Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

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 Pehrsson, Tamsin Albery, Nils Bomer, Martijn F Hoes, Cornelis J Boogerd, Michael Frisk, Eva van Rooij, Sagar Damle, William E LouchQing-Dong Wang, Regina Fritsche-Danielson, Kenneth R Chien, Kenny M Hansson, Adam E Mullick, Rudolf A de Boer, Peter van der Meer

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)5180
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 30 Aug 2021

Keywords

  • Animals
  • Calcium/metabolism
  • Calcium-Binding Proteins/genetics
  • Cardiomyopathies/genetics
  • Female
  • Genetic Therapy
  • Heart Failure/genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac/metabolism
  • Oligonucleotides, Antisense/genetics
  • Rats
  • Rats, Inbred Lew

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