Phospholamban Antisense Oligonucleotide ...

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C57. MLP-/-. PLN. PLN ASO Evaluation in MLP-/- Mice. All Mice. All Mice. All Mice. Ejection Fraction. End Systolic Volume. End Diastolic Volume. Heart RT-PCR.
Phospholamban Antisense Oligonucleotide Treatment Improved Cardiac Function and Reduced Transcriptional Markers of Heart Failure in a Mouse Model of Dilated Cardiomyopathy AE Mullick1,*, A Hidalgo Gonzalez2,3,*, Z Elbeck2, H Siga2, SS Damle1, ST Yeh1, M Palmér3, C Kuo1, QD Wang3, KR Chien1,4, R Fritsche-Danielson3, K Hansson3, D Später2,3,*, R Knöll2,3,*

Ionis Pharmaceuticals, Carlsbad, CA, USA 2Integrated Cardio Metabolic Center (ICMC), Karolinska Institute, Sweden 3Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden 4Department of Cell and Molecular Biology (CMB), Karolinska Institute, Stockholm, Sweden *equal contribution

ABSTRACT

BACKGROUND Phospholamban

Dilated cardiomyopathy (DCM) develops in mice lacking muscle LIM protein (MLP/Cspr3-/-). Previous work established this model to be amenable to improvements in cardiac function by genetic ablation of phospholamban (PLN). To test the hypothesis that therapeutic reductions of PLN would similarly improve cardiac function, MLP-/- mice were administered an antisense oligonucleotide (ASO) targeting PLN. Echocardiography assessments of ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) were performed before and after treatments. In addition, global transcriptome profiling using 3’RNA-seq was performed to identify changes in gene expression with disease and following PLN ASO treatments. MLP-/- mice with ejection fraction (EF%) of less than 45% (median, 37.6%; interquartile range, 32.2 – 42.0%) were treated with vehicle (n=10) or PLN ASO (n=9) for 4 weeks. Mice received three subcutaneous administrations of the PLN ASO resulting in 50%-70% PLN reductions. Echocardiography performed at study end revealed improvements of EF (60±8 vs. 46±12%), ESV (31±11 vs. 56±21ml) and EDV (79±22 vs. 100±25ml) with PLN ASO treatment. Corrected for baseline values, PLN ASO treatment improved all echocardiographic measurements (p