Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause a loss of critical amounts of cardiomyocytes, this loss initiates a cascade of detrimental events, including formation of scar tissue, ventricular wall thinning, pressure overload, ventricular remodelling (overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death. Restoring damaged heart muscle tissue therefore represents a fundamental mechanistic strategy to treat heart failure. However, conventional heart failure therapies still focus on unloading of the heart by blocking the heightened activity of the adrenergic and related neuro-endocrine systems. This 40-year-old concept has fuelled the development of systemic drugs that were clinically quite effective though no profoundly innovative therapies have been carried to clinical fruition since then.
The TRAIN-HEART network is founded on the assumption that heart failure therapy needs ground-breaking concepts to fuel the development of a completely novel class of therapeutics. We propose to focus on non-coding RNA molecules and non-coding RNA-based mechanisms that are exquisite for the cardiomyocyte to target essential and highly localized biological mechanisms, which avoids noise from distant systemic effects.
The TRAIN-HEART network puts forward 3 key objectives that will equip fellows with a unique blend of scientific competences to drastically advance the cardiovascular field towards new targets, safe, specific and tolerable RNA therapeutics, and distinct delivery systems suitable for gene therapy:
1. To elucidate the disease mechanisms contributing to the development ischemic heart failure at the level of molecular genomics and identify new therapeutic targets.
2. To study the mechanism of action of RNA therapeutics capable of silencing or stimulating ncRNA targets currently in preclinical development for ischemic heart failure, improve its affinity and specific binding capacity for their targets and assess most tolerable dose and best route of administration.
3. To design and implement novel drug delivery systems (nanoparticles) for efficient in vivo delivery of two previously identified RNA therapeutics in the (damaged) myocardium.
To expand the state-of-the-art in RNA therapeutics, a new generation of innovation-minded researchers is needed who are able to overcome present challenges and develop effective solutions for the personalised treatment of ischemic HF. TRAIN-HEART’s proposition is to train a set of 15 high-potentials who are able to explore and translate pathogenic insights, accelerate the development of existing RNA therapeutics, and effectively implement innovative drug delivery systems to improve safety and therapeutic efficacy. Research and training are offered at the intersection of cardiovascular biology, functional genomics and drug development by anetwork of 25 PIs from 9 world-class academic teams in various disciplines and 8 non-academic partners of which 6 comapnies, the European Society of Cardiology, and the Dutch cardiovascular patient association Harteraad.