Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy

Gramlich, Michael, Pane, Luna Simona, Zhou, Qifeng, Chen, Zhifen, Murgia, Marta, Schötterl, Sonja, Goedel, Alexander, Metzger, Katja, Brade, Thomas, Parrotta, Elvira, Schaller, Martin, Gerull, Brenda, Thierfelder, Ludwig, Aartsma-Rus, Annemieke, Labeit, Siegfried, Atherton, John J., Mcgaughran, Julie, Harvey, Richard P., Sinnecker, Daniel, Mann, Matthias, Laugwitz, Karl‐Ludwig, Gawaz, Meinrad Paul and Moretti, Alessandra (2015) Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Molecular Medicine, 7 5: 562-576. doi:10.15252/emmm.201505047

Author Gramlich, Michael
Pane, Luna Simona
Zhou, Qifeng
Chen, Zhifen
Murgia, Marta
Schötterl, Sonja
Goedel, Alexander
Metzger, Katja
Brade, Thomas
Parrotta, Elvira
Schaller, Martin
Gerull, Brenda
Thierfelder, Ludwig
Aartsma-Rus, Annemieke
Labeit, Siegfried
Atherton, John J.
Mcgaughran, Julie
Harvey, Richard P.
Sinnecker, Daniel
Mann, Matthias
Laugwitz, Karl‐Ludwig
Gawaz, Meinrad Paul
Moretti, Alessandra
Title Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy
Journal name EMBO Molecular Medicine   Check publisher's open access policy
ISSN 1757-4684
Publication date 2015-05-01
Year available 2015
Sub-type Article (original research)
DOI 10.15252/emmm.201505047
Open Access Status DOI
Volume 7
Issue 5
Start page 562
End page 576
Total pages 15
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Collection year 2016
Language eng
Formatted abstract
Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA-based strategies as a potential treatment option for DCM.
Keyword Dilated cardiomyopathy
Exon skipping
Induced pluripotent stem cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
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