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February 22, 2022International Journal of Molecular SciencesOpen Access

Antisense Therapy Attenuates Phospholamban p.(Arg14del) Cardiomyopathy in Mice and Reverses Protein Aggregation

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Why the study?

It was unknown whether administering a Pln-targeting antisense oligonucleotide could halt or reverse disease progression in advanced PLN-R14del cardiomyopathy.

Does Pln-targeting antisense oligonucleotide (ASO) improve disease progression and survival in homozygous PLN-R14del mice with advanced cardiomyopathy?

Population

Homozygous PLN-R14del (PLN-R14 Δ/Δ) mice with moderate or severe HF

Comparison

PLN-ASO injections starting at 5 or 6 weeks vs vehicle

Design

Preclinical animal study

Follow-up

4 months

Key result

PLN-ASO administration in mice with advanced PLN-R14del cardiomyopathy halted cardiac remodeling and extended life span to at least 22 weeks, compared to 8.1 weeks in vehicle-treated mice.

Authors

TETim R. EijgenraamNSNienke M. StegeVTVivian Oliveira Nunes Teixeira

Discussion

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Overview

Should not yet alter clinical management of PLN-R14del cardiomyopathy; hypothesis-generating for PLN-ASO translation in humans.

Structured PICO

Does Pln-targeting antisense oligonucleotide (ASO) improve disease progression and survival in homozygous PLN-R14del mice with advanced cardiomyopathy?

P
Population
Homozygous PLN-R14del mice with moderate or severe heart failure, treated starting at 5 or 6 weeks of age and monitored for 4 months.
I
Intervention
Pln-targeting antisense oligonucleotide (ASO) injections starting at 5 or 6 weeks of age
C
Comparator
Vehicle-treated PLN-R14 Δ/Δ mice
O
Outcome
Disease progression including cardiac remodeling, dysfunction, life span extension, and PLN aggregates over 4 monthssurrogate

In a mouse model of PLN-R14del cardiomyopathy, PLN-ASO therapy halted disease progression, extended lifespan, and resolved protein aggregates when administered after disease onset.

Limitations

  • Existing tissue damage was not reversed

Cite This Study

Eijgenraam et al. (2022) studied PLN-R14del cardiomyopathy. Pln-targeting antisense oligonucleotide (ASO) vs. vehicle was evaluated on Life span and cardiac remodeling. PLN-ASO administration in mice with advanced PLN-R14del cardiomyopathy halted cardiac remodeling and extended life span to at least 22 weeks, compared to 8.1 weeks in vehicle-treated mice.

synapsesocial.com/papers/6a24b5d48c55644ebb279b52https://doi.org/10.3390/ijms23052427
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy2021 · 97 citations
  2. 2In PLN-R14del mice, SR structure restoration, rather than calcium cycling, is the dominant effector of PLN-ASO treatment2025
  3. 3Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)–Related Cardiomyopathy: Development of PLN-R14del–Related Cardiomyopathy2021 · 41 citations
  4. 4The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy2020 · 66 citations
  5. 5Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy2026