Cardiomyopathy, or heart muscle disease, impairs the blood pumping function of the heart. These illnesses are often caused by genetic defects. A deleterious mutation of the arginine 14 codon in the phospholamban gene (PLN-R14del) causes 10% of the dilated cardiomyopathy and 15% of the arrhythmogenic cardiomyopathy patients in the Netherlands. Renée Maas used stem cell derived cardiomyocytes to study the disease with the aim of developing new treatments, resulting in the defence of her PhD thesis on March 13 2024.
PLN-R14del patients have dilated heart muscle, gradual replacement of the heart muscle by fat and connective tissue, or even cardiac arrest. The variable PLN manifestations complicate identification of people with the condition. This results in an underestimation of the number of people affected, Renée explains: ‘In the Netherlands, around 1700 people are known to have PLN-R14del, but from Sanquin blood tests we know many more people are carriers of the pathogenic mutation. Ultimately, everyone with this defective gene will develop heart failure, with variation in timing. One person can experience severe heart failure at the age of 20, while another can gradually develop something at 50 years of age.’
Renée has been working on the topic of heart disease since before her PhD. At her first internship 9 years ago, she was part of the UMC Utrecht cardiology team that developed the first beating human heart cells in a lab. ‘Adult stem cells do not typically regenerate,’ Renée explains. ‘But we used induced pluripotent stem cells to create human cardiomyocytes in vitro’. These cells were developed from stem cells of Pieter Glijnis, who was diagnosed with PLN-R14del himself and established the Dutch PLN foundation, Renée recalls: ‘He came to look at his own beating heart cells under a microscope in the lab, which was a very memorable moment.’
During her Master’s internship at Stanford University, she focused on disease modelling of PLN-R14del. She continued this research during her PhD, making rapid progress on the understanding of the causes and potential cures of PLN-R14del: ‘We now know of several mechanisms that are failing in diseased cells, as well as some potential therapies. This includes AAV gene therapy, through which we want to increase the expression of the healthy PLN protein or a protein that regulates PLN called I-1c. The I-1c therapy is already tested in an American trial for heart failure patients, and we are now investigating whether this can also be applied to people with PLN-R14del.’
“Heart tissue is very complex to cultivate in the lab, so most researchers are still studying 2D models. I am currently developing a model based on cardiac spheroids. With these more complex 3D models, we can study the heart in more detail.”
In order to efficiently screen new treatments, Renée is working on improved disease models: ‘Heart tissue is very complex to cultivate in the lab, so most researchers are still studying 2D models. I am currently developing a model based on cardiac spheroids. With these more complex 3D models, we can study the heart in more detail. Testing various therapeutic strategies in cardiac spheroids will allow us to choose the best potential cures for the PLN-R14del cardiomyopathy.’ Better cardiac in vitro models speed up the process of treatment development, Renée explains: ‘In vitro models such as cardiac spheroids help us test new medications on human cells sooner in the process, which shortens the route to the clinical trials’.
Renée looks back fondly on her time at the RMCU: ‘I remember being one of the first people to walk into the building when it just opened. I know almost everyone at the centre, and appreciate the sense of community and the level of expertise across the research groups.’
Having been awarded the prestigious NWO Rubicon fellowship grant, Renée will work at the Biodiscovery Institute in Nottingham for the next two years: ‘First, I want to finalize my work on the new PLN treatment. After that, I hope to apply the knowledge and skills I have gained throughout this experience to other genetic cardiomyopathies.’
