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

Author

Listed:
  • Erwin De Genst

    (Discovery Sciences, R&D, AstraZeneca
    Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet)

  • Kylie S. Foo

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Karolinska Institutet)

  • Yao Xiao

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Karolinska Institutet)

  • Eduarde Rohner

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Karolinska Institutet)

  • Emma de Vries

    (Discovery Sciences, R&D, AstraZeneca)

  • Jesper Sohlmér

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Karolinska Institutet)

  • Nevin Witman

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet)

  • Alejandro Hidalgo

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • Terje R. S. Kolstad

    (Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo
    University of Oslo)

  • William E. Louch

    (Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo
    University of Oslo)

  • Susanne Pehrsson

    (Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • Andrew Park

    (Biologics Engineering, R&D, AstraZeneca)

  • Yasuhiro Ikeda

    (Biologics Engineering, R&D, AstraZeneca)

  • Xidan Li

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet)

  • Lorenz M. Mayr

    (Discovery Sciences, R&D, AstraZeneca
    Vector BioPharma AG)

  • Kate Wickson

    (Discovery Sciences, R&D, AstraZeneca)

  • Karin Jennbacken

    (Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • Kenny Hansson

    (Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • Regina Fritsche-Danielson

    (Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca)

  • James Hunt

    (Discovery Sciences, R&D, AstraZeneca)

  • Kenneth R. Chien

    (Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
    Karolinska Institutet)

Abstract

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.

Suggested Citation

  • Erwin De Genst & Kylie S. Foo & Yao Xiao & Eduarde Rohner & Emma de Vries & Jesper Sohlmér & Nevin Witman & Alejandro Hidalgo & Terje R. S. Kolstad & William E. Louch & Susanne Pehrsson & Andrew Park , 2022. "Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29703-9
    DOI: 10.1038/s41467-022-29703-9
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    References listed on IDEAS

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    1. Pooja Munnilal Tiwari & Daryll Vanover & Kevin E. Lindsay & Swapnil Subhash Bawage & Jonathan L. Kirschman & Sushma Bhosle & Aaron W. Lifland & Chiara Zurla & Philip J. Santangelo, 2018. "Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Martin P. Stewart & Armon Sharei & Xiaoyun Ding & Gaurav Sahay & Robert Langer & Klavs F. Jensen, 2016. "In vitro and ex vivo strategies for intracellular delivery," Nature, Nature, vol. 538(7624), pages 183-192, October.
    3. Niels Grote Beverborg & Daniela Später & Ralph Knöll & Alejandro Hidalgo & Steve T. Yeh & Zaher Elbeck & Herman H. W. Silljé & Tim R. Eijgenraam & Humam Siga & Magdalena Zurek & Malin Palmér & Susanne, 2021. "Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Nicola Fenderico & Revina C. Scherpenzeel & Michael Goldflam & Davide Proverbio & Ingrid Jordens & Tomica Kralj & Sarah Stryeck & Tarek Z. Bass & Guy Hermans & Christopher Ullman & Teodor Aastrup & Pi, 2019. "Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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    Cited by:

    1. Fabrice Gonnot & Laura Boulogne & Camille Brun & Maya Dia & Yves Gouriou & Gabriel Bidaux & Christophe Chouabe & Claire Crola Da Silva & Sylvie Ducreux & Bruno Pillot & Andrea Kaczmarczyk & Christelle, 2023. "SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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