Antisense Therapy Attenuates Phospholamban p.(Arg14del) Cardiomyopathy in Mice and Reverses Protein Aggregation

Tim R. Eijgenraam, Nienke M. Stege, Vivian Oliveira Nunes Teixeira, Remco de Brouwer, Elisabeth M. Schouten, Niels Grote Beverborg, Liu Sun, Daniela Später, Ralph Knöll, Kenny M. Hansson, Carl Amilon, David Janzén, Steve T. Yeh, Adam E. Mullick, Peter van der Meer, Rudolf A. de Boer, Herman H.W. Silljé*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)


Inherited cardiomyopathy caused by the p.(Arg14del) pathogenic variant of the phos-pholamban (PLN) gene is characterized by intracardiomyocyte PLN aggregation and can lead to severe dilated cardiomyopathy. We recently reported that pre-emptive depletion of PLN attenuated heart failure (HF) in several cardiomyopathy models. Here, we investigated if administration of a Pln-targeting antisense oligonucleotide (ASO) could halt or reverse disease progression in mice with advanced PLN-R14del cardiomyopathy. To this aim, homozygous PLN-R14del (PLN-R14∆/∆ ) mice received PLN-ASO injections starting at 5 or 6 weeks of age, in the presence of moderate or severe HF, respectively. Mice were monitored for another 4 months with echocardiographic analyses at several timepoints, after which cardiac tissues were examined for pathological remodeling. We found that vehicle-treated PLN-R14∆/∆ mice continued to develop severe HF, and reached a humane endpoint at 8.1 ± 0.5 weeks of age. Both early and late PLN-ASO administration halted further cardiac remodeling and dysfunction shortly after treatment start, resulting in a life span extension to at least 22 weeks of age. Earlier treatment initiation halted disease development sooner, resulting in better heart function and less remodeling at the study endpoint. PLN-ASO treatment almost completely eliminated PLN aggregates, and normalized levels of autophagic proteins. In conclu-sion, these findings indicate that PLN-ASO therapy may have beneficial outcomes in PLN-R14del cardiomyopathy when administered after disease onset. Although existing tissue damage was not reversed, further cardiomyopathy progression was stopped, and PLN aggregates were resolved.

Original languageEnglish
Article number2427
JournalInternational Journal of Molecular Sciences
Issue number5
Publication statusPublished - 1 Mar 2022
Externally publishedYes

Bibliographical note

Funding Information:
Funding: This research was funded by The Netherlands Cardiovascular Research (CVON) and Dutch CardioVascular Alliance (DCVA) initiatives of the Dutch Heart Foundation [grants 2020B005 (DCVA-DOUBLE-DOSE), 2018-30 (CVON-PREDICT2), 2017-21 (CVON-SHE-PREDICTS-HF), 2017-11 (CVON-RED-CVD), 2014-40 (CVON-DOSIS)]; the Cure PhosphoLambaN-induced cardiomyopathy (Cure-PLaN) initiative of the Leducq Foundation; and a European Research Council Consolidator Grant (ERC CoG) [grant 818715 (SECRETE-HF)]. Generation of PLN-R14del mice was supported by the de Boer Foundation, Ubbo Emmius Fund, Netherlands Heart Institute (NHI) and PLN foundation.

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© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


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