Gramlich, Michael and Pane, Luna Simona and Zhou, Qifeng and Chen, Zhifen and Murgia, Marta and Schötterl, Sonja and Goedel, Alexander and Metzger, Katja and Brade, Thomas and Parrotta, Elvira and Schaller, Martin and Gerull, Brenda and Thierfelder, Ludwig and Aartsma-Rus, Annemieke and Labeit, Siegfried and Atherton, John J and McGaughran, Julie and Harvey, Richard P and Sinnecker, Daniel and Mann, Matthias and Laugwitz, Karl-Ludwig and Gawaz, Meinrad Paul and Moretti, Alessandra (2015) Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy. EMBO Molecular Medicine, 7 (5). pp.562-76. ISSN 1757-4684 (OA)
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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.
(NHMRC grants 573703, 573705).
| Item Type: | Article |
|---|---|
| Additional Information: | This is an open access article under the Creative Commons CC BY 4.0 license (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Jan 2016 22:47 |
| Last Modified: | 28 Apr 2016 02:26 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/213 |
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