Researchers at AstraZeneca are taking a focused approach to the growing challenge of heart failure. There are currently very few options to address the severe and progressive nature of heart failure, where the heart’s capacity deteriorates over time. The aim of AstraZeneca’s research in the area is to help a damaged heart repair itself, which sounds like science fiction but may be closer to reality than previously thought. Recent advances have demonstrated the presence of progenitor cells in the heart, which may play a role in cardiac repair.
In addition, it has been proven that adult cardiomyocytes are capable of proliferating. The stage is set for a changing treatment paradigm, and AstraZeneca is building on the latest scientific breakthroughs and technology to help heart failure patients. With the single goal in mind to help heart failure patients, we apply an integrated approach where the internal team works side-by-side with other world-leading scientists to find the best way forward.
Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide1. It severely debilitates the patient and the mortality rates following a diagnosis are even more alarming – 50% will die within five years and, after 10 years, nine out of 10 patients are deceased.
Global causes of death:
Infectious and parasitic diseases
Data according to the World Health Organisation
“As a clinician, I met many patients with heart failure who suffered so much, and there was little we could do to change their fate,” says Qing-Dong Wang, Principal Scientist at AstraZeneca. Apart from the significant impact on quality of life, heart failure is among the leading causes of death due to cardiovascular disease and, as no treatment can reverse the damage to heart muscle, the prognosis is worse than many cancers2. The global prevalence of cardiovascular disease is predicted to increase every year due to the aging population expanding and other influences of modern life3. Thus, there is an urgent need for novel therapeutic approaches to reduce the burden of heart failure for patients and society as a whole. This growing global issue is one of the major motivators for the focus on cardiac regeneration (CR) at AstraZeneca, which is a part of the overall cardiovascular and metabolic diseases (CVMD) research strategy. Drawing on new findings and technologies, the strategy pursues the discovery and development of therapeutics that will provide a significant difference both in terms of quality of life and mortality rates.
The cardiac regeneration strategy is based on the ground-breaking academic research discovery that heart tissue can regenerate after injury4. When researchers at the Karolinska Institutet clearly established that cardiomyocytes (cardiac muscle cells) proliferate in adult human hearts, this provided a path to finding ways to restore the heart’s full function, thus potentially ‘curing’ and not just managing the disease symptomatically as currently done with, for example, ACE inhibitors and beta blockers, and the limitations of invasive cardiac surgery and transplantation.
Even though the human heart has the capacity to regenerate cardiomyocytes, this process is extremely slow. Hence, following a heart attack or other ischaemic cardiac event, damaged cardiac tissue usually turns into non-functional connective (or scar) tissue. Cardiologist Anders Berggren, Senior Physician in AstraZeneca’s Early Clinical Development team comments, “Evolution had no need to sustain the regenerative capacity for a human heart in order to spare the life of a middle age man. Now we are able to examine mechanisms to change this long-standing paradigm and improve the lives of patients and their families.”
The discovery that human cardiac cells are capable of repairing the heart opened up a new avenue of research for drug development based on promoting the native regenerative capacity of cardiac muscle. The question was – and still is – how? In 2010, AstraZeneca assembled a multidisciplinary team to answer that question. Every Monday, Dr Regina Fritsche-Danielson, Senior Vice President and Head of Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D (Gothenburg, Sweden), leads a meeting that brings together the cardiac regeneration team. The cross-functional team includes cell biology and drug-formulation scientists, chemists, specialist technicians, and clinicians. In the meeting, members can discuss novel science and new ideas that could contribute to identifying an effective therapy for heart failure.
“We just talk about the science. Even if we need to prioritise our work there is also room to focus on testing new ideas and to explore novel science. If you have a good scientific rationale, there is no limit to what we can do,” explains Dr Fritsche-Danielson. “This free-form exchange of ideas is undertaken routinely at AstraZeneca to keep on top of any science that could ultimately provide a clinical benefit to patients.”
If you have a good scientific rationale, there is no limit to what we can do.
Dr Fritsche-Danielson and her team foster and support only original approaches that have the potential to make a marked difference in the lives of patients. This means setting the bar high in search of therapeutic interventions to stop the progression of heart failure or reverse the damage to cardiac muscle. “The cardiac regeneration research programme addresses the underlying cause of the disease,” explains Dr Fritsche-Danielson. “Our focus is on identifying targets and pathways which are involved in repairing damaged cardiac muscle. One of the most advanced projects looks at vascular endothelial growth factor-A (VEGF-A) which is a known growth factor in cardiac regeneration. If successful this would lead to more blood vessels and improved blood supply to the cardiac muscle and restored cardiac function which would impact significantly on these patients' life and survival.”
