Key result
PLN-targeted RNA therapy reduced PLN expression by up to 9.6-fold, partially normalized disease-specific cytoskeletal phosphorylation alterations, and enhanced calcium handling in human R14del iPSC-CMs.
Why the study?
The molecular disease mechanisms and potential therapeutic effects of RNA therapy in human phospholamban R14Δ/+ cardiomyopathy remain poorly defined.
Does PLN-targeted RNA therapy improve phosphoproteomic and functional abnormalities in human phospholamban cardiomyopathy models?
Does PLN-targeted RNA therapy improve phosphoproteomic and functional abnormalities in human phospholamban cardiomyopathy models?
PLN-targeted RNA therapy partially normalizes the distinct phosphoproteomic signature and improves functional abnormalities in human models of PLN R14Δ/+ cardiomyopathy, supporting its potential as a therapeutic strategy.
Answers are grounded in this paper and cite their sources.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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 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.”
“We became interested in phosphoproteomics because many kinases and phosphatases are highly sensitive to intracellular calcium signaling. Since PLN itself is a key regulator of calcium handling in cardiomyocytes, we wanted to understand how a pathogenic variant in a calcium-handling protein could reshape the cardiac phosphoproteome and downstream signaling pathways. While the novelty of phosphoproteomics created exciting opportunities, it also came with uncertainty.”
Hypothesis-generating in human iPSC-CM models; prospective trials needed before clinical adoption in PLN cardiomyopathy.
Phospholamban (PLN) p.Arg14del (R14Δ/+, also known as R14del) is a pathogenic variant that causes inherited cardiomyopathy. RNA therapy improves cardiac function and survival in murine PLN R14Δ/+. However, the molecular disease mechanisms and potential therapeutic effects of RNA therapy in the human setting remain poorly defined. Proteomic and phosphoproteomic profiling was performed on cardiac tissue from R14Δ/+ patients (N = 6) and compared to other causes of dilated cardiomyopathy (DCM; N = 10). Findings were validated in CRISPR-Cas9-engineered R14Δ/+ induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and isogenic controls. To assess reversibility, PLN-targeted RNA therapy using antisense oligonucleotides was applied to iPSC-CMs. Proteomics revealed enrichment of fibrotic pathways, while phosphoproteomics highlighted altered actomyosin structural organization uniquely distinguishing R14Δ/+ from other DCM. This phosphoproteomic profile was recapitulated in R14Δ/+ iPSC-CMs. RNA therapy concentration-dependently reduced PLN expression and modified the disease-specific phosphorylation profile. Twenty-eight phosphorylation sites were consistently altered across patient tissue and iPSC-CMs; twenty-two were reversed by RNA therapy and were enriched for cadherin- and actin-binding functions, implicating cytoskeletal remodeling. PLN/LC3 protein aggregates, a hallmark of PLN cardiomyopathy, were reduced after RNA therapy. Functionally, R14Δ/+ cardiomyocytes exhibited accelerated calcium handling and contractile kinetics, which increased further upon RNA therapy. Human PLN R14Δ/+ cardiomyopathy is characterized by a distinct phosphoproteomic signature involving cytoskeletal and contractile machinery. PLN-targeted RNA therapy reduced PLN expression, partially normalized these alterations, diminished protein aggregation, and enhanced calcium handling and contractile performance. These findings clarify the molecular mechanisms underlying R14Δ/+ pathogenesis and support RNA therapy as a promising therapeutic strategy for PLN cardiomyopathy.
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Deiman et al. (2026) studied Phospholamban (PLN) p.Arg14del cardiomyopathy (n=16). PLN-targeted RNA therapy (antisense oligonucleotides) vs. Vehicle or scrambled ASO was evaluated on PLN protein expression reduction (9.6-fold reduction). PLN-targeted RNA therapy reduced PLN expression by up to 9.6-fold, partially normalized disease-specific cytoskeletal phosphorylation alterations, and enhanced calcium handling in human R14del iPSC-CMs.
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