Phenotypic screening of human cardiac cells breaks new ground in regenerative medicine

Wednesday, 9 December 2015

Can phenotypic screening lead to the discovery of new regenerative approaches for the treatment of heart failure? There is hope, but also challenges to overcome in this area of large unmet medical need and pioneering science.

The use of phenotypic screening of human epicardium-derived cells (EPDCs) seems to be one of the most promising approaches in the field of cardiac regeneration, addressing the growing epidemic of heart failure. Although phenotypic screening is a widely used approach in biological research, to our knowledge we are pioneering phenotypic screening of EPDCs with the aim of addressing heart failure through regenerative treatment. Our advances were presented and discussed during the International Society for Stem Cell Research (ISSCR) annual meeting in Stockholm June 24-27, 2015, where stem cell scientists from across the world met, and it was encouraging to discuss the science and get feedback and challenges from fellow researchers. Scientific exchange is crucial to achieving rigour, relevance and ultimately success in ground breaking areas such as regenerative medicine.

What’s unique with AstraZeneca’s approach is the use of human cardiac cells on this scale for pre-clinical testing. The cells are isolated from patients who underwent cardiac surgery, and we are able to expand the cells for use in primary and subsequent screens. To date, a 10,000-compound subset of the AstraZeneca compound collection has been screened. The selection was based on compounds known to interact with a broad range of biological targets and we have discovered a number of compounds and chemical clusters that have been effective in proliferating the epicardium-derived cells.

Access to human tissue from a number of patient donors is possible through our collaboration with Leiden University Medical Center in the Netherlands. Another collaboration relevant to this endeavour is with the Chemical Genomics Centre of the Max-Planck Society in Dortmund, Germany, which has helped to build our understanding and application of phenotypic screening.

In addition, by running screens on multiple relevant cardiac cell types and ensuring collaboration between scientists from different fields, we are gaining deep understanding of the biology underlying potential regenerative mechanisms in the heart, and our research is driving rapidly toward testing lead compounds in vivo to test these novel biological principles and drive forward the science in this area. This progress would not have been possible without the combined expertise and collaboration of bioscientists, chemists, DMPK and translational science experts on our team across both CVMD and Discovery Sciences.

As a scientist it’s easy to get caught in the cell or even molecular level of your work, but in the case of heart failure we are constantly encouraged by the enormous and growing unmet medical need. More than 23 million patients are diagnosed with heart failure worldwide – half are expected to die within five years, and 90 percent within 10 years. No treatment apart from symptom relief and transplantation is currently available. We believe that replacing the damaged heart muscle through activating endogenous cardiac cells could regenerate and restore the function of a damaged heart and have the potential to provide a transformational therapy for heart failure patients in the future.

We are eager to collaborate with leading academic researchers and industry partners in this field and, through collaboration, we are breaking new ground.