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Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy
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 b...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492817/ https://www.ncbi.nlm.nih.gov/pubmed/25759365 http://dx.doi.org/10.15252/emmm.201505047 |
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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 |
author_facet | 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 |
author_sort | Gramlich, Michael |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4492817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-44928172015-07-13 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 Moretti, Alessandra EMBO Mol Med Research Articles 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. BlackWell Publishing Ltd 2015-05 2015-03-10 /pmc/articles/PMC4492817/ /pubmed/25759365 http://dx.doi.org/10.15252/emmm.201505047 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles 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 Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title | Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title_full | Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title_fullStr | Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title_full_unstemmed | Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title_short | Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
title_sort | antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492817/ https://www.ncbi.nlm.nih.gov/pubmed/25759365 http://dx.doi.org/10.15252/emmm.201505047 |
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