RNA Therapy Shows Promise for Rare Cause of Sudden Cardiac Death
In a new study, RNA therapy normalized disease pathways in PLN cardiomyopathy models.
Sudden cardiac death is a devastating event; loss of heart function, either due to circulatory or electrical issues, quickly leads to fatality.
Phospholamban (PLN) cardiomyopathy sits among the many causes of sudden cardiac death. The PLN protein is predominantly expressed in the heart, where it modulates calcium homeostasis, a process critical to cardiac contraction and function.
Mutations in the PLN gene can lead to dysfunction. For example, the most prevalent variant, R14del, can result in disrupted calcium homeostasis, abnormal heart rhythms (arrhythmias), and, over time, structural abnormalities.
If left untreated, PLN cardiomyopathy carries a high lifetime risk of heart failure and sudden cardiac death. Treatment is largely management-based, including heart failure medications and implantable defibrillators. In severe cases, patients may require a heart transplant.
Dr. Frederik Deiman, a cardiovascular researcher at the University Medical Center Groningen, is focused on finding an alternative. In an interview with Technology Networks, Deiman reflected on his latest research. In this work, Deiman and his team not only elucidated disease-specific mechanisms in PLN cardiomyopathy but also investigated—and found potential in—a novel therapeutic approach.
What led you to focus your research on PLN cardiomyopathy?
Frederik Deiman, PhD (FD):
PLN cardiomyopathy has a large impact in the Netherlands because the PLN R14del variant is relatively common due to a founder effect.
Founder effect
The founder effect refers to the loss of genetic diversity when a small number of individuals start a new population from a larger parent population. In the Netherlands, multiple founder mutations—specific genetic changes traceable to one of the founding individuals of the smaller population—have been identified.
At our center, ~15% of patients diagnosed with arrhythmogenic or dilated cardiomyopathy carry this pathogenic variant. These patients are at high risk of heart failure and arrhythmias. What drew me to PLN cardiomyopathy was seeing the impact of the disease on patients and families.
“Despite advances in heart failure treatment, many patients continue to develop progressive disease, experience life-threatening arrhythmias, or ultimately require heart transplantation. Current therapies can alleviate symptoms but do not address the underlying genetic cause.” — Dr. Frederik Deiman.
From a scientific perspective, PLN is also an attractive therapeutic target because its function is largely restricted to the heart. Although it is expressed in skeletal muscle, its role there is much less important. This creates a unique opportunity for precision medicine, where therapies can target a disease-causing protein with limited effects on other organs.
IH:
FD:
A central finding of our study was that phosphoproteomics revealed disease-specific alterations in signaling pathways involved in calcium handling, cytoskeletal organization, and contractile function. Importantly, many of these changes were not detectable using conventional proteomics alone, highlighting the additional biological insight provided by studying protein phosphorylation.
RNA therapy for PLN cardiomyopathy: Study overview
Proteomic and phosphoproteomic profiling were performed on cardiac tissue from six patients with the R14del variant and compared to other causes of cardiomyopathy to elucidate disease mechanisms. Findings were validated using PLN R14del variant stem cell models. Researchers assessed reversibility of disease mechanisms, including protein aggregation and cytoskeleton remodeling, using RNA therapy.
“These findings were accompanied by a reduction in pathogenic PLN protein aggregation following RNA therapy, which we believe is an important hallmark of PLN cardiomyopathy.” — Dr. Frederik Deiman.
The combination of studying patient-derived cardiac tissue and CRISPR-engineered induced pluripotent stem cell-derived cardiomyocytes was critical to these discoveries. Human cardiac tissue allowed us to investigate disease mechanisms directly in affected hearts, while stem cell-derived cardiomyocytes enabled controlled mechanistic studies and therapeutic testing.
Observing similar molecular signatures across both systems strengthened our confidence that the identified pathways were related to disease biology rather than model-specific artifacts.
IH:
FD:
The PLN R14del variant causes disease by producing a pathogenic protein that disrupts normal cardiomyocyte function and forms intracellular protein aggregates. RNA therapeutics allow us to reduce PLN expression and thereby modify the molecular processes associated with disease.
In our study, we investigated antisense oligonucleotides (ASOs). This approach was particularly attractive because it directly targets PLN mRNA and can be precisely controlled. Unlike permanent gene-editing strategies, ASOs have a transient effect, allowing treatment to be adjusted or discontinued if needed. This is especially important when targeting a protein that plays an important physiological role in the heart.
Mechanistically, reducing PLN expression in PLN R14del cardiomyocytes was associated with reduced protein aggregation and partial normalization of disease-associated signaling pathways. Together, these findings suggest that lowering PLN levels may help alleviate key molecular processes underlying the associated cardiomyopathy.
IH:
FD:
Demonstrating efficacy in human disease models is an important first step, but ultimately, clinical studies are needed to determine whether these molecular and cellular improvements translate into meaningful benefits for patients. A clinical trial represents an important step in this process.
In addition to evaluating safety and tolerability, the trial will investigate whether RNA therapy reduces PLN mRNA levels in cardiac tissue, providing evidence of whether the treatment has engaged the target in patients.
Long term, we will need to determine whether these molecular changes are associated with improvements in clinically relevant outcomes. This includes slowing disease progression, reducing arrhythmias, preserving cardiac function, and improving quality of life. Biomarkers, cardiac imaging, electrocardiographic monitoring, and long-term clinical follow-up will all be important in establishing whether the molecular and cellular changes we observed translate into meaningful patient outcomes.
IH:
What is the long-term hope for PLN cardiomyopathy treatment?
FD:
The long-term goal is to move beyond symptom management and develop therapies that directly target the underlying cause of inherited cardiomyopathies. For patients with PLN cardiomyopathy, we hope to combine improved risk stratification with precision medicine approaches. Not all PLN R14del carriers develop severe disease at the same rate, and one of our goals is to better understand which individuals are at greatest risk of disease progression.
“Ultimately, we hope to identify these high-risk individuals before irreversible cardiac damage occurs and intervene with targeted therapies that can slow or prevent disease progression.” — Dr. Frederik Deiman.
RNA therapeutics represent a promising approach, but their greatest impact may come when they can be offered to the right patients at the right stage of disease.
More broadly, we hope this work provides a framework for precision medicine in cardiovascular disease, where therapies are tailored to the specific genetic and molecular mechanisms driving disease in individual patients.
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