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

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, Yasuhiro Ikeda, Xidan Li, Lorenz M. Mayr, Kate Wickson, Karin Jennbacken, Kenny Hansson, Regina Fritsche-Danielson, James Hunt () and Kenneth R. Chien ()
Additional contact information
Erwin De Genst: Discovery Sciences, R&D, AstraZeneca
Kylie S. Foo: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
Yao Xiao: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet
Eduarde Rohner: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, 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
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
Terje R. S. Kolstad: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo
William E. Louch: Institute for Experimental Medical Research, Oslo University Hospital and 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
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

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29703-9

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