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

• Published in: International journal of molecular sciences 2022-02, Vol.23 (5), p.2427
• Main Authors: Eijgenraam, Tim R, Stege, Nienke M, Oliveira Nunes Teixeira, Vivian, de Brouwer, Remco, Schouten, Elisabeth M, Grote Beverborg, Niels, Sun, Liu, Später, Daniela, Knöll, Ralph, Hansson, Kenny M, Amilon, Carl, Janzén, David, Yeh, Steve T, Mullick, Adam E, van der Meer, Peter, de Boer, Rudolf A, Silljé, Herman H W
• Format: Article
• Language: English
• Subjects: Age; Aggregates; Amino Acid Substitution; Animals; Antisense oligonucleotides; Antisense therapy; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Cardiomyocytes; Cardiomyopathies - drug therapy; Cardiomyopathies - genetics; Cardiomyopathies - physiopathology; Cardiomyopathy; Cardiovascular disease; Congestive heart failure; Depletion; Dilated cardiomyopathy; Disease Models, Animal; Female; Gene expression; gene therapy; genetic mutation; Heart failure; Heart function; Heart Function Tests - drug effects; Humans; Kinases; Life span; Male; Mice; Mutation; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - pharmacology; Phospholamban; Protein Aggregates - drug effects; protein aggregation; Protein interaction; Proteins; Rodents; Treatment Outcome
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23052427

Inherited cardiomyopathy caused by the p.(Arg14del) pathogenic variant of the phospholamban ( ) 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 -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 ) 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 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.