Regina Fritsche-Danielson Senior Vice President & Head of Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D
Johan Hyllner Head of Regenerative Medicine, Research and Early Development, CVRM, BioPharmaceuticals R&D
Across our Cardiovascular, Renal and Metabolism (CVRM) research programmes, a new Regeneration Team is integrating cell and gene therapy expertise to accelerate our leading heart regeneration research from laboratory to clinic, and build regeneration capabilities in diabetes, kidney disease and liver disease.
As our projects advance, we are accessing a rich array of skills and technologies available in-house and through academic and industry collaborations to ensure progress in our aim of delivering much needed regenerative therapies to patients.
Multiple approaches to cardiac regeneration
The human heart is the focus of our most advanced regeneration research and we are actively investigating potential gene, cell and drug therapies to restore damaged cardiac muscle and blood vessels. An estimated 1 billion heart muscle cells (cardiomyocytes) are lost during a heart attack,1 which is why we are pursuing multiple approaches to assess how we could repair the damage that typically leads to heart failure and its debilitating effects.
In the short-term, we want to learn more about the mechanisms and pathways driving regeneration of cardiomyocytes and cardiac blood vessels, and we are excited about our first venture into stem cell therapy for cardiac regeneration.
Through our ambitious collaboration with Procella Therapeutics and the Karolinska Institute in Sweden, we are developing robust protocols for producing highly purified ventricular progenitor cells from human embryonic stem cell lines. Ventricular progenitor cells differentiate into the ventricular cardiomyocytes essential for the pumping action of the heart. We have already watched progenitor cells differentiate into beating ventricular cardiomyocytes in our laboratory dishes. The next step is to get them to repopulate and proliferate in pre-clinical in vivo models to create new heart tissue. Our ambition is also to use CRISPR gene editing technologies to change the DNA of these new cells to reduce the risk of rejection after implantation, and to insert a ‘kill switch’ to prevent unwanted cell proliferation.
Alongside cardiac cell therapy, we have initiated clinical trials to investigate the potential for gene therapy. In a Phase IIa clinical trial, mRNA is being injected into the heart during coronary artery bypass surgery with the aim of boosting production of vascular endothelial growth factor A (VEGF-A). This has the potential to stimulate growth of blood vessels around damaged heart muscle to improve blood flow and oxygen supply.
We are also seeking small molecule treatments with potential for use alone or in combination with cell and gene therapies. We are screening thousands of our small molecules against human cardiomyocytes to test their ability to trigger cell division and proliferation of new cells. In a recent publication, we described the validation of a novel 3D bioengineered cardiac organoid for screening small molecules and identifying potential targets for induction of cardiomyocyte proliferation.2 As our understanding of regenerative pathways increases, we expect to explore the effects of our antisense oligonucleotides, micro-RNAs and other novel modalities on cardiomyocyte activity.
Beyond cardiac regeneration
From cardiac regeneration, we are developing strategies for tissue regeneration in chronic kidney disease, type 1 diabetes and liver disease.
Central to all our plans for regenerative medicine are the 5R criteria which guide the way we discover and develop new medicines (right target, right patient, right tissue, right safety, right commercial potential). In cardiac regeneration, this scientific rigour was key to our important contribution in identifying embryonic stem cells as essential precursors of cardiomyocyte progenitor cells, rather than the bone marrow or adult cardiac progenitor cells previously thought important.3
As a result, we are shaping science-driven strategies with the aim of bringing effective regenerative therapies to patients with heart failure, diabetes, liver and other metabolic diseases.
1. Sahara M, Santoro F, Chien KR. Programming and reprogramming a human heart cell. The EMBO Journal 2015; 34: 710-738
2. Mills RJ, Parker BL, Quaife-Ryan GA et al. Drug screening in human PSC-cardiac organoids identifies pro-proliferative compounds acting via the mevalonate pathway. Cell Stem Cell, published 28 March 2019. https://doi.org/10.1016/j.stem.2019.03.009
3. Chien KR, Frisén J, Fritsche-Danielson R et al. Regenerating the field of cardiovascular cell therapy. Nature Biotechnology 2019; 37: 232-237