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- Title
Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy.
- Authors
Grote Beverborg, Niels; Später, Daniela; Knöll, Ralph; Hidalgo, Alejandro; Yeh, Steve T.; Elbeck, Zaher; Silljé, Herman H. W.; Eijgenraam, Tim R.; Siga, Humam; Zurek, Magdalena; Palmér, Malin; Pehrsson, Susanne; Albery, Tamsin; Bomer, Nils; Hoes, Martijn F.; Boogerd, Cornelis J.; Frisk, Michael; van Rooij, Eva; Damle, Sagar; Louch, William E.
- 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. Heart failure is a major cause of morbidity and mortality worldwide. Here the authors show that subcutaneous administration of antisense oligonucleotides targeting PLN is an effective strategy in preclinical models of genetic cardiomyopathy and ischemia-driven heart failure.
- Subjects
HEART failure; CARDIOMYOPATHIES; PHOSPHOLAMBAN; SURVIVAL rate; HEART diseases; OLIGONUCLEOTIDES
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-25439-0