P6348Phospholamban antisense oligonucleotides drive the reversal of cardiac dysfunction and multiple heart failure parameters during murine dilated cardiomyopathy
| Autor: | Kenny M. Hansson, H Siga, D Spaeter, R Knoell, A Hidalgo Gonzalez, Kenneth R. Chien, A E Mullick, Zaher Elbeck, Regina Fritsche-Danielson, S S Damle, S T Yeh, Malin Palmér, Caroline Kuo, Qing-Dong Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Cardiac function curve
endocrine system medicine.medical_specialty Ejection fraction business.industry Genetic enhancement Diastole Dilated cardiomyopathy medicine.disease Phospholamban Heart failure Internal medicine Antisense oligonucleotides medicine Cardiology Cardiology and Cardiovascular Medicine business |
| Zdroj: | European Heart Journal. 40 |
| ISSN: | 1522-9645 0195-668X |
| Popis: | Background Mice lacking muscle LIM protein (Mlp/Cspr3 −/−) develop dilated cardiomyopathy (DCM). Previous work established this model to be amenable to improvements in cardiac function by genetic ablation of phospholamban (PLN). Purpose To test the hypothesis that therapeutic reductions of PLN would similarly improve cardiac function, Mlp KO mice were administered an antisense oligonucleotide (ASO) targeting PLN. Methods Echocardiography measurements of ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) were performed before and after treatment. In addition, global transcriptome profiling using 3'RNA-seq was performed to identify gene expression changes in diseased Mlp KO mice and following PLN ASO treatments. Mlp KO 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. Results Three subcutaneous injections of PLN ASO were administered to Mlp KO mice 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±21μl) and EDV (79±22 vs. 100±25μl) with PLN ASO treatment. Corrected for baseline values, PLN ASO treatment improved all echocardiographic measurements (p In conclusion, antisense inhibition of PLN reduced functional and transcriptional indices of heart failure in a DCM model. In view of the failed CUPID trials, a gene therapy approach to improve SERCA2a activity, targeting PLN with ASO may be advantageous due to a likely more robust pharmacological profile. |
| Databáze: | OpenAIRE |
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