dc.date.accessioned | 2023-01-31T18:14:52Z | |
dc.date.available | 2023-01-31T18:14:52Z | |
dc.date.created | 2022-09-02T15:07:01Z | |
dc.date.issued | 2022 | |
dc.identifier.citation | De Genst, Erwin Foo, Kylie S. Xiao, Yao Rohner, Eduarde de Vries, Emma Sohlmér, Jesper Witman, Nevin Hidalgo, Alejandro Kolstad, Terje R Selnes Louch, William Edward Pehrsson, Susanne Park, Andrew Ikeda, Yasuhiro Li, Xidan Mayr, Lorenz M. Wickson, Kate Jennbacken, Karin Hansson, Kenny Fritsche-Danielson, Regina Hunt, James Chien, Kenneth R. . Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure. Nature Communications. 2022, 13(1) | |
dc.identifier.uri | http://hdl.handle.net/10852/99504 | |
dc.description.abstract | Abstract The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca 2+ ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities. | |
dc.language | EN | |
dc.publisher | Nature Portfolio | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure | |
dc.title.alternative | ENEngelskEnglishBlocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure | |
dc.type | Journal article | |
dc.creator.author | De Genst, Erwin | |
dc.creator.author | Foo, Kylie S. | |
dc.creator.author | Xiao, Yao | |
dc.creator.author | Rohner, Eduarde | |
dc.creator.author | de Vries, Emma | |
dc.creator.author | Sohlmér, Jesper | |
dc.creator.author | Witman, Nevin | |
dc.creator.author | Hidalgo, Alejandro | |
dc.creator.author | Kolstad, Terje R Selnes | |
dc.creator.author | Louch, William Edward | |
dc.creator.author | Pehrsson, Susanne | |
dc.creator.author | Park, Andrew | |
dc.creator.author | Ikeda, Yasuhiro | |
dc.creator.author | Li, Xidan | |
dc.creator.author | Mayr, Lorenz M. | |
dc.creator.author | Wickson, Kate | |
dc.creator.author | Jennbacken, Karin | |
dc.creator.author | Hansson, Kenny | |
dc.creator.author | Fritsche-Danielson, Regina | |
dc.creator.author | Hunt, James | |
dc.creator.author | Chien, Kenneth R. | |
cristin.unitcode | 185,53,15,10 | |
cristin.unitname | Institutt for eksperimentell medisinsk forskning | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 2048401 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature Communications&rft.volume=13&rft.spage=&rft.date=2022 | |
dc.identifier.jtitle | Nature Communications | |
dc.identifier.volume | 13 | |
dc.identifier.issue | 1 | |
dc.identifier.pagecount | 0 | |
dc.identifier.doi | https://doi.org/10.1038/s41467-022-29703-9 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 2041-1723 | |
dc.type.version | PublishedVersion | |
cristin.articleid | 3018 | |