LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 4 of total 4

Search options

  1. Article: Investigating discovery strategies and pharmacological properties of stereodefined phosphorodithioate LNA gapmers.

    Duschmalé, Jörg / Schäublin, Adrian / Funder, Erik / Schmidt, Steffen / Kiełpiński, Łukasz J / Nymark, Helle / Jensen, Klaus / Koch, Troels / Duschmalé, Martina / Koller, Erich / Møller, Marianne Ravn / Schadt, Simone / Husser, Christophe / Brink, Andreas / Sewing, Sabine / Minz, Tanja / Wengel, Jesper / Bleicher, Konrad / Li, Meiling

    Molecular therapy. Nucleic acids

    2022  Volume 29, Page(s) 176–188

    Abstract: The introduction of sulfur into the phosphate linkage of chemically synthesized oligonucleotides creates the stereocenters on phosphorus atoms. Researchers have valued the nature of backbone stereochemistry and early on investigated drug properties for ... ...

    Abstract The introduction of sulfur into the phosphate linkage of chemically synthesized oligonucleotides creates the stereocenters on phosphorus atoms. Researchers have valued the nature of backbone stereochemistry and early on investigated drug properties for the individual stereocenters in dimers or short oligomers. Only very recently, it has become possible to synthesize fully stereodefined antisense oligonucleotides in good yield and purity. Non-bridging phosphorodithioate (PS
    Language English
    Publishing date 2022-06-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2662631-7
    ISSN 2162-2531
    ISSN 2162-2531
    DOI 10.1016/j.omtn.2022.06.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: Investigating receptor-mediated antibody transcytosis using blood-brain barrier organoid arrays.

    Simonneau, Claire / Duschmalé, Martina / Gavrilov, Alina / Brandenberg, Nathalie / Hoehnel, Sylke / Ceroni, Camilla / Lassalle, Evodie / Kassianidou, Elena / Knoetgen, Hendrik / Niewoehner, Jens / Villaseñor, Roberto

    Fluids and barriers of the CNS

    2021  Volume 18, Issue 1, Page(s) 43

    Abstract: Background: The pathways that control protein transport across the blood-brain barrier (BBB) remain poorly characterized. Despite great advances in recapitulating the human BBB in vitro, current models are not suitable for systematic analysis of the ... ...

    Abstract Background: The pathways that control protein transport across the blood-brain barrier (BBB) remain poorly characterized. Despite great advances in recapitulating the human BBB in vitro, current models are not suitable for systematic analysis of the molecular mechanisms of antibody transport. The gaps in our mechanistic understanding of antibody transcytosis hinder new therapeutic delivery strategy development.
    Methods: We applied a novel bioengineering approach to generate human BBB organoids by the self-assembly of astrocytes, pericytes and brain endothelial cells with unprecedented throughput and reproducibility using micro patterned hydrogels. We designed a semi-automated and scalable imaging assay to measure receptor-mediated transcytosis of antibodies. Finally, we developed a workflow to use CRISPR/Cas9 gene editing in BBB organoid arrays to knock out regulators of endocytosis specifically in brain endothelial cells in order to dissect the molecular mechanisms of receptor-mediated transcytosis.
    Results: BBB organoid arrays allowed the simultaneous growth of more than 3000 homogenous organoids per individual experiment in a highly reproducible manner. BBB organoid arrays showed low permeability to macromolecules and prevented transport of human non-targeting antibodies. In contrast, a monovalent antibody targeting the human transferrin receptor underwent dose- and time-dependent transcytosis in organoids. Using CRISPR/Cas9 gene editing in BBB organoid arrays, we showed that clathrin, but not caveolin, is required for transferrin receptor-dependent transcytosis.
    Conclusions: Human BBB organoid arrays are a robust high-throughput platform that can be used to discover new mechanisms of receptor-mediated antibody transcytosis. The implementation of this platform during early stages of drug discovery can accelerate the development of new brain delivery technologies.
    MeSH term(s) Animals ; Antibodies/analysis ; Antibodies/metabolism ; Astrocytes/chemistry ; Astrocytes/metabolism ; Bioengineering/methods ; Blood-Brain Barrier/chemistry ; Blood-Brain Barrier/cytology ; Blood-Brain Barrier/metabolism ; Cells, Cultured ; Coculture Techniques ; Endothelial Cells/chemistry ; Endothelial Cells/metabolism ; Humans ; Organoids/chemistry ; Organoids/cytology ; Organoids/metabolism ; Pericytes/chemistry ; Pericytes/metabolism ; Receptors, Transferrin/analysis ; Receptors, Transferrin/metabolism ; Transcytosis/physiology
    Chemical Substances Antibodies ; Receptors, Transferrin
    Language English
    Publishing date 2021-09-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2595406-4
    ISSN 2045-8118 ; 2045-8118
    ISSN (online) 2045-8118
    ISSN 2045-8118
    DOI 10.1186/s12987-021-00276-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3' and 5' thiophosphate linkages.

