Current treatment options are mainly directed to the neuro hormonal system. The biggest disruption of the heart muscle cell is a deviating calcium metabolism. In the last years several attempts have been made to add more calcium pumps in the cells. Unfortunately, this was unsuccessful. Grote Beverborg and van der Meer have been researching ways to ‘take the brakes off the pumps’. This proverbial brake is phospholamban (PLN).
‘With Ionis Pharmaceuticals en AstraZeneca we developed a new modality; antisense oligonucleotides (ASOs). In this project we investigated the effectiveness of antisense-oligonucleotides targeting PLN.’ With promising results. Grote Beverborg tested the effects first in cell models. ‘We discovered that PLN decreases and the calcium metabolism improves. The next step was to investigate the effects of ASO’s in mouse models of heart failure.’
In the first model we looked at PLN cardiomyopathy, a common form of heart failure occurring in people in the north of the Netherlands. In this genetic model the ASO’s prevented heart failure completely and the mice lived up to 28 weeks instead of a maximum of nine weeks.
Thereafter we looked at two models of heart failure where the effects of deviating calciums and PLN are less influential. In these cases the ASO’s improved the pumping function of the heart.
This data shows that treatment with antisense oligonucleotides is an effective strategy in treating heart failure in rodents. ‘Our next step is clinical research with patient material. We are currently investigating the impact of ASO’s in the lab with heart muscle tissues from human cells.’
For his research Grote Beverborg has won the Young Investigator Award from the European Society of Cardiology in the category Basic Science. Also the manuscript from his research is published today in Nature Communications