To support research into new therapies for heart failure, the cardiac regeneration team is engaged well beyond the location of AstraZeneca’s research sites. One of the more significant collaborations is the groundbreaking partnership with US-based Biotech company Moderna Therapeutics as well as Professor Ken Chien and his research group at the Integrated Cardio-Metabolic Centre at Karolinska Institutet in Stockholm. Moderna Therapeutics is using modified RNA (mRNA) to stimulate the targeted production of various growth factors. Together with Professor Chien, Dr Fritsche-Danielson’s team is progressing a programme focused on VEGF-A. This is a protein produced by the body to promote the growth of new vessels which in turn would improve blood and oxygen supply to damaged cardiac tissue. VEGF-A has also been hypothesized to be an important factor involved in cardiac stem cell proliferation5.
mRNA being read by a ribosome – a potential technology for helping the heart self-repair
The partnership dates back to March 2013, when Moderna Therapeutics and AstraZeneca signed a five year exclusive option agreement to apply the company’s platform in the search for new ways to treat cardiovascular and other diseases. In preparation for the first in-human safety studies the two companies are now working towards taking a mRNA therapeutic candidate through toxicology studies while addressing further in vivo proof of concept and targeted delivery. “Ken and I speak several times a week to keep the programme moving and to discuss novel applications of this fascinating technology,” says Dr Fritsche-Danielson.
Other significant collaboration partners include the University of Singapore, Shanghai Institute of Biological Sciences and the University of Virginia that all contribute to advancing the programme. “The challenge is to keep connected, the field moves fast. It’s not just about finding new compounds, you need to think further ahead. At AstraZeneca, we have a good academic collaboration culture,” says Dr Gabriella Brolén, Senior Scientist in AstraZeneca’s Discovery Sciences department.
Helping the team shed light on the disease by linking patient phenotypes to the different types of heart failure is a collaboration with Singapore’s Agency for Science, Technology and Research (A*STAR), National University Heart Centre, and National University of Singapore. The collaboration will draw data from Singapore’s ethnically-diverse, patient population. The focus will be on heart failure patients with preserved ejection fraction (HFpEF), which comprises almost half the heart failure population.
In parallel with the modified RNA approaches, Dr Fritsche-Danielson’s team is working to identify novel targets for cardiac regeneration using phenotypic screens. With the common goal of stimulating the proliferation and differentiation of endogenous stem cells in the heart, other candidates for the drug development pipeline have been selected using various progenitor cell populations and cardiac cells as a discovery tool for screening. “We take advantage of phenotypic screening to identify promising candidates. We screened 10,000 compounds from the AstraZeneca library for a primary target to increase proliferation of [iPS derived] cardiac progenitor cells," explains Dr Wang. “It’s so exciting. Looking at the data, it was possible to identify a compound that shows activity on cell proliferation in vitro and in vivo without having an effect on cardiac fibroblasts. The cardiac regeneration team is also working characterising primary cardiac progenitor-like cells derived from patients to better understand the biology of relevant cells and to ensure that the compounds we identify from using iPS derived cells also work on primary cells derived from patients. In the end we need to translate our findings from in vitro cell systems to being active in the patient's heart to really improve cardiac function and make a difference for the patient.”
Another angle explored by the team under the leadership by Senior Physician Li-Ming Gan is genetic phenotypes linked to heart failure to understand potential disease pathways. However, it is critical to ensure that any target relates back to the pathophysiology of the general heart failure population, and this is something Dr Gan feels is a strength of the pharmaceutical industry. “If you are a fan of integrated physiology, pharma is the place. It’s good for me to work at AstraZeneca. I am dedicating my career to doing something I believe in.”
1. Braunwald E. Lancet (2015) 385 (9970): 812-824.
2. Stewart S, MacIntyre K,et al. Eur J Heart Fail.(2001) Jun; 3(3):315-22.
3. Roth G A. et al.. N Engl J Med (2015) 2 April; 372:1333-1341.
4. Bergmann O1, Bhardwaj RD et al. Science (2009) 324, 98.
5. Taimeh Z, Loughran J, et al. Nature Reviews Cardiology (2013) September:10, 519-530.