The study of Niels Grote Beverborg et al. published in Nature Communications, shows that inhibiting phospholamban, a cardiac contractility regulator, using antisense oligonucleotides can successfully treat heart failure in three different model of murine cardiomyopathy. Thereby, this study is the first proof of concept study using antisense oligonucleotides in heart disease. The study is the result of a collaboration between the department of Cardiology (Lead authors Peter van der Meer and Rudolf de Boer), the Karolinska Institute in Stockholm (Kenneth Chien), AstraZeneca and Ionis Pharmaceuticals.
The role of abnormal calcium regulation in heart failure
Heart failure and the role of abnormal calcium regulation
Heart failure is worldwide a major cause of morbidity and mortality. Patients diagnosed with heart failure have a 50 percent chance of passing away in the following 5 years. Despite recent treatment improvements there is still an urgent need for new treatment options. Current treatment options are mainly targeting 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 (SERCA2a) to the cells. Unfortunately, this was unsuccessful. Grote Beverborg has been researching ways to “take the brakes off the pumps”. This proverbial brake is phospholamban (PLN). Abnormal PLN function has an important role in different forms of cardiomyopathy, but is especially relevant for patients with a mutation in PLN: PLN R14del. This mutation likely originates from east Friesland around 800 years ago, explaining the large prevalence in the norther provinces. Around 1:1000 inhabitants of the city of Groningen carry this mutation. The subject can develop severe heart failure. As there are currently no proven therapies for this disease, patients frequently need a mechanical cardiac assist device or a heart transplant.
Conceptual figure of the mechanism of action of antisense oligonucleotides
Preclinical data shows efficacy of the antisense oligonucleotide targeting PLN
‘With Ionis Pharmaceuticals and 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 R14del cardiomyopathy. 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 calcium 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.’
Young Investigator Award and publication in Nature Communications
For his research Grote Beverborg has won the Young Investigator Award from the European Society of Cardiology in the category Basic Science.
Antisense oligonucleotides targeting PLN improve cardiac function and survival in murine PLN R14del cardiomyopathy