    Duschmalé, Jörg / Hansen, Henrik Frydenlund / Duschmalé, Martina / Koller, Erich / Albaek, Nanna / Møller, Marianne Ravn / Jensen, Klaus / Koch, Troels / Wengel, Jesper / Bleicher, Konrad

    Nucleic acids research

    2019  Volume 48, Issue 1, Page(s) 63–74

    Abstract: The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well ...

    Abstract The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3' thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3' and 5' thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications.
    MeSH term(s) Animals ; Apolipoprotein B-100/antagonists & inhibitors ; Apolipoprotein B-100/genetics ; Apolipoprotein B-100/metabolism ; Cell Line, Tumor ; Female ; Humans ; Kidney/cytology ; Kidney/metabolism ; Liver/cytology ; Liver/metabolism ; Lung/metabolism ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Oligonucleotides/chemical synthesis ; Oligonucleotides/genetics ; Oligonucleotides/metabolism ; Phosphates/chemistry ; Phosphates/metabolism ; Phosphorothioate Oligonucleotides/chemical synthesis ; Phosphorothioate Oligonucleotides/genetics ; Phosphorothioate Oligonucleotides/metabolism ; RNA Stability ; RNA, Long Noncoding/antagonists & inhibitors ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Ribonuclease H/chemistry ; Ribonuclease H/metabolism ; Stereoisomerism
    Chemical Substances Apob protein, mouse ; Apolipoprotein B-100 ; MALAT1 long non-coding RNA, human ; Oligonucleotides ; Phosphates ; Phosphorothioate Oligonucleotides ; RNA, Long Noncoding ; locked nucleic acid ; Ribonuclease H (EC 3.1.26.4) ; thiophosphoric acid (TYM4M7EWCW)
    Language English
    Publishing date 2019-11-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkz1099
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: Evaluation of bovine milk extracellular vesicles for the delivery of locked nucleic acid antisense oligonucleotides.

    Grossen, Philip / Portmann, Michaela / Koller, Erich / Duschmalé, Martina / Minz, Tanja / Sewing, Sabine / Pandya, Nikhil Janak / van Geijtenbeek, Sabine Kux / Ducret, Axel / Kusznir, Eric-André / Huber, Sylwia / Berrera, Marco / Lauer, Matthias E / Ringler, Philippe / Nordbo, Bettina / Jensen, Marianne Lerbech / Sladojevich, Filippo / Jagasia, Ravi / Alex, Rainer /
    Gamboni, Remo / Keller, Michael

    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

    2020  Volume 158, Page(s) 198–210

    Abstract: The natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for ... ...

    Abstract The natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for their potential to shuttle locked nucleic acid-modified antisense oligonucleotides (LNA ASOs) into the systemic circulation after oral administration. To this end, a broad array of analytical methods including proteomics and lipidomics were used to thoroughly characterize BMEVs. We found that additional purification by density gradients efficiently reduced levels of non-EV associated proteins. The potential of BMEVs to functionally transfer LNA ASOs was tested using advanced in vitro systems (i.e. hPSC-derived neurons and primary human cells). A slight increase in cellular LNA ASO internalization and target gene reduction was observed when LNA ASOs were delivered using BMEVs. When dosed orally in mice, only a small fraction (about 1% of total administered dose) of LNA ASOs was recovered in the peripheral tissues liver and kidney, however, no significant reduction in target gene expression (i.e. functional knockdown) was observed.
    Language English
    Publishing date 2020-11-26
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1065368-5
    ISSN 1873-3441 ; 0939-6411
    ISSN (online) 1873-3441
    ISSN 0939-6411
    DOI 10.1016/j.ejpb.2020.11.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.B 1651: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top