Author: Beverborg, Niels Grote; Spater, Daniela; Knoll, Ralph; Hidalgo, Alejandro; Yeh, Steve T; Elbeck, Zaher; Sillje, Herman H W; Eijgenraam, Tim R; Siga, Humam; Zurek, Magdalena; Palmer, Malin; Pehrsson, Susanne; Albery, Tamsin; Bomer, Nils; Hoes, Martijn F; Boogerd, Cornelis J; Frisk, Michael; van Rooij, Eva; Damle, Sagar; Louch, William E; Wang, Qing-Dong; Fritsche-Danielson, Regina; Chien, Kenneth R; Hansson, Kenny M; Mullick, Adam E; de Boer, Rudolf A; van der Meer, Peter
Department: Inst för cell- och molekylärbiologi / Dept of Cell and Molecular Biology
Abstract
Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp−/−), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.
Institution:
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Department of Cardiology University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Integrated Cardio Metabolic Center (ICMC), Department of Medicine, Karolinska Institutet, Huddinge, Sweden
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Murdoch Children's Research Institute (MCRI), Flemington, Melbourne, VIC, Australia
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Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
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Ionis Pharmaceuticals, Carlsbad, CA, USA
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Laboratory of Experimental Biomedicine, Core Facilities, Sahlgrenska Academy, Gothenburg University, Göteborg, Sweden
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Department of Molecular Cardiology, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Center Utrecht, Utrecht, The Netherlands
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Institute for Experimental Medical Research, Oslo University Hospital and KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
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Department of Cell and Molecular Biology (CMB), Karolinska Institute, Stockholm, Sweden
Citation: Nat Commun. 2021 Aug 30;12(1):5180.
Publishing journal: Nature Communications
Eprint status: Peer Reviewed
Version: Published
Issue date: 2022-08-18
Sponsorship:
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European Research Council ERC AdG 743225
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European Research Council ERC CoG 818715
Rights:
CC BY 4.0
Publication year: 2021