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December 2021

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Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue. Science Translational Medicine (2021) 13, 8952. DZHK authors: Michael Radke, Victor Badillo-Lisakowski, Thiago Britto-Borges, Pragati Parakkat, Judith Hüttemeister, Martin Liss, Arne Hansen, Christoph Dieterich, Michael Gotthardt.

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Patients with a stiff cardiac ventricle cannot efficiently fill their heart with blood and eventually develop heart failure. There is currently no effective treatment for this prevalent and deadly condition, where diastolic filling and not systolic contraction is the underlying problem.

In this study scientists from the DZHK partner sites Berlin, Heidelberg and Hamburg partnered with Ionis Pharmaceuticals to develop antisense oligonucleotides (ASO) targeting the splicing factor RBM20 to induce the expression of a longer, more compliant isoform of the giant protein titin. They evaluated the therapeutic implications in a mouse model of titin-based diastolic dysfunction and in human engineered heart tissue (EHT).

RBM20 downregulation by weekly ASO injections led to adapted titin splicing, improved ventricular filling and restored cardiac function with limited side effects. In human engineered heart tissue, ASO treatment was effective, well tolerated and resulted in improved relaxation kinetics. Taken together, this work sets a proof of principle for the future development of splicing modulators with therapeutic potential for patients with stiffened heart muscle such as in heart failure with preserved ejection fraction (HFpEF).

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