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 Rooij, Sagar Damle, William E. Louch, Qing-Dong Wang, Regina Fritsche-Danielson, Kenneth R. Chien, Kenny M. Hansson, Adam E. Mullick (), Rudolf A. Boer and Peter Meer ()
Additional contact information
Niels Grote Beverborg: University of Groningen
Daniela Später: AstraZeneca
Ralph Knöll: AstraZeneca
Alejandro Hidalgo: AstraZeneca
Steve T. Yeh: Ionis Pharmaceuticals
Zaher Elbeck: Karolinska Institutet
Herman H. W. Silljé: University of Groningen
Tim R. Eijgenraam: University of Groningen
Humam Siga: Karolinska Institutet
Magdalena Zurek: AstraZeneca
Malin Palmér: AstraZeneca
Susanne Pehrsson: AstraZeneca
Tamsin Albery: AstraZeneca
Nils Bomer: University of Groningen
Martijn F. Hoes: University of Groningen
Cornelis J. Boogerd: University Medical Center Utrecht
Michael Frisk: University of Oslo
Eva Rooij: University Medical Center Utrecht
Sagar Damle: Ionis Pharmaceuticals
William E. Louch: University of Oslo
Qing-Dong Wang: AstraZeneca
Regina Fritsche-Danielson: AstraZeneca
Kenneth R. Chien: Karolinska Institutet
Kenny M. Hansson: AstraZeneca
Adam E. Mullick: Ionis Pharmaceuticals
Rudolf A. Boer: University of Groningen
Peter Meer: University of Groningen

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25439-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25439-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25439-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().