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

Autor:	Eijgenraam TR; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Stege NM; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Oliveira Nunes Teixeira V; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., de Brouwer R; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.; Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, The Netherlands., Schouten EM; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Grote Beverborg N; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Sun L; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Später D; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden., Knöll R; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden., Hansson KM; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden., Amilon C; Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden., Janzén D; Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden., Yeh ST; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA., Mullick AE; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA., van der Meer P; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., de Boer RA; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands., Silljé HHW; University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Jazyk:	angličtina
Zdroj:	International journal of molecular sciences [Int J Mol Sci] 2022 Feb 22; Vol. 23 (5). Date of Electronic Publication: 2022 Feb 22.
DOI:	10.3390/ijms23052427
Abstrakt:	Inherited cardiomyopathy caused by the p.(Arg14del) pathogenic variant of the phospholamban ( 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 Δ/Δ ) 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 Δ/Δ 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 conclusion, 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.
Databáze:	MEDLINE
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