Approximately 5.8 million people are currently diagnosed with heart failure in the United States alone, and more than 23 million worldwide. Even more alarming are the mortality rates following a diagnosis — 50 percent will die within five years and after ten years, nine out of ten patients are deceased. Thus, there is an emerging need for novel therapeutic approaches to reduce the burden of heart failure for patients and society as a whole.
Thanks to recent advances in the field of stem cell biology, there is now a consensus that the adult mammalian heart is capable of self-renewal through the activation of endogenous cardiac stem cells (Beltrami et al 2003). A recent paper in Cell shows that ckit+ cardiac stem cells lead to cardiac regeneration and overall improvement in cardiac function in rats (Ellison et al. 2013). Although clinical trials using stem cells have shown variable results in terms of improving cardiac function, most of those trials have used stem cells derived from bone-marrow. However, a recent trial (SCIPIO) used ckit+ cardiac stem cells and reported positive findings on cardiac function (Bolli et al 2011). It seems science is on to something quite exciting here.
Further evidence that supports the regenerative capacity and reprogramming potential of human cells comes from the break-through findings of Burton and Yamanaka. This 2012 Nobel Prize-winning research found that any fully differentiated human cell can be reprogrammed back to a progenitor stage using only four factors.
The big question is: Can the regenerative capacity of stem cells be used for novel pharmacological approaches that activate endogenous cardiac stem cell to induce regeneration of cardiac tissue also in man? We believe there is enough proof to pursue this research.
In line with AstraZeneca’s focus on cardiac regeneration we initiated a collaboration with Professor Kenneth Chien at Karolinska Institutet on single factor approaches to change the fate of cardiac stem cells (epicardial stem cells, EPDC). Using a completely novel modality, messenger Ribonucleic acid (mRNA) provided by Moderna Therapeutics it is now possible to produce a transient pulse expression of any relevant protein in the target tissue.
As shown in a recent publication by Professor Chien and colleagues, a single injection of mRNA for VEGF-A* led to remarkable effects in terms of reducing the scar area and improving vessel density and cardiac function in mice after a myocardial infarction (Zangi et al, 2013). To further explore this route, we will be progressing this research, as well as doing experiments with human cells and tissues. We will also be focusing our efforts on improving the safety of the mRNA modality as well as the VEGF-A target.
In parallel with this project we are working to identify novel targets for cardiac regeneration using a phenotypic screening approach. Our cardiac regeneration activities capitalise on the already established translational imaging and in vivo pharmacology platform where we can image coronary vascular function and cardiac performance from rodent to man. As scientists, this is some of the most rewarding and engaging work we have been involved in.
More than three decades ago AstraZeneca introduced the use of beta blockers and revolutionised the heart failure clinical praxis in close collaboration with academic researchers Hjalmarsson, Waagstein and Swedberg at the Sahlgrenska Academy. We are committed to building on this collaborative clinical platform to develop novel heart failure treatments in the future.