SMASH Splice Modulation Approach to suppress HFpEF
- Funded period
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2025 – 2029
- Granted budget
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€ 664,705
- Indication
heart failure
- Therapeutic Principle
Drug
- Principal Investigator
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Michael Gotthardt, Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft; Alessio Alogna, Deutsches Herzzentrum der Charité
Targeted inhibition of the titin splice factor RBM20 using antisense oligonucleotides (ASOs) offers a novel approach for treating heart failure with preserved ejection fraction (HFpEF) and is being advanced through preclinical studies.
Heart failure with preserved ejection fraction (HFpEF) affects more than 50% of all heart failure patients and is becoming increasingly common in our ageing society. A key factor is titin-based stiffness, which affects diastolic filling of the heart. Our research has shown that targeted inhibition of the titin splicing factor RBM20 using antisense oligonucleotides (ASOs) improves diastolic function, adjusts heart filling and normalises heart size.
We have developed ASOs for mouse and human models and are now optimising their targeted delivery to the heart to improve efficacy and safety. These approaches are being tested in animal models, human iPSC-derived cardiomyocytes and engineered heart tissue. Preclinical studies in Göttingen minipigs are paving the way for clinical trials in collaboration with the DZHK and our partners.