Professor Thomas Thum is Chair of the ESC’s Working Group on Myocardial Function and Director of the Institute of Molecular and Translational Therapeutic Strategies at Hannover Medical School (Germany), one of the leading centres spearheading the development of therapies targeting non-coding RNAs. Here he discusses some of his group’s exciting work and provides guidance on how to successfully translate laboratory findings into clinical benefit:
“Non-coding RNAs hold promise to improve the diagnosis, prognosis and treatment of cardiovascular diseases. For therapeutics, we have moved into the clinical testing stage within a relatively short timeframe. One of the keys to success is conducting so-called ‘target discovery’ research, where we evaluate functional screens in diseased and healthy organs in animal models, and study human tissues, to identify interesting biologically active non-coding RNA targets. In this way, we can try to identify targets and to develop therapies that are likely to be mechanistically active, rather than simply relieving symptoms as with many of today’s cardiovascular drugs.
A very advanced novel non-coding RNA-based therapeutic approach to date, which has been licensed by our group to a pharmaceutical company, targets microRNA-21 (miR-21), a short-non-coding RNA that we have shown to contribute to myocardial disease by stimulating fibrosis.1 Silencing of miR-21 is currently being tested in a phase II trial in patients with kidney fibrosis and, if successful, there may be further evaluation in other fibrotic diseases, such as those involving the heart and the lungs.
We have also used target discovery research with specific cell types, including the cardiomyocyte. Unbiased robot-based library screening of hundreds of miRs helped us to identify miR-132,2 which, in different preclinical models, appears to be both necessary and sufficient to drive the pathological growth of cardiomyocytes, a hallmark of adverse cardiac remodelling.3 Since then, we have developed a locked nucleic acid based antisense inhibitor of miR-132 (antimiR-132) and have tested it in vitro, and in small and large animals.3 When administered to pigs, after an experimentally induced myocardial infarction, antimiR-132 reversed severe heart failure, with an dose-dependent increase in ejection fraction, less fibrosis and less hypertrophy. AntimiR-132 has also successfully completed two-species toxicology testing.
Potential new therapies may falter at this stage as it is very difficult to find sufficient funding at the university level for clinical development. However, we have recently set up our own spin-off biotech company to help progress antimiR-132 into clinical assessment. Results from a phase Ib study in 28 patients with heart failure of ischaemic origin are eagerly awaited (www.clinicaltrial.gov; NCT04045405).
When performing translational research, it is important to use multiple models to explore the target. In addition, with any new target and therapy, I would advocate performing testing on human cells and tissues as soon as possible to show that the mechanism is not only confined to animal models.
Non-coding RNA therapies have the potential to enable significant progress in the development of next-generation therapeutics for cardiovascular disease and I look forward to seeing this emerging field expand further.”
- Thum T, et al.Nature2008;456:980–4.
- Ucar A, et al.Nat Commun2012;3:1078.
- FoinquinosA, et al. Nat Commun 2020;11:633.
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