RNA Therapy Reverses Cellular Defects in Genetic Heart Disease

Using patient-derived cardiac tissue and stem cell-based models, the team of translational researchers demonstrated that targeting the genetic cause of disease improved cellular abnormalities and identified the biological pathways involved. The results of this study were published in Signal Transduction and Targeted Therapy, part of the Nature portfolio.

A common inherited cause of heart failure in the Netherlands

PLN R14del is a Dutch founder pathogenic variant that originated in the province of Friesland several centuries ago and is therefore particularly common in the north of the Netherlands. Although rare in the general population, it is one of the most common genetic causes of inherited cardiomyopathy in the Netherlands and accounts for approximately 10-15% of Dutch patients with dilated or arrhythmogenic cardiomyopathy. Due to this founder effect, many Dutch families carry the same genetic defect. As a result, the Netherlands has one of the largest known populations of PLN R14del carriers worldwide.

Treating the cause rather than the symptoms

Current treatments for PLN cardiomyopathy mainly focus on managing symptoms of heart failure and preventing complications. However, they do not address the underlying genetic cause of disease. As part of his PhD research at UMCG, Dr. Frits Deiman investigated whether RNA therapy could provide a more targeted approach. RNA therapies can selectively reduce the production of disease-causing proteins. In PLN cardiomyopathy, the mutant PLN protein is known to form aggregates inside heart muscle cells, which are believed to contribute to disease development. Reducing PLN levels could therefore help target the disease process at its source.

To investigate whether this approach could work, induced pluripotent stem cell-derived heart cells carrying the pathogenic PLN variant were used. Following RNA treatment, PLN protein aggregation was reduced and several disease-associated abnormalities improved, suggesting that targeting the underlying molecular defect may help restore heart cell function.

Understanding why the therapy works

The researchers also wanted to understand how the treatment exerts its effects. To do this, they used phosphoproteomics, a technique that measures changes in protein phosphorylation, the molecular switches that regulate cellular signaling. Their analyses revealed disease-specific alterations in pathways involved in calcium regulation and heart cell function. Remarkably, several of these abnormalities were reversed following RNA therapy. Together, these findings suggest that RNA therapy reduces PLN protein aggregation and may help restore key cellular processes disrupted in PLN cardiomyopathy.

Towards precision medicine for genetic heart disease

Importantly, PLN-targeted RNA therapy has recently progressed towards early clinical testing in patients with PLN cardiomyopathy. This represents one of the first clinical trials using RNA therapy to directly target the underlying cause of an inherited cardiomyopathy and highlights the leading role of Dutch cardiovascular research in advancing precision medicine for genetic heart disease. By revealing how RNA therapy affects disease processes inside heart muscle cells, these findings provide important insight into the biological mechanisms underlying treatment response. As genetic therapies move into human studies, understanding their biological effects may help accelerate the development of personalized treatments for genetic heart disease.

International recognition

This work received international recognition at the annual Heart Failure 2026 congress of the Heart Failure Association of the European Society of Cardiology, where first author Frits Deiman was awarded the Young Investigator Award for presenting these findings.