</dc:creator> <dc:contributor>Gottschling, Dirk</dc:contributor> <dc:contributor>Kreuz, Sebastian</dc:contributor> <dc:creator>Gottschling, Dirk</dc:creator> <dc:contributor>Braun, Clemens</dc:contributor> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/29"/> <dc:contributor>Schmid, Bernhard</dc:contributor> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:abstract xml:lang="eng">Adeno-associated viral (AAV) vector-mediated gene therapy holds great potential for future medical applications. However, to facilitate safer and broader applicability and to enable patient-centric care, therapeutic protein expression should be controllable, ideally by an orally administered drug. The use of protein-based systems is considered rather undesirable, due to potential immunogenicity and the limited coding space of AAV. Ligand-dependent riboswitches, in contrast, are small and characterized by an attractive mode-of-action based on mRNA-self-cleavage, independent of coexpressed foreign protein. While a promising approach, switches available to date have only shown moderate potency in animals. In particular, ON-switches that induce transgene expression upon ligand administration so far have achieved rather disappointing results. Here we present the utilization of the previously described tetracycline-dependent ribozyme K19 for controlling AAV-mediated transgene expression in mice. Using this tool switch, we provide first proof for the feasibility of clinically desired key features, including multiorgan functionality, potent regulation (up to 15-fold induction), reversibility, and the possibility to fine-tune and repeatedly induce expression. The systematic assessment of ligand and reporter protein plasma levels further enabled the characterization of pharmacokinetic-pharmacodynamic relationships. Thus, our results strongly support future efforts to develop engineered riboswitches for applications in clinical gene therapy.</dcterms:abstract> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:contributor>Rechtsteiner, Philipp</dc:contributor> <dc:contributor>Hartig, Jörg S.</dc:contributor> </rdf:Description> </rdf:RDF>

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