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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 \u0394\/\u0394) 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 \u0394\/\u0394 mice continued to develop severe HF, and reached a humane endpoint at 8.1 \u00b1 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.<\/jats:p>","DOI":"10.3390\/ijms23052427","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T22:34:30Z","timestamp":1645569270000},"page":"2427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Antisense Therapy Attenuates Phospholamban p.(Arg14del) Cardiomyopathy in Mice and Reverses Protein Aggregation"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-9656","authenticated-orcid":false,"given":"Tim R.","family":"Eijgenraam","sequence":"first","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7658-9291","authenticated-orcid":false,"given":"Nienke M.","family":"Stege","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-7158","authenticated-orcid":false,"given":"Vivian","family":"Oliveira Nunes Teixeira","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-2034","authenticated-orcid":false,"given":"Remco","family":"de Brouwer","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"},{"name":"Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth M.","family":"Schouten","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4629-9960","authenticated-orcid":false,"given":"Niels","family":"Grote Beverborg","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Sun","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Sp\u00e4ter","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-112X","authenticated-orcid":false,"given":"Ralph","family":"Kn\u00f6ll","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny M.","family":"Hansson","sequence":"additional","affiliation":[{"name":"Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Amilon","sequence":"additional","affiliation":[{"name":"Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4134-3849","authenticated-orcid":false,"given":"David","family":"Janz\u00e9n","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve T.","family":"Yeh","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-961X","authenticated-orcid":false,"given":"Adam E.","family":"Mullick","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-9140","authenticated-orcid":false,"given":"Rudolf A.","family":"de Boer","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-6302","authenticated-orcid":false,"given":"Herman H. W.","family":"Sillj\u00e9","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Cardiology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41569-019-0284-0","article-title":"Genetics of Dilated Cardiomyopathy: Practical Implications for Heart Failure Management","volume":"17","author":"Rosenbaum","year":"2020","journal-title":"Nat. Rev. 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