Using patient-derived heart tissue and stem cell-based models, a team of translational researchers demonstrated that targeting the genetic causes of the disease ameliorated 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.
Common genetic causes of heart failure in the Netherlands
PLN R14del is a pathogenic variant that originated in the Netherlands centuries ago in Friesland and is particularly common in the northern Netherlands. Although rare in the general population, it is one of the most common genetic causes of inherited cardiomyopathy in the Netherlands, accounting for approximately 10–15% of patients with dilated or arrhythmogenic cardiomyopathy in the Netherlands. Due to this founder effect, many Dutch families carry the same genetic defect. As a result, the Netherlands has one of the highest numbers of PLN R14del carriers in the world.
Treat the cause, not the symptoms
Current treatments for PLN cardiomyopathy primarily focus on managing heart failure symptoms and preventing complications. However, they do not address the underlying genetic causes of the disease. As part of his doctoral research at UMCG, Dr. Fritz Deimann investigated whether RNA therapy could offer a more targeted approach. RNA therapy can selectively reduce the production of disease-causing proteins. In PLN cardiomyopathy, mutant PLN protein is known to form aggregates within cardiomyocytes, which is thought to contribute to the development of the disease. Therefore, reducing PLN levels may help target the disease process from its source.
To test whether this approach works, induced pluripotent stem cell-derived cardiac cells harboring pathogenic PLN variants were used. After RNA treatment, PLN protein aggregation was reduced and several disease-associated abnormalities were ameliorated, suggesting that targeting the underlying molecular defects may help restore cardiac cell function.
Understand why treatments work
The researchers also wanted to understand how the treatment worked. To do this, they used phosphoproteomics, a technique that measures changes in the phosphorylation of proteins, which are molecular switches that regulate cell signaling. Their analysis revealed disease-specific changes in pathways involved in calcium regulation and cardiac cell function. Remarkably, some of these abnormalities were restored after RNA therapy. Taken together, these findings suggest that RNA therapy may reduce PLN protein aggregation and help restore important cellular processes disrupted in PLN cardiomyopathy.
Aiming for precision medicine for genetic heart diseases
Importantly, PLN-targeted RNA therapies have recently advanced toward early clinical trials in patients with PLN cardiomyopathy. This is one of the first clinical trials using RNA therapy to directly target the underlying cause of inherited cardiomyopathy, highlighting the leading role of Dutch cardiovascular research in advancing precision medicine for inherited heart diseases. By revealing how RNA therapy affects disease processes within cardiomyocytes, these findings provide important insight into the biological mechanisms underlying treatment response. As gene therapy moves into human studies, understanding its biological effects could help accelerate the development of personalized treatments for inherited heart diseases.
international recognition
This research was internationally recognized at the 2026 Annual Heart Failure Congress of the European Society of Cardiology’s Heart Failure Society, where first author Fritz Deimann received the Young Investigator Award for presenting these findings.
sauce:
Groningen University Medical Center
Reference magazines:
Dayman, F.E.; Others. (2026). Phosphoproteomics distinguishes disease-specific mechanisms of human phospholamban cardiomyopathy that are reversible by RNA therapy. Signal transduction and targeted therapy. DOI: 10.1038/s41392-026-02791-5. https://www.nature.com/articles/s41392-026-02791-5
