Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy
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.; Wang, Qing Dong; Fritsche-Danielson, Regina; Chien, Kenneth R.; Hansson, Kenny M.; Mullick, Adam E.; de Boer, Rudolf A.; van der Meer, Peter
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 15
(Article)
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
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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.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The excellent technical assistance of Martin Dokter, Silke Oberdorf-Maass, Kees van der Kolk, Marloes Schouten, and David Kijlstra are gratefully acknowledged. We thank Utrecht Sequencing Facility (USEQ) for providing sequencing service and data. We acknowledge Peter Konings for the statistical analyses of experiment related to the Cspr3/ Mlp−/− mouse studies 1 and 2, and the adult cardiomyocyte calcium imaging, as well as the rat MI study. Additionally, Kirk Peterson, Nancy Dalton, and Yusu Gu of the Seaweed Canyon Cardiovascular Physiology Laboratory, University of California at San Diego School of Medicine are acknowledged for their excellent technical assistance. H.H.W.S., T.R.E. and R.A.B. received support from the de Boer Foundation, Ubbo Emmius Foundation, PLN Foundation, the Netherlands Heart Foundation (CVON DOSIS, grant 2014–40 and CVON PREDICT2, grant 2018–30) and the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN). R.A.B. receives further support from Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017–21; CVON RED-CVD, grant 2017–11) and the European Research Council (ERC CoG 818715, SECRETE-HF). Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute and Utrecht University. C.J.B. received support from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 751988. R.K. received funding from AstraZeneca, Karolinska Institutet, Leducq Transatlantic Network of Excellence #13CVD04, Hjart och Lungfonden #20200265, and German Research Foundation (DFG) #Kn448/9-1 and 10-1. K.R.C. received funding from the ERC (ERC grant No. 743225) and the Swedish Research Council. Publisher Copyright: © 2021, The Author(s).
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