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  • De Genst, Erwin (author)

Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-05-31
  • Stockholm :Karolinska Institutet, Dept of Cell and Molecular Biology,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:openarchive.ki.se:10616/48168
  • ISSN:2041-1723
  • 10616/48168hdl
  • http://hdl.handle.net/10616/48168URI
  • https://doi.org/10.1038/s41467-022-29703-9DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:150207310URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca2+ 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.

Added entries (persons, corporate bodies, meetings, titles ...)

  • Foo, Kylie S (author)
  • Xiao, YaoKarolinska Institutet (author)
  • Rohner, Eduarde (author)
  • de Vries, Emma (author)
  • Sohlmér, Jesper (author)
  • Witman, Nevin (author)
  • Hidalgo, Alejandro (author)
  • Kolstad, Terje R S (author)
  • Louch, William E (author)
  • Pehrsson, Susanne (author)
  • Park, Andrew (author)
  • Ikeda, Yasuhiro (author)
  • Li, Xidan (author)
  • Mayr, Lorenz M (author)
  • Wickson, Kate (author)
  • Jennbacken, Karin (author)
  • Hansson, Kenny (author)
  • Fritsche-Danielson, Regina (author)
  • Hunt, James (author)
  • Chien, Kenneth RKarolinska Institutet (author)
  • Karolinska Institutet
  • Karolinska Institutet
  • Karolinska Institutet (creator_code:org_t)

Related titles

  • In:Nature CommunicationsStockholm : Karolinska Institutet, Dept of Cell and Molecular Biology2041-1723

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